Hamid R. Tavakoli, MD

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

The gut-brain axis (GBA) refers to the link between the human brain with its various cognitive and affective functions and the gastrointestinal (GI) system, which includes the enteric nervous system and the diverse microbiome inhabiting the gut lumen. The neurochemical aspects of the GBA have been studied in germ-free mice; these studies demonstrate how absence or derangement of this microbiome can cause significant alterations in levels of serotonin, brain-derived neurotrophic factor, tryptophan, and other neurocompounds.^1,2 These neurotransmitter alterations have demonstrable effects on anxiety, cognition, socialization, and neuronal development in mice.^1,2

Current evidence suggests that the GBA works through a combination of both fast-acting neural and delayed immune-mediated mechanisms in a bidirectional manner with feedback on and from both systems.³ In addition to their direct effects on neural pathways and immune modulation, intestinal microbiota are essential in the production of a vast array of vitamins, cofactors, and nutrients required for optimal health and metabolism.⁴ Existing research on the GBA demonstrates the direct functional impact of the intestinal microbiome on neurologic and psychiatric health.

We will review current knowledge regarding this intriguing relationship. In doing so, we take a closer look at several specific genera and families of intestinal microbiota, review the microbiome’s effects on immune function, and examine the relationship between this microbiome and mental disease, using specific examples such as generalized anxiety disorder (GAD) and major depressive disorder (MDD). We seek to consolidate existing knowledge on the intricacies of the GBA in the hope that it may promote individual health and become a standard component in the treatment of mental illness.

Direct Activation of Neuronal Pathways

Vagal and spinal afferent nerve pathways convey information regarding hormonal, chemical, and mechanical stimuli from the intestines to the brain.³ These afferent neurons have been shown to be responsive to microbial signals and cytokines as well as to gut hormones. This provides the basis for research that presumes that neurobehavioral change may ensue from manipulating the gut microbes emitting these chemical signals to which these afferent neurons respond.³ Using these same pathways, efferent neurons of the parasympathetic and sympathetic nervous systems can modulate the intestinal environment by altering acid and bile secretion, mucous production, and motility. This modulation can directly impact the relative diversity of intestinal flora, and in more extreme states, may result in bacterial overgrowth.⁵ Of particular relevance to mental health (MH) is that the frequency of migrating motor complexes that promote peristalsis can be directly influenced by readily modifiable behaviors such as sleep and food intake, which can cause one bacterial species to dominate in a higher percentage.⁵ This imbalance of gut microbes has been implicated in contributing to somatic conditions, such as irritable bowel syndrome (IBS), which the literature has shown is related to psychiatric conditions such as anxiety. ⁵

The Microbiome and Host Immunity

The GI tract is colonized with commensal microorganisms from dozens of bacterial, archaeal, fungal, and protozoal groups.⁶ This relationship has its most classical immunologic interaction in the toll-like receptors. These receptors are on the lymphoid Peyer patches of the GI tract, which sample microorganisms and develop immunoglobulin (IgA) antibodies to them. Evidence exists that commensal microflora play a critical role in the regulation of host inflammatory response.⁷

The relationship between the microbiome and the immune system remains poorly understood, yet evidence has shown that the use of probiotics may reduce inflammation and its sequelae. Probiotics have been shown to have a beneficial effect on autoimmune diseases, such as Crohn disease and ulcerative colitis, specifically with certain strains of Escherichia coli (E coli) and a proprietary probiotic from VSL pharmaceuticals.^8,9 However, these interventions are not without risk. Fecal microbiota transplants have a risk of transferring unwanted organisms, potentially including COVID-19.¹⁰ Additionally, the use of probiotics is generally discouraged in immunocompromised, chronically ill, and/or hospitalized patients, as these patients may be at greater risk of developing probiotic bacteremia and sepsis.¹¹

Studies have also demonstrated that ingesting probiotics may decrease the expression of pro-inflammatory cytokines.¹¹ In a study comparing patients with ulcerative colitis who were prescribed both sulfasalazine and probiotic supplements vs sulfasalazine alone, patients who took the probiotic supplements were shown to have less colonic inflammation and decreased expression of cytokines such as IL-6, tumor necrosis factor-α (TNF-α), and nuclear factor-κβ.¹²

Gut-Specific Bacterial Phyla

Over the past decade, much attention has been paid toward 2 bacterial phyla that compromise a large proportion of the human gut microbiome: Firmicutes and Bacteroidetes. Intestinal Firmicutes species are predominantly Gram positive and are found as both cocci and bacilli. Well-known classes within the phylum Firmicutes include Bacilli (orders Bacillales and Lactobacillales) and Clostridia. The phylum Bacteroidetes is composed of Gram-negative rods and includes the genus Bacteroides—a substantial component of mammalian gut biomes. The ratio of Firmicutes to Bacteroidetes, also known as the F/B ratio, have shown fascinating patterns in certain psychiatric conditions. This knowledge may be applied to better identify, treat, and manage such patients.

Regarding bacterial phyla and their relationship to mood disorders, interesting patterns have been observed. In one population of patients with anorexia nervosa (AN) lower diversity within classes of Firmicutes bacteria was observed compared with age- and sex-matched controls without AN.¹³ As patients were re-fed and treated in this study, there was a significant corresponding increase in microbiome diversity; however, the level of bacterial diversity in re-fed patients with AN was still far less than that of patients in the control group. In patients with AN with comorbid depression, diversity was noted to be exceptionally reduced. Similarly, patients with AN with a more severe eating disorder psychopathology demonstrated decreased microbial diversity.¹³

The impact of intestinal microbiome diversity and relative bacterial population density in MH conditions such as anxiety, depression, and eating disorders remains an intriguing avenue worth further exploring. Modulating these phenomena may reduce overall dysfunction and serve as a possible treatment modality.

Anxiety and the Microbiome

GAD is characterized by decreased social and occupational functioning. Anxiolytic pharmacotherapy combined with psychotherapy are the current mainstays of GAD treatment. Given the interplay of the gut microbiome and MH, probiotics may prove to be a promising alternative or adjunct treatment option.

The human stress response is enacted largely through the hypothalamus-pituitary-adrenal (HPA) axis. Anxiety and situational fear trigger a stress response that results in increased cortisol being released from the adrenal glands, thereby disrupting typical GI function by modifying the frequency of migrating motor complexes, the electromechanical impulses within the smooth muscle of the stomach and small bowel that allow for propagation of chyme. This, in turn, has downstream consequences on the composition of the intestinal microbiome.¹⁴ Patients with GAD have a lower prevalence of Faecalibacterium, Eubacterium rectale, Lachnospira, Butyricioccus, and Sutterella, all important producers of short-chain fatty acids (SCFA).^15,16 Diminished SCFA production has been linked to intestinal barrier dysfunction, contributing to increases in gut endothelial permeability and facilitating a proinflammatory response with resultant neural feedback loops.^17,18 Indeed, proinflammatory cytokines, namely C-reactive protein (CRP), interleukin 6 (IL-6), and TNF-α were found to be elevated in patients with diagnosed GAD.¹⁹ These proinflammatory cytokines are critical in neurochemical modulation as they inhibit the essential enzyme tetrahydrobiopterin, a cofactor of monoamine synthesis, thereby decreasing the monoamine neurotransmitters serotonin, dopamine, and norepinephrine.²⁰ Decrease in the monoamine neurotransmitters serves as the lynchpin for the monoamine hypothesis of both anxiety and depression and currently guides our choice in pharmacotherapy.²¹

Anxiolytic pharmacotherapy targets the neurochemical consequences of GAD to ameliorate social, functional, and emotional impairment. However, the physiology of the gut-brain feedback loop in GAD is an attractive target for the creation and trialing of probiotics, which can rebalance intestinal flora, reduce inflammation, and allow for increased synthesis of monoamine neurotransmitters. Indeed, Lactobacillus and Bifidobacterium have been shown to possess anxiolytic properties by increasing serotonin and SCFAs while reducing the HPA adrenergic response.²²

Depression and the Microbiome

MDD significantly diminishes quality of life and is the leading cause of disability worldwide, affecting nearly 350 million individuals.²³ Psychotherapy in conjunction with pharmacotherapy aimed at increasing cerebral serotonin availability are the current mainstays of MDD treatment. Yet the brain does not exist in isolation: It has 3 known methods of bidirectional communication with the GI tract via the vagus nerve, immune mediators, and bacterial metabolites.^24,25

The vagus nerve (vagus means wandering in Latin), is the longest nerve of the autonomic nervous system (ANS) and historically has been called the pneumogastric nerve for its parasympathetic innervation of the heart, lungs, and digestive tract. Current research supports that up to 80% of the fibers within the vagus nerve are afferent, relaying signals from the GI tract to the brain.²⁶ Therefore, modulation of vagus nerve signaling may theoretically impact mental health. Indeed, studies have demonstrated clinically significant improvement in patients with treatment-resistant depression who underwent vagal nerve stimulation (VNS).²⁷ Although the mechanism by which it exerts its mood-modulating activity is not well understood, recent human and animal studies indicate that VNS may alter central neurotransmitter levels, having demonstrated the ability to increase serotonin levels.²⁵ Also the vagus nerve possesses the ability to differentiate between pathogenic and nonpathogenic gut microorganisms; beneficial gut flora emit signals within the gut lumen, which in turn, are transmitted through afferent vagus nerve fibers to the brain, effecting both anti-inflammatory and mood-modulating responses.^25,28

Immunomediators involving intestinal microbiota also are known to play a critical role in the pathophysiology of MDD. Depression is closely tied to systemic inflammation; both are hypothesized to have played a role in the evolutionary response to fighting infection and healing wounds.²⁹ With regard to the gut, MDD is associated with increased GI permeability, which allows for microorganisms to leak through the intestinal mucosa into the systemic circulation and stimulate an inflammatory response.¹⁸ Levels of IgM and IgA against enterobacteria lipopolysaccharides (LPS) were found to be markedly greater in patients with MDD vs those of nondepressed controls.³⁰ Current research indicates that IgM and IgA against LPS of translocated bacteria serve to amplify immune pathways seen in the pathophysiology of chronic MDD.^30,31 Further research is indicated to deduce whether bacterial translocation with subsequent immune response induces MDD in susceptible individuals, or whether translocation occurs secondary to the systemic inflammation seen in MDD.

The makeup of the GI microbiome is fundamentally altered in patients with MDD, with a marked reduction in both microorganism diversity and density.³⁰ Patients with MDD have been shown to have increased levels of Alistipes, a bacterium that also is elevated in chronic fatigue syndrome and irritable bowel syndrome (IBS), diagnoses that are associated with MDD.^32-34 Lower counts of Bifidobacterium and Lactobacillus are documented in both MDD and IBS patients as well.³⁵ Decreased Bifidobacterium and Lactobacillus might indicate a causal rather than correlative relationship as these bacterium take the precursor monosodium glutamate to create γ-aminobutyric acid (GABA).³⁶

Psychobiotics and Mental Health

The pathophysiology of the bidirectional communication between the gut and the brain offers an attractive approach for treatment modalities. Currently, the research into probiotic supplementation to treat mental disorders, such as anxiety and depression, is still in its infancy, and treatment guidelines do not support their routine administration. There is great promise in the use of probiotics to ameliorate psychiatric symptomatology, referred to by many in the field as psychobiotics.

One pathophysiology of the stress response seen in anxiety can be traced to the HPA axis and increased cortisol levels, with downstream effects on the microbiome through modification of the migrating motor complexes. Healthy volunteers tasked with taking a trademarked galactooligosaccharide prebiotic daily for 3 weeks had a reduced salivary cortisol awakening response compared with that of a placebo (maltodextrin). The same group demonstrated decreased attentional vigilance to negative information in a dot-probe task compared with attentional vigilance with positive information.³⁷ It is possible that this was due to the decreased stress response secondary to probiotic consumption. In mice models, a probiotic consisting of Lactobacillus helveticus and Bifidobacterium longum (B longum) (bacterium that are decreased in GAD and MDD) demonstrated anxiolytic-like behavior. The same formulation also demonstrated beneficial psychological effects in healthy human volunteers.²² In mice models, Lactobacillus feeding was superior to citalopram in anxiolysis and in cognitive functioning.³⁸

Like GAD, the pathophysiology of the GBA in MDD is an attractive target for psychobiotic therapy. Although current research is not yet sufficient to create general guidelines or recommendations for the routine administration of psychobiotics, it holds significant promise as an effective primary and/or adjunct treatment. In patients with IBS, administration of B longum reduced depression and increased quality of life. This same study demonstrated that probiotic administration was associated with reduced limbic activity in the brain.³⁹ In MDD, the hippocampus demonstrates altered expression of various transcription factors and cellular metabolism.⁴⁰ In a double-blind placebo-controlled trial, Lactobaccillus rhamnosus supplementation in postnatal mothers resulted in less severe depressive symptoms reported.⁴¹ Furthermore, probiotic supplementation consisting of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum in patients with MDD for 8 weeks had significant decreases in score on the Beck Depression Inventory scale.⁴² Also, a meta-analysis of probiotic administration on depression scales demonstrated appreciably lower scores after administration in both patients with MDD and healthy patients aged 60 years, although these results were found to be correlative.⁴³ However, while promising, another meta-analysis of 10 randomized controlled trials found probiotic supplementation had no significant effect on mood.⁴⁴

The Role of Diet

Although there has been tremendous focus on new and improved therapeutics to address MH conditions, such as depression and anxiety, there also has been renewed interest in the fundamental importance and benefit of a wholesome diet. Recent literature has shown how diet may play a pivotal role in the development and severity of mental illness and holds promise as another potential target for treatment. A 2010 cross-sectional population study of more than 1000 adult women aged 20 to 93 years demonstrated that women with a largely Western dietary pattern (ie, largely composed of processed meats, pizza, chips, hamburgers, white bread, sugar, flavored milk drinks, and beer) were more likely to have dysthymic disorder or major depression, whereas women in this same cohort with a more traditional dietary pattern (ie, composed mainly of vegetables, fruit, lamb, beef, fish, and whole grains) were found to have significantly reduced odds for depression or dysthymic disorder as well as anxiety disorders.⁴⁵

Several other large-scale population studies such as the SUN cohort study, Hordaland Health study, Whitehall II cohort study, and RHEA mother and baby cohort study have demonstrated similar findings: that a more wholesome diet composed mainly of lean meats, vegetables, fruits, and whole grains was associated with significantly reduced risk of depression compared with a largely processed, high fat, and high sugar diet. This trend also has been observed in children and adolescents and is of particular importance when considering that many psychological and psychiatric problems tend to arise in the formative and often turbulent years prior to adulthood.⁴⁶

The causal relationship between diet and MH may be better understood by taking a closer look at a crucial intermediate factor: the gut microbiome. The interplay between diet and intestinal microbiome was well elucidated in a landmark 2010 study by De Filippo and colleagues.⁴⁷ In this study, the microbiota of 14 healthy children from a small village in Burkina Faso (BF) were compared with those of 15 healthy children from an urban area of Florence, Italy (EU). The BF children were reported to consume a traditional rural African diet that is primarily vegetarian, rich in fiber, and low in animal protein and fat, whereas the EU children were noted as consuming a typical Western diet low in fiber but rich in animal protein, fat, sugar, and starch. Comparison revealed that EU children had a higher F/B ratio than their BF counterparts, a metric that has been associated with obesity.⁴⁷ Furthermore, increased exposure to environmental microbes associated with a fiber-rich diet has been postulated to increase the richness of intestinal flora and serve as a protective factor against noninfectious and inflammatory colonic diseases, which are found to be more prevalent in Western nations whose diets lack fiber. BF children were found to have increased microbial diversity and increased abundance of bacteria capable of producing SCFA relative to their EU counterparts, both of which have a positive influence on the gut, systemic inflammation, and MH.⁴⁷

Conclusions

Diet has a powerful impact on the intestinal microbiome, which in turn directly impacts our physical and MH in myriad ways. The well-known benefits of a wholesome, nutritious, and well-varied diet include reduced cardiovascular risk, improved glycemic control, GI regularity, and decreased depression. Along with a balanced diet, patients may achieve further benefit with the addition of probiotics.

With regard to psychiatry in particular, increased awareness of the intimate relationship between the gut and the brain is expected to have profound implications for the field. Given this mounting data, immunology, microbiology, and GI pathophysiology should be included in future discussions regarding MH. Their application will likely improve both somatic and mental well-being. We anticipate that newly discovered probiotics and other psychobiotic formulations will be routinely included in a psychiatrist’s pharmacopeia in the near future. Unfortunately, as is clear from our review of the current literature, we do not yet have specific interventions targeting the intestinal microbiome to recommend for the management of specific psychiatric conditions. However, this should not deter further exploring diet modification and psychobiotic supplementation as a means of impacting the intestinal microbiome in the pursuit of psychiatric symptom relief.

Dietary modification is already a standard component of sound primary care medicine, designed to mitigate risk for cardiovascular disease. This exploration can occur as part of otherwise standard psychiatric care and be used as a form of behavioral activation for the patient. Furthermore, explaining the interconnectedness of the mind, brain, and body along with the rationale for experimentation could further help destigmatize the experience of mental illness.

Editor’s Note: This article has been adapted from an article originally published in Federal Practitioner (Tavakoli HR, et al. Kratom: a new product in an expanding substance abuse market. Fed Prac. 2016;33[11]:132-136. http://www.fedprac.com).

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opioids, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most emergency physicians (EPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of this type of Web site and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite the purported raison d’être of these Web sites, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer et al⁴ of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patients’ digital habits, the researchers demonstrated that the majority of subjects used these Web sites and, as a result, either increased their drug use or learned about (and tried) new substances.

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opioid withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and has become increasingly popular in the United States and in the United Kingdom.^2,5,6 In the United States, this poses a problem for EPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the US Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the United States.³ In late 2016, out of concern for public safety, the DEA placed a temporary ban on kratom. The Agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of April 2017, the DEA did not have a timetable for banning or scheduling the drug, though some states have banned it.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined Web sites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about $13 US currency).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a kratom product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least nine deaths.⁷

This article presents a case of kratom abuse. It describes a brief history of the substance, its pharmacological characteristics, the clinical presentation of kratom abuse, and the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the United States, a basic working knowledge of the drug is quickly becoming a must for EPs.

Case Presentation

At his employer’s request, a 33-year-old man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disk resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he became concerned that he was abusing his opioid medication, and it was discontinued. The patient was transferred to the local ED and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline, consistent with opioid withdrawal. Initial point-of-care (POC) admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s opioid withdrawal resolved, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia.^2,3 The leaves of these trees contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-like effect, which at mega doses produces an intense euphoric state and has led to a steady growth in abuse worldwide. Although the government of Thailand banned the planting of Mitragyna speciosa as early as 1943, its continued proliferation in Southeast Asia and throughout the world has not ceased.^2,3,6

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the two major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including mu-, delta-, and kappa-opioid receptors, leading to its opioid-like effects, including analgesia and euphoria. Also similar to common opioids, withdrawal symptomatology can present after only 5 days of daily use. There is limited evidence that mitragynine can activate postsynaptic alpha-2 adrenergic receptors, which may act synergistically with the mu-agonist with regard to its analgesic effect.^2,5

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for EPs to be aware of the presentation of patients with kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from Web sites such as Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5-15 g of raw crushed leaves), it is believed that the mu-opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed with supportive and symptomatic care and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of a patient with an acute kratom overdose (typically requiring ingestion of >15 g of crushed leaves) begins with addressing airway support, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including POC glucose testing, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, as indicated).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong mu agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid withdrawal.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, alpha-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to EPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurological and mental status examinations.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and psychosis.^3-7 Additionally, a study by Kittirattanapaiboon et al¹² correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥14,000 individuals included in the study sample) with statistically significant higher suicide risk.

Detection

Because kratom is a relatively new compound in the United States, medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and two metabolites of mitragynine in urine.⁷ Le et al¹³ were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours. Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at the Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the case study patient’s urine because a urine test was not done until hospital day 5.

Case Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid-use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Conclusion

Kratom is an emerging drug of abuse in the Western world. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the United States and multiple other Western countries, kratom is easily accessible. Emergency physicians need to be aware of kratom, and during their evaluations, question appropriate patients about kratom and other legal highs.

Editor’s Note: This article has been adapted from an article originally published in Federal Practitioner (Tavakoli HR, et al. Kratom: a new product in an expanding substance abuse market. Fed Prac. 2016;33[11]:132-136. http://www.fedprac.com).

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opioids, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most emergency physicians (EPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of this type of Web site and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite the purported raison d’être of these Web sites, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer et al⁴ of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patients’ digital habits, the researchers demonstrated that the majority of subjects used these Web sites and, as a result, either increased their drug use or learned about (and tried) new substances.

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opioid withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and has become increasingly popular in the United States and in the United Kingdom.^2,5,6 In the United States, this poses a problem for EPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the US Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the United States.³ In late 2016, out of concern for public safety, the DEA placed a temporary ban on kratom. The Agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of April 2017, the DEA did not have a timetable for banning or scheduling the drug, though some states have banned it.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined Web sites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about $13 US currency).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a kratom product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least nine deaths.⁷

This article presents a case of kratom abuse. It describes a brief history of the substance, its pharmacological characteristics, the clinical presentation of kratom abuse, and the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the United States, a basic working knowledge of the drug is quickly becoming a must for EPs.

Case Presentation

At his employer’s request, a 33-year-old man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disk resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he became concerned that he was abusing his opioid medication, and it was discontinued. The patient was transferred to the local ED and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline, consistent with opioid withdrawal. Initial point-of-care (POC) admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s opioid withdrawal resolved, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia.^2,3 The leaves of these trees contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-like effect, which at mega doses produces an intense euphoric state and has led to a steady growth in abuse worldwide. Although the government of Thailand banned the planting of Mitragyna speciosa as early as 1943, its continued proliferation in Southeast Asia and throughout the world has not ceased.^2,3,6

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the two major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including mu-, delta-, and kappa-opioid receptors, leading to its opioid-like effects, including analgesia and euphoria. Also similar to common opioids, withdrawal symptomatology can present after only 5 days of daily use. There is limited evidence that mitragynine can activate postsynaptic alpha-2 adrenergic receptors, which may act synergistically with the mu-agonist with regard to its analgesic effect.^2,5

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for EPs to be aware of the presentation of patients with kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from Web sites such as Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5-15 g of raw crushed leaves), it is believed that the mu-opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed with supportive and symptomatic care and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of a patient with an acute kratom overdose (typically requiring ingestion of >15 g of crushed leaves) begins with addressing airway support, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including POC glucose testing, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, as indicated).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong mu agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid withdrawal.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, alpha-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to EPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurological and mental status examinations.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and psychosis.^3-7 Additionally, a study by Kittirattanapaiboon et al¹² correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥14,000 individuals included in the study sample) with statistically significant higher suicide risk.

Detection

Because kratom is a relatively new compound in the United States, medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and two metabolites of mitragynine in urine.⁷ Le et al¹³ were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours. Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at the Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the case study patient’s urine because a urine test was not done until hospital day 5.

Case Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid-use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Conclusion

Kratom is an emerging drug of abuse in the Western world. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the United States and multiple other Western countries, kratom is easily accessible. Emergency physicians need to be aware of kratom, and during their evaluations, question appropriate patients about kratom and other legal highs.

Editor’s Note: This article has been adapted from an article originally published in Federal Practitioner (Tavakoli HR, et al. Kratom: a new product in an expanding substance abuse market. Fed Prac. 2016;33[11]:132-136. http://www.fedprac.com).

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opioids, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most emergency physicians (EPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of this type of Web site and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite the purported raison d’être of these Web sites, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer et al⁴ of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patients’ digital habits, the researchers demonstrated that the majority of subjects used these Web sites and, as a result, either increased their drug use or learned about (and tried) new substances.

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opioid withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and has become increasingly popular in the United States and in the United Kingdom.^2,5,6 In the United States, this poses a problem for EPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the US Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the United States.³ In late 2016, out of concern for public safety, the DEA placed a temporary ban on kratom. The Agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of April 2017, the DEA did not have a timetable for banning or scheduling the drug, though some states have banned it.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined Web sites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about $13 US currency).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a kratom product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least nine deaths.⁷

This article presents a case of kratom abuse. It describes a brief history of the substance, its pharmacological characteristics, the clinical presentation of kratom abuse, and the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the United States, a basic working knowledge of the drug is quickly becoming a must for EPs.

Case Presentation

At his employer’s request, a 33-year-old man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disk resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he became concerned that he was abusing his opioid medication, and it was discontinued. The patient was transferred to the local ED and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline, consistent with opioid withdrawal. Initial point-of-care (POC) admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s opioid withdrawal resolved, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia.^2,3 The leaves of these trees contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-like effect, which at mega doses produces an intense euphoric state and has led to a steady growth in abuse worldwide. Although the government of Thailand banned the planting of Mitragyna speciosa as early as 1943, its continued proliferation in Southeast Asia and throughout the world has not ceased.^2,3,6

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the two major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including mu-, delta-, and kappa-opioid receptors, leading to its opioid-like effects, including analgesia and euphoria. Also similar to common opioids, withdrawal symptomatology can present after only 5 days of daily use. There is limited evidence that mitragynine can activate postsynaptic alpha-2 adrenergic receptors, which may act synergistically with the mu-agonist with regard to its analgesic effect.^2,5

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for EPs to be aware of the presentation of patients with kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from Web sites such as Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5-15 g of raw crushed leaves), it is believed that the mu-opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed with supportive and symptomatic care and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of a patient with an acute kratom overdose (typically requiring ingestion of >15 g of crushed leaves) begins with addressing airway support, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including POC glucose testing, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, as indicated).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong mu agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid withdrawal.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, alpha-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to EPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurological and mental status examinations.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and psychosis.^3-7 Additionally, a study by Kittirattanapaiboon et al¹² correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥14,000 individuals included in the study sample) with statistically significant higher suicide risk.

Detection

Because kratom is a relatively new compound in the United States, medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and two metabolites of mitragynine in urine.⁷ Le et al¹³ were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours. Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at the Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the case study patient’s urine because a urine test was not done until hospital day 5.

Case Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid-use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Conclusion

Kratom is an emerging drug of abuse in the Western world. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the United States and multiple other Western countries, kratom is easily accessible. Emergency physicians need to be aware of kratom, and during their evaluations, question appropriate patients about kratom and other legal highs.

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!⁴

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.^2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the U.S.³ In the past few months, out of concern for public safety, the DEA placed a temporary ban on kratom. The agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of September 2016, the DEA does not have a timetable for banning or scheduling the drug.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.⁷

This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.

Case Presentation

At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).^2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurologic and mental status exams.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.^3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.¹²

Detection

Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.⁷ Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.¹³ Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.

Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!⁴

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.^2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the U.S.³ In the past few months, out of concern for public safety, the DEA placed a temporary ban on kratom. The agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of September 2016, the DEA does not have a timetable for banning or scheduling the drug.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.⁷

This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.

Case Presentation

At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).^2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurologic and mental status exams.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.^3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.¹²

Detection

Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.⁷ Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.¹³ Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.

Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.

According to the United Nations Office on Drugs and Crime, the last decade saw an alarming rise in the use of recreational substances.¹ There was an escalation not only in the use of the more well-known street drugs (cannabis, stimulants, opiates, and hallucinogens), but also an exponential increase in the abuse of novel psychoactive substances. Although most health care providers (HCPs) are at least relatively familiar with some of these designer drugs—often synthesized analogues of common street drugs—region-specific herbal products with psychoactive properties are now entering the market worldwide. Certainly, the cause of this increased use is multifactorial: Ease of access to these drugs and ambiguous legality are believed to be among the largest contributors. Infrastructure established through globalization promotes easy drug transportation and distribution across borders, and widespread Internet use makes knowledge of and accessibility to such substances exceedingly simple.^2,3

In particular, widespread online access has permanently altered the acquisition of knowledge in all realms—including drug use. Although Erowid Center remains one of the oldest and best-known of the “dark Internet” websites and bills itself as providing “harm reduction,” others have cropped up online and disseminate information about many forms of potentially psychoactive substances. Despite these websites’ purported raison d’être, recent studies have demonstrated these sites’ efficacy in promoting drug use under the guise of safety, particularly among adolescents and young adults. Among these is a qualitative study by Boyer and colleagues of 12 drug users admitted to a pediatric psychiatry unit. Through extensive questioning about the patient’s digital habits, the researchers demonstrated that the majority of subjects used these websites and as a result either increased their drug use or learned about (and tried) new substances!⁴

One drug that has benefited from globalization and the Internet is kratom (Mitragyna speciosa korth). This formerly regionally confined herbal psychoactive substance is native to Southeast Asia, where it has been used (and abused) for centuries as a mild stimulant, to prevent opiate withdrawal, and for recreational purposes. In recent years, kratom has been marketed as a psychotropic drug and is increasingly popular in the U.S. and in the United Kingdom.^2,5,6 In the U.S., this poses a problem for HCPs who often are unaware of this plant’s existence, much less its abuse potential or health effects.² Also known as ketum, kakuam, thang, thom, or biak, kratom is marketed in stores and online as a cheap, safe alternative to opioids.

Although considered a “substance of concern” without any approved medical use by the U.S. Drug Enforcement Agency (DEA), kratom is not a regulated or controlled substance in the U.S.³ In the past few months, out of concern for public safety, the DEA placed a temporary ban on kratom. The agency’s move was followed by a substantial negative reaction from kratom supporters and was quickly rescinded. As of September 2016, the DEA does not have a timetable for banning or scheduling the drug.

To that end, users consider kratom a legal high, and it is easily purchased online. A 2010 study in the United Kingdom examined websites where kratom and many other quasilegal substances (including Salvia divinorum and legal precursors to LSD) could be purchased for an average of £10 (about U.S. $13).⁵ This study’s authors also noted a significant lack of product information on these marketplaces. As these products are not overseen by any regulatory body, the risk of overdose or adulteration is extremely high.^2,3,6-8 In fact, Krypton, a product sold online, was found to be adulterated with O-desmethyltramadol—the active metabolite of the synthetic opiate tramadol—and implicated in at least 9 deaths.⁷

This article presents a case of kratom abuse and will outline a brief history, the pharmacologic characteristics, clinical presentation of kratom abuse, and conclude with an overview of the treatment of kratom-related illness and evaluation of potential toxic sequelae. In light of the rapid proliferation of kratom in the U.S., a basic working knowledge of the drug is quickly becoming a must for federal HCPs.

Case Presentation

At his employer’s request, a 33-year-old married man presented to his family physician for a worsening of his uncontrolled back pain from a herniated lumbar disc resulting from a motor vehicle collision 3 months before. At his physician’s office he stated, “I don’t care if I live or die, I’m tired of the pain,” and “I’m going to go off on somebody if I can’t get this pain under control.” He also endorsed having auditory hallucinations for several years and a history of violence and homicide. The problem arose precipitously after he thought that he was abusing his opiate medication, and it was discontinued. The patient was transferred to the local hospital and admitted to the psychiatric service for his suicidal ideations and risk of harming self and others.

On admission to the psychiatric service, the patient complained of body aches, chills, rhinorrhea, and significantly worsened irritability from his baseline. Initial point-of-care admission drug testing had been negative as had expanded urine tests looking for synthetic opioids, cannabinoids, and cathinones. The patient reported no opioid use but was unable to explain his current symptom patterns, which were worsening his chronic pain and hampering any attempt to build rapport. On hospital day 3, the patient’s additional sequelae had passed, and psychiatric treatment was able to progress fully. On hospital day 4, the inpatient treatment team received a message from the patient’s primary care manager stating that a friend of the patient had found a bottle of herbal pills in the patient’s car. This was later revealed to be a kratom formulation that he had purchased online.

Background

Kratom is the colloquial name of a tree that is native to Thailand, Malaysia, and other countries in Southeast Asia. These trees, which can grow to 50 feet high and 15 feet wide, have long been the source of herbal remedies in Southeast Asia (eFigure).^2,3 The leaves contain psychoactive substances that have a variety of effects when consumed. At low doses, kratom causes a stimulant effect (akin to the leaves of the coca plant in South America); laborers and farmers often use it to help boost their energy. At higher doses, kratom causes an opioid-l

In the United Kingdom, kratom is currently the second most common drug that is considered a legal high, only behind salvia (Salvia divinorum), a hallucinogenic herb that is better known as a result of its use by young celebrities over the past decade.^5,8 Presently, kratom’s legal status in the U.S. continues to be nebulous: It has not been officially scheduled by the DEA, and it is easily obtained.

Kratom can be taken in a variety of ways: Crushed leaves often are placed in gel caps and swallowed; it can be drunk as a tea, juice, or boiled syrup; and it can be smoked or insufflated.^2,3,5,6

Pharmacology and Clinical Presentation

More than 20 psychoactive compounds have been isolated from kratom. Although a discussion of all these compounds is beyond the scope of this review, the 2 major compounds are mitragynine and 7-hydroxymitragynine.

Mitragynine

Mitragynine, the most abundant psychoactive compound found in kratom, is an indole alkaloid (Figure 1). Extraction and analysis of this compound has demonstrated numerous effects on multiple receptors, including μ, δ, and κ opioid receptors, leading to its opioid-like ef

7-Hydroxymitragynine

7-hydroxymitragynine, despite being far less concentrated in kratom preparations, is about 13 times more potent than morphine and 46 times more potent than mitragynine. It is thought that its hydroxyl side chain added to C7 (Figure 2) adds to its lipophilicity and ability to cross the blood-brain barrier at a far more rapid rate than that of mitragynine.²

Mitragynine and 7-hydroxymitragynine remain the best-studied psychoactive components of kratom at this time. Other compounds that have been isolated, such as speciociliatine, paynantheine, and speciogynine, may play a role in kratom’s analgesic and psychoactive effects. Animal studies have demonstrated antimuscarinic properties in these compounds, but the properties do not seem to have any demonstrable effect at the opioid receptors.²

Intoxication and Withdrawal

Due to its increasing worldwide popularity, it is now imperative for HCPs to be aware of the clinical presentation of kratom abuse as well as the management of withdrawal in light of its dependence potential. However, large-scale studies have not been performed, and much of the evidence comes not from the medical literature but from prodrug websites like Erowid or SageWisdom.^2,5-9 To that end, such information will be discussed along with the limited research and expert consensuses available in peer-reviewed medical literature.

Kratom seems to have dose-dependent effects. At low doses (1 g-5 g of raw crushed leaves), kratom abusers often report a mild energizing effect, thought to be secondary to the stimulant properties of kratom’s multiple alkaloids. Users have reported mild euphoria and highs similar to those of the abuse of methylphenidate or modafinil.^2,9,10 Also similar to abuse of those substances, users have reported anxiety, irritability, and aggressiveness as a result of the stimulant-like effects.

At moderate-to-high doses (5 g-15 g of raw crushed leaves), it is believed that the μ opiate receptor agonism overtakes the stimulant effects, leading to the euphoria, relaxation, and analgesia seen with conventional opioid use and abuse.^2,10 In light of the drug’s substantial binding and agonism of all opioid receptors, constipation and itching also are seen.² As such, if an individual is intoxicated, he or she should be managed symptomatically with judicious use of benzodiazepines and continuous monitoring of heart rate, blood pressure, respiratory rate, and oxygen saturation.^2,10 Kratom intoxication can precipitate psychotic episodes similar to those caused by opiate intoxication, so monitoring for agitation or psychotic behaviors is also indicated.^9,10

The medical management of an acute kratom overdose (typically requiring ingestion of > 15 g of crushed leaves) begins with addressing airway blockage, breathing, and circulation along with continuous vital sign monitoring and laboratory testing, including point-of-care glucose, complete blood count, electrolytes, lactate, venous blood gas, and measurable drug levels (ethanol, acetaminophen, tricyclic antidepressants, etc).¹¹ If it is determined that kratom was the intoxicant, the greatest concern of death is similar to that of opioid overdose: respiratory depression. Although there are no large-scale human studies demonstrating efficacy, multiple authors suggest the use of naloxone in kratom-related hypoventilation.^9,10

The development of dependence on kratom and its subsequent withdrawal phenomena are thought to be similar to that of opioids, in light of its strong μ agonism.^2,5,9,10 Indeed, kratom has a long history of being used by opioid-dependent patients as an attempt to quit drug abuse or stave off debilitating withdrawal symptoms when they are unable to acquire their substance of choice.^2,5-10 As such, withdrawal and the treatment thereof will also mimic that of opioid detoxification.

The kratom-dependent individual will often present with rhinorrhea, lacrimation, dry mouth, hostility, aggression, and emotional lability similar to the case study described earlier.^2,9,10 Kratom withdrawal, much like intoxication, also may precipitate or worsen psychotic symptoms, and monitoring is necessary throughout the detoxification process.^2,5,10 Withdrawal management should proceed along ambulatory clinic or hospital opioid withdrawal protocols that include step-down administration of opioids or with nonopioid medications for symptomatic relief, including muscle relaxants, α-2 agonists, and antidiarrheal agents.^5,9,10

Kratom Toxicity

A review of the available medical literature has demonstrated a number of toxic effects with kratom abuse, either as the sole agent or in concert with prescribed medications, recreational coingestants, or as a result of manufacturer’s adulteration with other chemicals or drugs. Of particular interest to HCPs are manic or psychotic episode precipitation, seizure, hypothyroidism, intrahepatic cholestatic injury, and even sudden cardiac death.^2,3,5-10 In addition to the basic history, physical, and laboratory examination, the workup of patients identified as kratom users should include the following:

• Fastidious medication reconciliation with drug-interaction check;
• Exhaustive substance abuse history;
• Identification of the brand name and source of kratom purchased, to determine whether there are advertised coingestants or reports of adulteration;
• Electrocardiogram;
• Thyroid function testing;
• Hepatic function testing; and
• Comprehensive neurologic and mental status exams.

In chronic users of kratom, a number of effects have been seen whose etiologies have not yet been determined. These effects include depression, anxiety, tremulousness, weight loss, and permanent psychosis.^3-7 Additionally, a 2008 study by Kittirattanapaiboon and colleagues correlated drug use by those with concurrent mental health disorders (in particular, kratom, which was used in 59% of the ≥ 14,000 individuals included in the study sample) with statistically significant higher suicide risk.¹²

Detection

Because kratom is a relatively new compound in the U.S., medical and forensic laboratories are only now implementing kratom detection protocols. Many laboratories now use high-performance liquid chromatography to analyze for mitragynine, 7-hydroxymitragynine, and 2 metabolites of mitragynine in urine.⁷ Le and colleagues were able to detect mitragynine in the urine in levels as low as 1 ng/mL, which is clinically useful as mitragynine has a half-life determined in animal studies to be 3.85 hours.¹³ Similar detection limits for mitragynine and 7-hydroxymitragynine are used only at Naval Medical Center Portsmouth in Virginia; however, kratom was not detected in the study patient’s urine because a urine test was not done until hospital day 5.

Conclusion

When gently confronted about the kratom found in his car, the case study patient admitted that he had purchased kratom online after he was “cut off” from prescription opioids for his pain. He admitted that although it was beneficial for his pain, he did notice worsening in his aggression toward his spouse and coworkers. This progressed to an exacerbation of his psychotic symptoms of hallucinations and persecutory delusions. These symptoms remained well hidden in this highly intelligent individual—but were present for years prior to his presentation at the hospital. The patient was discharged from the inpatient psychiatric unit on hospital day 16 with a diagnosis of schizoaffective disorder, depressive type in addition to opioid use disorder. The patient agreed to seek a pain management specialist and discontinue kratom use.

Kratom is an emerging drug of abuse in the Western World. Although significant research is being conducted on its possible medical uses, little is known about kratom beyond the “trip reports” of kratom users posted online. Because of its technically legal status in the U.S. and multiple other Western countries, kratom is easily accessible and is difficult to detect. Health care providers need to be aware of kratom, and during their evaluations, question patients about kratom and other legal highs.

Mrs. X, age 43, gravida 4 para 1, is a married woman of sub-Saharan African heritage with a history of idiopathic hypertension, uterine leiomyomas, and multiple spontaneous miscarriages. She has no psychiatric history and had never been evaluated by a mental health professional. Mrs. X is well known to the hospital’s emergency room and obstetrics and gynecology services for several presentations claiming to be pregnant, continuously, over the last 11 months, despite evidence—several negative serum beta human chorionic gonadotropin (ß-hCG) tests and transvaginal sonograms—to the contrary.

Mrs. X reports that after feeling ill for “a few days,” she began to believe that she was “losing [her] mucous plug” and needed urgent evaluation in preparation for the delivery of her “child.” She again is given a ß-hCG test, which is negative, as well as a negative transvaginal sonogram.

Mrs. X’s blood pressure is 220/113 mm Hg, and she emergently receives captopril, 25 mg sublingually, which lowers her systolic blood pressure to 194 mm Hg. The internal medicine team learns that Mrs. X stopped taking her blood pressure medications, lisinopril and hydrochlorothiazide, approximately 2 weeks earlier because she “didn’t want it [the antihypertensive agents] to hurt [her] baby.”

What explains Mrs. X’s belief that she is pregnant?

a) polycystic ovary syndrome (PCOS)
b) delusional disorder
c) bipolar I disorder
d) somatic symptom disorder

The authors’ observations

Pseudocyesis is a psychosomatic condition with an estimated incidence of 1 in 160 maternity admissions in many African countries and 1 in 22,000 in the United States.¹ According to DSM-5, pseudocyesis is a false belief of being pregnant along with signs and symptoms of pregnancy.²

Pseudocyesis is more common in:

• developing countries
• areas of low socioeconomic status with minimal education
• societies that place great importance on childbirth
• areas with low access to care.³

The primary presenting symptoms are changes in menses, enlarging abdomen, awareness of fetal movement, enlarged and tender breasts, galactorrhea, and weight gain.⁴

The exact pathophysiology of the disorder has not been determined, but we believe the psychosomatic hypothesis offers the most compelling explanation. According to this hypothesis, intense social pressures, such as an overwhelming desire to become pregnant because of cultural considerations, personal reasons, or both, could alter the normal function of the hypothalamic-pituitary-ovarian axis,⁵ which could result in physical manifestations of pregnancy. Tarín et al¹ found that rodents with chronic psychosocial stress had decreased brain norepinephrine and dopamine activity and elevated plasma levels of norepinephrine. This can translate to human models, in which a deficit or dysfunction of catecholaminergic activity in the brain could lead to increased pulsatile gonadotropin-releasing hormone, luteinizing hormone (LH), prolactin, and an elevated LH:follicle-stimulating hormone ratio.¹ These endocrine changes could induce traits found in most women with pseudocyesis, such as hypomenorrhea or amenorrhea, diurnal or nocturnal hyperprolactinemia (or both), and galactorrhea.¹

How would you approach Mrs. X’s care?

a) confront her with the negative pregnancy tests
b) admit her to the inpatient psychiatric unit
c) begin antipsychotic therapy
d) discharge her with outpatient follow-up

EVALUATION A curse on her

Although Mrs. X initially refused to see the psychiatry team, she is more receptive on hospital Day 3. Mrs. X reports that she and her husband had been trying to have a child since they were married 17 years earlier. She had a child with another man before she met her husband, causing her in-laws in Africa to become suspicious that she is intentionally not producing a child for her husband. She had 3 spontaneous abortions since her marriage; these added stress to the relationship because the couple would feel elated when learning of a pregnancy and increasingly devastated with each miscarriage.

Mrs. X reports that she and her husband have been seeing a number of reproductive endocrinologists for 7 years to try to become pregnant. She reports feeling that these physicians are not listening to her or giving her adequate treatment, which is why she has not been able to become pregnant. At the time of the evaluation, she reports that she is pregnant, and the tests have been negative because her mother-in-law placed a “curse” on her. This “curse” caused the baby to be invisible to the laboratory tests and sonograms.

During the psychiatric evaluation, Mrs. X displays her protuberant abdomen and says that she feels the fetus kicking. In addition, she also reports amenorrhea and breast tenderness and engorgement.

During her hospital stay, Mrs. X’s mental status exam does not demonstrate signs or symptoms of a mood disorder, bipolar disorder, or psychosis. Nonetheless, she remains delusional and holds to her fixed false belief of being pregnant. She refuses to be swayed by evidence that she is not pregnant. Despite this, clinicians build enough rapport that Mrs. X agrees to follow up with psychiatry in the outpatient clinic after discharge.

The internal medicine team is apprehensive that Mrs. X will continue to refuse anti­hypertensive medications out of concern that the medications would harm her pregnancy, as she had in the hospital. She remains hypertensive, with average systolic blood pressure in the 180 to 200 mm Hg range; however, after much discussion with her and her family members, she agrees to try amlodipine, 5 mg/d, a category C drug. She says that she will adhere to the medication if she does not experience any side effects.

Mrs. X is discharged on hospital Day 4 to outpatient follow-up.

The authors’ observations

When considering a diagnosis of pseudocyesis, the condition should be distinguished from others with similar presentations. Before beginning a psychiatric evaluation, a normal pregnancy must be ruled out. This is easily done with a positive urine or serum ß-hCG and an abdominal or transvaginal ultrasound. Pseudocyesis can be differentiated from:

• delusion of pregnancy (sometimes referred to as psychotic pregnancy)—a delusional disorder often seen in psychotic illness without any physical manifestations of pregnancy
• pseudopregnancy (sometimes referred to as erroneous pseudocyesis), another rare condition in which signs and symptoms of pregnancy are manifested^1,6,7 but the patient does not have a delusion of pregnancy.

Pseudocyesis, in contrast, comprises the delusion of pregnancy and physical manifestations.² These distinctions could be difficult to make clinically; for example, an increase in abdominal girth could be a result of pseudocyesis or obesity. In the setting of physical manifestations of pregnancy, a diagnosis of pseudocyesis is more likely  (Table¹).

Patients with pseudocyesis exhibit subjective and objective findings of pregnancy, such as abdominal distension, enlarged breasts, enhanced pigmentation, lordotic posture, cessation of menses, morning sickness, and weight gain.^8,9 Furthermore, approximately 1% of pseudocyesis patients have false labor, as Mrs. X did.¹⁰ Typically, the duration of these symptoms range from a few weeks to 9 months. In some cases, symptoms can last longer¹¹; at admission, Mrs. X reported that she was 11 months pregnant. She saw nothing wrong with this assertion, despite knowing that human gestation lasts 9 months.

In delusion of pregnancy, a patient might exhibit abdominal distension and cessation of menses but have no other objective findings of pregnancy.⁷ Rather than being a somatoform disorder such as pseudocyesis, a delusion of pregnancy is a symptom of psychosis or, rarely, dementia.¹²

Pseudopregnancy is a somatic state resembling pregnancy that can arise from a variety of medical conditions. A full medical workup and intensive mental status and cognitive evaluation are necessary for diagnostic clarity. Although the pathology and workup of delusional pregnancy is beyond the scope of this article, we suggest Seeman¹³ for a review and Chatterjee et al¹⁴ and Tarín et al¹ for guidance on making the diagnosis.

Theories about pathophysiology

As with many psychosomatic conditions, the pathological process of pseudocyesis originally was thought of in a psychodynamic context. Several psychodynamic theories have been proposed, including instances in which the internal desire to be pregnant is strong enough to induce a series of physiological changes akin to the state of pregnancy.⁶

Other examiners of pseudocyesis have noted its development from fears and societal pressure, including the loss of companionship or “womanhood.”^6,9 Last, the tenuous interplay of desire for a child and substantial fear of pregnancy appears to play a role in many cases.^9-11 Rosenberg et al¹⁵ reported on a teenager with pseudocyesis who desired to be pregnant to appease her husband and family, but feared pregnancy and the implications of having a child at such a young age. As this team wrote, “this pregnancy sans child fulfilled the needs of the entire family, at least temporarily.”¹⁵

Prevailing modern theories behind the somatic presentations of these patients hinge on an imbalance of the hypothalamic-pituitary-adrenal axis.⁹ Although this remains the area of ongoing research, most literature has not shown a consistent change or trend in laboratory levels of hormones associated with pseudocyesis.¹⁶ Tarín et al,¹ however, did show a similar hormonal profile between patients with pseudocyesis and those with PCOS. Although urine or serum pregnancy testing and ultrasonography are indicated to rule out pseudopregnancy, we see no benefit in obtaining other lab work in most cases beyond that of a general medical workup, because such evaluations are not helpful in diagnosis or treatment.

Mrs. X’s abdomen was protuberant and she displayed the typical linea nigra of pregnancy. Many authors have theorized the physiological mechanism behind the abdominal enlargement to include contraction of the diaphragm, which reduces the abdominal cavity and forces the bowel outwards. As abdominal fat increases, the patient becomes constipated, and the bowel becomes distended.^10,16 Although the cause of our patient’s abdominal enlargement was not pursued, we note that the literature reported that the abdominal enlargement disappears when the patient is under general anesthesia.^10,16,17

Characteristics of pseudocyesis

Bivin and Klinger’s 1937 compilation of >400 cases of pseudocyesis over nearly 200 years remains a landmark in the study of this condition.¹⁸ In their analysis, patients range in age from 20 to 44; >75% were married. The authors noted that many of the women they studied had borne children previously. Further social and psychological studies came from this breakthrough article, which shed light on the dynamics of pseudocyesis in many patients with the condition.

According to Koic,¹¹ pseudocyesis is a form of conversion disorder with underlying depression. This theory is based on literature reports of patients displaying similar personal, cultural, and social factors. These similarities, although not comprehensive, are paramount in both the diagnosis and treatment of this condition.

Often, pseudocyesis presents in patients with lower education and socioeconomic status.^1,3,11 This is particularly true in developing nations in sub-Saharan Africa and the Indian subcontinent. Case reports, cross-sectional, and longitudinal studies from these developing nations in particular note the extremely high stress placed on women to produce children for their husbands and family in male-dominated society; it is common for a woman to be rejected by her husband and family if she is unable to reproduce.³

The effect of a lower level of education on development of pseudocyesis appears to be multifactorial:

• Lack of understanding of the human body and reproductive health can lead to misperception of signs of pregnancy and bodily changes
• Low education correlates with poor earnings and worse prenatal care; delayed or no prenatal care also has been associated with an increased incidence of pseudocyesis.³

In Ouj’s study of pseudocyesis in Nigeria, the author postulated that an educated woman does not endure the same stress of fertility as an uneducated woman; she is already respected in her society and will not be rejected if she does not have children.³

Mrs. X’s ethnic background and continued close ties with sub-Saharan Africa are notable: Her background is one that is typically associated with pseudocyesis. She is from an developing country, did not complete higher education, was ostracized by her mother-in-law because of her inability to conceive, and was told several times, during her visits to Ghana, that she was indeed pregnant.

Mrs. X noted a strong desire to conceive for her husband and family and carried with her perhaps an even stronger fear of loss of marriage and female identity—which has been bolstered by the importance placed on the woman’s raison d’être in the family by her cultural upbringing.^3,6,9-11,15 What Mrs. X never made clear, however, was whether she wanted another child at her age and in the setting of having many friends and rewarding full-time employment.

Epidemiology of pseudocyesis worldwide has been evaluated in a handful of studies. As compiled by Cohen,⁸ the prevalence of pseudocyesis in Boston, Massachusetts, was 1/22,000 births, whereas it was dramatically higher in Sudan (1/160 women who had previously been managed for reproductive failure).¹ This discrepancy in prevalance is consistent with current theories on patient characteristics that lead to increased incidence of pseudocyesis in underdeveloped nations. A 1951 study at an academic hospital in Philadelphia, Pennsylvania, noted 27 cases of pseudocyesis in maternity admissions during the study period—an incidence of 1 in 250.¹⁹ Of note, 85% of cases were of African American heritage; in 89% of cases, the woman had been trying to conceive for as long as 17 years.

Avoiding confrontation

Initially, Mrs. X was resistant to talking with a psychiatrist; this is consistent with studies showing that a patient can be suspicious and even hostile when a clinician attempts to engage her in mental health treatment.^10,16 The patient interprets the physical sensations she experiences during pseudocyesis, for example, as a real pregnancy, a perception that is contradicted by medical testing.

It is important to understand this conflict and to avoid confronting the patient directly about false beliefs; confrontation has been shown to be detrimental to patient recovery. Instead, offer the patient alternatives to her symptoms (ie, sensations of abdominal movement also can be caused by indigestion), while not directly discounting her experiences.^6,9 Indeed, from early on in the study of pseudocyesis, there have been many reports of resolution of symptoms when the physician helped the patient understand that she is not pregnant.^20,21

OUTCOME Supportive therapy

Mrs. X is seen for outpatient psychiatry follow-up several weeks after hospitalization. She acknowledges that, although she still thought pregnancy is possible, she is willing to entertain the idea that there could be another medical explanation for her symptoms.

Mrs. X is provided with supportive therapy techniques, and her marital and societal stressors are discussed. Psychotropic medications are considered, but eventually deemed unnecessary; the treatment team is concerned that Mrs. X, who remains wary of mental health providers, would view the offer of medication as offensive.

Mrs. X is seen in the gynecology clinic approximately 2 weeks later; there, a diagnosis of secondary anovulation is made and a workup for PCOS initiated.

Subsequent review of the medical record states that, during further follow-up with gynecology, Mrs. X no longer believes that she is pregnant.

Mrs. X, age 43, gravida 4 para 1, is a married woman of sub-Saharan African heritage with a history of idiopathic hypertension, uterine leiomyomas, and multiple spontaneous miscarriages. She has no psychiatric history and had never been evaluated by a mental health professional. Mrs. X is well known to the hospital’s emergency room and obstetrics and gynecology services for several presentations claiming to be pregnant, continuously, over the last 11 months, despite evidence—several negative serum beta human chorionic gonadotropin (ß-hCG) tests and transvaginal sonograms—to the contrary.

Mrs. X reports that after feeling ill for “a few days,” she began to believe that she was “losing [her] mucous plug” and needed urgent evaluation in preparation for the delivery of her “child.” She again is given a ß-hCG test, which is negative, as well as a negative transvaginal sonogram.

Mrs. X’s blood pressure is 220/113 mm Hg, and she emergently receives captopril, 25 mg sublingually, which lowers her systolic blood pressure to 194 mm Hg. The internal medicine team learns that Mrs. X stopped taking her blood pressure medications, lisinopril and hydrochlorothiazide, approximately 2 weeks earlier because she “didn’t want it [the antihypertensive agents] to hurt [her] baby.”

What explains Mrs. X’s belief that she is pregnant?

a) polycystic ovary syndrome (PCOS)
b) delusional disorder
c) bipolar I disorder
d) somatic symptom disorder

The authors’ observations

Pseudocyesis is a psychosomatic condition with an estimated incidence of 1 in 160 maternity admissions in many African countries and 1 in 22,000 in the United States.¹ According to DSM-5, pseudocyesis is a false belief of being pregnant along with signs and symptoms of pregnancy.²

Pseudocyesis is more common in:

• developing countries
• areas of low socioeconomic status with minimal education
• societies that place great importance on childbirth
• areas with low access to care.³

The primary presenting symptoms are changes in menses, enlarging abdomen, awareness of fetal movement, enlarged and tender breasts, galactorrhea, and weight gain.⁴

The exact pathophysiology of the disorder has not been determined, but we believe the psychosomatic hypothesis offers the most compelling explanation. According to this hypothesis, intense social pressures, such as an overwhelming desire to become pregnant because of cultural considerations, personal reasons, or both, could alter the normal function of the hypothalamic-pituitary-ovarian axis,⁵ which could result in physical manifestations of pregnancy. Tarín et al¹ found that rodents with chronic psychosocial stress had decreased brain norepinephrine and dopamine activity and elevated plasma levels of norepinephrine. This can translate to human models, in which a deficit or dysfunction of catecholaminergic activity in the brain could lead to increased pulsatile gonadotropin-releasing hormone, luteinizing hormone (LH), prolactin, and an elevated LH:follicle-stimulating hormone ratio.¹ These endocrine changes could induce traits found in most women with pseudocyesis, such as hypomenorrhea or amenorrhea, diurnal or nocturnal hyperprolactinemia (or both), and galactorrhea.¹

How would you approach Mrs. X’s care?

a) confront her with the negative pregnancy tests
b) admit her to the inpatient psychiatric unit
c) begin antipsychotic therapy
d) discharge her with outpatient follow-up

EVALUATION A curse on her

Although Mrs. X initially refused to see the psychiatry team, she is more receptive on hospital Day 3. Mrs. X reports that she and her husband had been trying to have a child since they were married 17 years earlier. She had a child with another man before she met her husband, causing her in-laws in Africa to become suspicious that she is intentionally not producing a child for her husband. She had 3 spontaneous abortions since her marriage; these added stress to the relationship because the couple would feel elated when learning of a pregnancy and increasingly devastated with each miscarriage.

Mrs. X reports that she and her husband have been seeing a number of reproductive endocrinologists for 7 years to try to become pregnant. She reports feeling that these physicians are not listening to her or giving her adequate treatment, which is why she has not been able to become pregnant. At the time of the evaluation, she reports that she is pregnant, and the tests have been negative because her mother-in-law placed a “curse” on her. This “curse” caused the baby to be invisible to the laboratory tests and sonograms.

During the psychiatric evaluation, Mrs. X displays her protuberant abdomen and says that she feels the fetus kicking. In addition, she also reports amenorrhea and breast tenderness and engorgement.

During her hospital stay, Mrs. X’s mental status exam does not demonstrate signs or symptoms of a mood disorder, bipolar disorder, or psychosis. Nonetheless, she remains delusional and holds to her fixed false belief of being pregnant. She refuses to be swayed by evidence that she is not pregnant. Despite this, clinicians build enough rapport that Mrs. X agrees to follow up with psychiatry in the outpatient clinic after discharge.

The internal medicine team is apprehensive that Mrs. X will continue to refuse anti­hypertensive medications out of concern that the medications would harm her pregnancy, as she had in the hospital. She remains hypertensive, with average systolic blood pressure in the 180 to 200 mm Hg range; however, after much discussion with her and her family members, she agrees to try amlodipine, 5 mg/d, a category C drug. She says that she will adhere to the medication if she does not experience any side effects.

Mrs. X is discharged on hospital Day 4 to outpatient follow-up.

The authors’ observations

When considering a diagnosis of pseudocyesis, the condition should be distinguished from others with similar presentations. Before beginning a psychiatric evaluation, a normal pregnancy must be ruled out. This is easily done with a positive urine or serum ß-hCG and an abdominal or transvaginal ultrasound. Pseudocyesis can be differentiated from:

• delusion of pregnancy (sometimes referred to as psychotic pregnancy)—a delusional disorder often seen in psychotic illness without any physical manifestations of pregnancy
• pseudopregnancy (sometimes referred to as erroneous pseudocyesis), another rare condition in which signs and symptoms of pregnancy are manifested^1,6,7 but the patient does not have a delusion of pregnancy.

Pseudocyesis, in contrast, comprises the delusion of pregnancy and physical manifestations.² These distinctions could be difficult to make clinically; for example, an increase in abdominal girth could be a result of pseudocyesis or obesity. In the setting of physical manifestations of pregnancy, a diagnosis of pseudocyesis is more likely  (Table¹).

Patients with pseudocyesis exhibit subjective and objective findings of pregnancy, such as abdominal distension, enlarged breasts, enhanced pigmentation, lordotic posture, cessation of menses, morning sickness, and weight gain.^8,9 Furthermore, approximately 1% of pseudocyesis patients have false labor, as Mrs. X did.¹⁰ Typically, the duration of these symptoms range from a few weeks to 9 months. In some cases, symptoms can last longer¹¹; at admission, Mrs. X reported that she was 11 months pregnant. She saw nothing wrong with this assertion, despite knowing that human gestation lasts 9 months.

In delusion of pregnancy, a patient might exhibit abdominal distension and cessation of menses but have no other objective findings of pregnancy.⁷ Rather than being a somatoform disorder such as pseudocyesis, a delusion of pregnancy is a symptom of psychosis or, rarely, dementia.¹²

Pseudopregnancy is a somatic state resembling pregnancy that can arise from a variety of medical conditions. A full medical workup and intensive mental status and cognitive evaluation are necessary for diagnostic clarity. Although the pathology and workup of delusional pregnancy is beyond the scope of this article, we suggest Seeman¹³ for a review and Chatterjee et al¹⁴ and Tarín et al¹ for guidance on making the diagnosis.

Theories about pathophysiology

As with many psychosomatic conditions, the pathological process of pseudocyesis originally was thought of in a psychodynamic context. Several psychodynamic theories have been proposed, including instances in which the internal desire to be pregnant is strong enough to induce a series of physiological changes akin to the state of pregnancy.⁶

Other examiners of pseudocyesis have noted its development from fears and societal pressure, including the loss of companionship or “womanhood.”^6,9 Last, the tenuous interplay of desire for a child and substantial fear of pregnancy appears to play a role in many cases.^9-11 Rosenberg et al¹⁵ reported on a teenager with pseudocyesis who desired to be pregnant to appease her husband and family, but feared pregnancy and the implications of having a child at such a young age. As this team wrote, “this pregnancy sans child fulfilled the needs of the entire family, at least temporarily.”¹⁵

Prevailing modern theories behind the somatic presentations of these patients hinge on an imbalance of the hypothalamic-pituitary-adrenal axis.⁹ Although this remains the area of ongoing research, most literature has not shown a consistent change or trend in laboratory levels of hormones associated with pseudocyesis.¹⁶ Tarín et al,¹ however, did show a similar hormonal profile between patients with pseudocyesis and those with PCOS. Although urine or serum pregnancy testing and ultrasonography are indicated to rule out pseudopregnancy, we see no benefit in obtaining other lab work in most cases beyond that of a general medical workup, because such evaluations are not helpful in diagnosis or treatment.

Mrs. X’s abdomen was protuberant and she displayed the typical linea nigra of pregnancy. Many authors have theorized the physiological mechanism behind the abdominal enlargement to include contraction of the diaphragm, which reduces the abdominal cavity and forces the bowel outwards. As abdominal fat increases, the patient becomes constipated, and the bowel becomes distended.^10,16 Although the cause of our patient’s abdominal enlargement was not pursued, we note that the literature reported that the abdominal enlargement disappears when the patient is under general anesthesia.^10,16,17

Characteristics of pseudocyesis

Bivin and Klinger’s 1937 compilation of >400 cases of pseudocyesis over nearly 200 years remains a landmark in the study of this condition.¹⁸ In their analysis, patients range in age from 20 to 44; >75% were married. The authors noted that many of the women they studied had borne children previously. Further social and psychological studies came from this breakthrough article, which shed light on the dynamics of pseudocyesis in many patients with the condition.

According to Koic,¹¹ pseudocyesis is a form of conversion disorder with underlying depression. This theory is based on literature reports of patients displaying similar personal, cultural, and social factors. These similarities, although not comprehensive, are paramount in both the diagnosis and treatment of this condition.

Often, pseudocyesis presents in patients with lower education and socioeconomic status.^1,3,11 This is particularly true in developing nations in sub-Saharan Africa and the Indian subcontinent. Case reports, cross-sectional, and longitudinal studies from these developing nations in particular note the extremely high stress placed on women to produce children for their husbands and family in male-dominated society; it is common for a woman to be rejected by her husband and family if she is unable to reproduce.³

The effect of a lower level of education on development of pseudocyesis appears to be multifactorial:

• Lack of understanding of the human body and reproductive health can lead to misperception of signs of pregnancy and bodily changes
• Low education correlates with poor earnings and worse prenatal care; delayed or no prenatal care also has been associated with an increased incidence of pseudocyesis.³

In Ouj’s study of pseudocyesis in Nigeria, the author postulated that an educated woman does not endure the same stress of fertility as an uneducated woman; she is already respected in her society and will not be rejected if she does not have children.³

Mrs. X’s ethnic background and continued close ties with sub-Saharan Africa are notable: Her background is one that is typically associated with pseudocyesis. She is from an developing country, did not complete higher education, was ostracized by her mother-in-law because of her inability to conceive, and was told several times, during her visits to Ghana, that she was indeed pregnant.

Mrs. X noted a strong desire to conceive for her husband and family and carried with her perhaps an even stronger fear of loss of marriage and female identity—which has been bolstered by the importance placed on the woman’s raison d’être in the family by her cultural upbringing.^3,6,9-11,15 What Mrs. X never made clear, however, was whether she wanted another child at her age and in the setting of having many friends and rewarding full-time employment.

Epidemiology of pseudocyesis worldwide has been evaluated in a handful of studies. As compiled by Cohen,⁸ the prevalence of pseudocyesis in Boston, Massachusetts, was 1/22,000 births, whereas it was dramatically higher in Sudan (1/160 women who had previously been managed for reproductive failure).¹ This discrepancy in prevalance is consistent with current theories on patient characteristics that lead to increased incidence of pseudocyesis in underdeveloped nations. A 1951 study at an academic hospital in Philadelphia, Pennsylvania, noted 27 cases of pseudocyesis in maternity admissions during the study period—an incidence of 1 in 250.¹⁹ Of note, 85% of cases were of African American heritage; in 89% of cases, the woman had been trying to conceive for as long as 17 years.

Avoiding confrontation

Initially, Mrs. X was resistant to talking with a psychiatrist; this is consistent with studies showing that a patient can be suspicious and even hostile when a clinician attempts to engage her in mental health treatment.^10,16 The patient interprets the physical sensations she experiences during pseudocyesis, for example, as a real pregnancy, a perception that is contradicted by medical testing.

It is important to understand this conflict and to avoid confronting the patient directly about false beliefs; confrontation has been shown to be detrimental to patient recovery. Instead, offer the patient alternatives to her symptoms (ie, sensations of abdominal movement also can be caused by indigestion), while not directly discounting her experiences.^6,9 Indeed, from early on in the study of pseudocyesis, there have been many reports of resolution of symptoms when the physician helped the patient understand that she is not pregnant.^20,21

OUTCOME Supportive therapy

Mrs. X is seen for outpatient psychiatry follow-up several weeks after hospitalization. She acknowledges that, although she still thought pregnancy is possible, she is willing to entertain the idea that there could be another medical explanation for her symptoms.

Mrs. X is provided with supportive therapy techniques, and her marital and societal stressors are discussed. Psychotropic medications are considered, but eventually deemed unnecessary; the treatment team is concerned that Mrs. X, who remains wary of mental health providers, would view the offer of medication as offensive.

Mrs. X is seen in the gynecology clinic approximately 2 weeks later; there, a diagnosis of secondary anovulation is made and a workup for PCOS initiated.

Subsequent review of the medical record states that, during further follow-up with gynecology, Mrs. X no longer believes that she is pregnant.

Mrs. X, age 43, gravida 4 para 1, is a married woman of sub-Saharan African heritage with a history of idiopathic hypertension, uterine leiomyomas, and multiple spontaneous miscarriages. She has no psychiatric history and had never been evaluated by a mental health professional. Mrs. X is well known to the hospital’s emergency room and obstetrics and gynecology services for several presentations claiming to be pregnant, continuously, over the last 11 months, despite evidence—several negative serum beta human chorionic gonadotropin (ß-hCG) tests and transvaginal sonograms—to the contrary.

Mrs. X reports that after feeling ill for “a few days,” she began to believe that she was “losing [her] mucous plug” and needed urgent evaluation in preparation for the delivery of her “child.” She again is given a ß-hCG test, which is negative, as well as a negative transvaginal sonogram.

Mrs. X’s blood pressure is 220/113 mm Hg, and she emergently receives captopril, 25 mg sublingually, which lowers her systolic blood pressure to 194 mm Hg. The internal medicine team learns that Mrs. X stopped taking her blood pressure medications, lisinopril and hydrochlorothiazide, approximately 2 weeks earlier because she “didn’t want it [the antihypertensive agents] to hurt [her] baby.”

What explains Mrs. X’s belief that she is pregnant?

a) polycystic ovary syndrome (PCOS)
b) delusional disorder
c) bipolar I disorder
d) somatic symptom disorder

The authors’ observations

Pseudocyesis is a psychosomatic condition with an estimated incidence of 1 in 160 maternity admissions in many African countries and 1 in 22,000 in the United States.¹ According to DSM-5, pseudocyesis is a false belief of being pregnant along with signs and symptoms of pregnancy.²

Pseudocyesis is more common in:

• developing countries
• areas of low socioeconomic status with minimal education
• societies that place great importance on childbirth
• areas with low access to care.³

The primary presenting symptoms are changes in menses, enlarging abdomen, awareness of fetal movement, enlarged and tender breasts, galactorrhea, and weight gain.⁴

The exact pathophysiology of the disorder has not been determined, but we believe the psychosomatic hypothesis offers the most compelling explanation. According to this hypothesis, intense social pressures, such as an overwhelming desire to become pregnant because of cultural considerations, personal reasons, or both, could alter the normal function of the hypothalamic-pituitary-ovarian axis,⁵ which could result in physical manifestations of pregnancy. Tarín et al¹ found that rodents with chronic psychosocial stress had decreased brain norepinephrine and dopamine activity and elevated plasma levels of norepinephrine. This can translate to human models, in which a deficit or dysfunction of catecholaminergic activity in the brain could lead to increased pulsatile gonadotropin-releasing hormone, luteinizing hormone (LH), prolactin, and an elevated LH:follicle-stimulating hormone ratio.¹ These endocrine changes could induce traits found in most women with pseudocyesis, such as hypomenorrhea or amenorrhea, diurnal or nocturnal hyperprolactinemia (or both), and galactorrhea.¹

How would you approach Mrs. X’s care?

a) confront her with the negative pregnancy tests
b) admit her to the inpatient psychiatric unit
c) begin antipsychotic therapy
d) discharge her with outpatient follow-up

EVALUATION A curse on her

Although Mrs. X initially refused to see the psychiatry team, she is more receptive on hospital Day 3. Mrs. X reports that she and her husband had been trying to have a child since they were married 17 years earlier. She had a child with another man before she met her husband, causing her in-laws in Africa to become suspicious that she is intentionally not producing a child for her husband. She had 3 spontaneous abortions since her marriage; these added stress to the relationship because the couple would feel elated when learning of a pregnancy and increasingly devastated with each miscarriage.

Mrs. X reports that she and her husband have been seeing a number of reproductive endocrinologists for 7 years to try to become pregnant. She reports feeling that these physicians are not listening to her or giving her adequate treatment, which is why she has not been able to become pregnant. At the time of the evaluation, she reports that she is pregnant, and the tests have been negative because her mother-in-law placed a “curse” on her. This “curse” caused the baby to be invisible to the laboratory tests and sonograms.

During the psychiatric evaluation, Mrs. X displays her protuberant abdomen and says that she feels the fetus kicking. In addition, she also reports amenorrhea and breast tenderness and engorgement.

During her hospital stay, Mrs. X’s mental status exam does not demonstrate signs or symptoms of a mood disorder, bipolar disorder, or psychosis. Nonetheless, she remains delusional and holds to her fixed false belief of being pregnant. She refuses to be swayed by evidence that she is not pregnant. Despite this, clinicians build enough rapport that Mrs. X agrees to follow up with psychiatry in the outpatient clinic after discharge.

The internal medicine team is apprehensive that Mrs. X will continue to refuse anti­hypertensive medications out of concern that the medications would harm her pregnancy, as she had in the hospital. She remains hypertensive, with average systolic blood pressure in the 180 to 200 mm Hg range; however, after much discussion with her and her family members, she agrees to try amlodipine, 5 mg/d, a category C drug. She says that she will adhere to the medication if she does not experience any side effects.

Mrs. X is discharged on hospital Day 4 to outpatient follow-up.

The authors’ observations

When considering a diagnosis of pseudocyesis, the condition should be distinguished from others with similar presentations. Before beginning a psychiatric evaluation, a normal pregnancy must be ruled out. This is easily done with a positive urine or serum ß-hCG and an abdominal or transvaginal ultrasound. Pseudocyesis can be differentiated from:

• delusion of pregnancy (sometimes referred to as psychotic pregnancy)—a delusional disorder often seen in psychotic illness without any physical manifestations of pregnancy
• pseudopregnancy (sometimes referred to as erroneous pseudocyesis), another rare condition in which signs and symptoms of pregnancy are manifested^1,6,7 but the patient does not have a delusion of pregnancy.

Pseudocyesis, in contrast, comprises the delusion of pregnancy and physical manifestations.² These distinctions could be difficult to make clinically; for example, an increase in abdominal girth could be a result of pseudocyesis or obesity. In the setting of physical manifestations of pregnancy, a diagnosis of pseudocyesis is more likely  (Table¹).

Patients with pseudocyesis exhibit subjective and objective findings of pregnancy, such as abdominal distension, enlarged breasts, enhanced pigmentation, lordotic posture, cessation of menses, morning sickness, and weight gain.^8,9 Furthermore, approximately 1% of pseudocyesis patients have false labor, as Mrs. X did.¹⁰ Typically, the duration of these symptoms range from a few weeks to 9 months. In some cases, symptoms can last longer¹¹; at admission, Mrs. X reported that she was 11 months pregnant. She saw nothing wrong with this assertion, despite knowing that human gestation lasts 9 months.

In delusion of pregnancy, a patient might exhibit abdominal distension and cessation of menses but have no other objective findings of pregnancy.⁷ Rather than being a somatoform disorder such as pseudocyesis, a delusion of pregnancy is a symptom of psychosis or, rarely, dementia.¹²

Pseudopregnancy is a somatic state resembling pregnancy that can arise from a variety of medical conditions. A full medical workup and intensive mental status and cognitive evaluation are necessary for diagnostic clarity. Although the pathology and workup of delusional pregnancy is beyond the scope of this article, we suggest Seeman¹³ for a review and Chatterjee et al¹⁴ and Tarín et al¹ for guidance on making the diagnosis.

Theories about pathophysiology

As with many psychosomatic conditions, the pathological process of pseudocyesis originally was thought of in a psychodynamic context. Several psychodynamic theories have been proposed, including instances in which the internal desire to be pregnant is strong enough to induce a series of physiological changes akin to the state of pregnancy.⁶

Other examiners of pseudocyesis have noted its development from fears and societal pressure, including the loss of companionship or “womanhood.”^6,9 Last, the tenuous interplay of desire for a child and substantial fear of pregnancy appears to play a role in many cases.^9-11 Rosenberg et al¹⁵ reported on a teenager with pseudocyesis who desired to be pregnant to appease her husband and family, but feared pregnancy and the implications of having a child at such a young age. As this team wrote, “this pregnancy sans child fulfilled the needs of the entire family, at least temporarily.”¹⁵

Prevailing modern theories behind the somatic presentations of these patients hinge on an imbalance of the hypothalamic-pituitary-adrenal axis.⁹ Although this remains the area of ongoing research, most literature has not shown a consistent change or trend in laboratory levels of hormones associated with pseudocyesis.¹⁶ Tarín et al,¹ however, did show a similar hormonal profile between patients with pseudocyesis and those with PCOS. Although urine or serum pregnancy testing and ultrasonography are indicated to rule out pseudopregnancy, we see no benefit in obtaining other lab work in most cases beyond that of a general medical workup, because such evaluations are not helpful in diagnosis or treatment.

Mrs. X’s abdomen was protuberant and she displayed the typical linea nigra of pregnancy. Many authors have theorized the physiological mechanism behind the abdominal enlargement to include contraction of the diaphragm, which reduces the abdominal cavity and forces the bowel outwards. As abdominal fat increases, the patient becomes constipated, and the bowel becomes distended.^10,16 Although the cause of our patient’s abdominal enlargement was not pursued, we note that the literature reported that the abdominal enlargement disappears when the patient is under general anesthesia.^10,16,17

Characteristics of pseudocyesis

Bivin and Klinger’s 1937 compilation of >400 cases of pseudocyesis over nearly 200 years remains a landmark in the study of this condition.¹⁸ In their analysis, patients range in age from 20 to 44; >75% were married. The authors noted that many of the women they studied had borne children previously. Further social and psychological studies came from this breakthrough article, which shed light on the dynamics of pseudocyesis in many patients with the condition.

According to Koic,¹¹ pseudocyesis is a form of conversion disorder with underlying depression. This theory is based on literature reports of patients displaying similar personal, cultural, and social factors. These similarities, although not comprehensive, are paramount in both the diagnosis and treatment of this condition.

Often, pseudocyesis presents in patients with lower education and socioeconomic status.^1,3,11 This is particularly true in developing nations in sub-Saharan Africa and the Indian subcontinent. Case reports, cross-sectional, and longitudinal studies from these developing nations in particular note the extremely high stress placed on women to produce children for their husbands and family in male-dominated society; it is common for a woman to be rejected by her husband and family if she is unable to reproduce.³

The effect of a lower level of education on development of pseudocyesis appears to be multifactorial:

• Lack of understanding of the human body and reproductive health can lead to misperception of signs of pregnancy and bodily changes
• Low education correlates with poor earnings and worse prenatal care; delayed or no prenatal care also has been associated with an increased incidence of pseudocyesis.³

In Ouj’s study of pseudocyesis in Nigeria, the author postulated that an educated woman does not endure the same stress of fertility as an uneducated woman; she is already respected in her society and will not be rejected if she does not have children.³

Mrs. X’s ethnic background and continued close ties with sub-Saharan Africa are notable: Her background is one that is typically associated with pseudocyesis. She is from an developing country, did not complete higher education, was ostracized by her mother-in-law because of her inability to conceive, and was told several times, during her visits to Ghana, that she was indeed pregnant.

Mrs. X noted a strong desire to conceive for her husband and family and carried with her perhaps an even stronger fear of loss of marriage and female identity—which has been bolstered by the importance placed on the woman’s raison d’être in the family by her cultural upbringing.^3,6,9-11,15 What Mrs. X never made clear, however, was whether she wanted another child at her age and in the setting of having many friends and rewarding full-time employment.

Epidemiology of pseudocyesis worldwide has been evaluated in a handful of studies. As compiled by Cohen,⁸ the prevalence of pseudocyesis in Boston, Massachusetts, was 1/22,000 births, whereas it was dramatically higher in Sudan (1/160 women who had previously been managed for reproductive failure).¹ This discrepancy in prevalance is consistent with current theories on patient characteristics that lead to increased incidence of pseudocyesis in underdeveloped nations. A 1951 study at an academic hospital in Philadelphia, Pennsylvania, noted 27 cases of pseudocyesis in maternity admissions during the study period—an incidence of 1 in 250.¹⁹ Of note, 85% of cases were of African American heritage; in 89% of cases, the woman had been trying to conceive for as long as 17 years.

Avoiding confrontation

Initially, Mrs. X was resistant to talking with a psychiatrist; this is consistent with studies showing that a patient can be suspicious and even hostile when a clinician attempts to engage her in mental health treatment.^10,16 The patient interprets the physical sensations she experiences during pseudocyesis, for example, as a real pregnancy, a perception that is contradicted by medical testing.

It is important to understand this conflict and to avoid confronting the patient directly about false beliefs; confrontation has been shown to be detrimental to patient recovery. Instead, offer the patient alternatives to her symptoms (ie, sensations of abdominal movement also can be caused by indigestion), while not directly discounting her experiences.^6,9 Indeed, from early on in the study of pseudocyesis, there have been many reports of resolution of symptoms when the physician helped the patient understand that she is not pregnant.^20,21

OUTCOME Supportive therapy

Mrs. X is seen for outpatient psychiatry follow-up several weeks after hospitalization. She acknowledges that, although she still thought pregnancy is possible, she is willing to entertain the idea that there could be another medical explanation for her symptoms.

Mrs. X is provided with supportive therapy techniques, and her marital and societal stressors are discussed. Psychotropic medications are considered, but eventually deemed unnecessary; the treatment team is concerned that Mrs. X, who remains wary of mental health providers, would view the offer of medication as offensive.

Mrs. X is seen in the gynecology clinic approximately 2 weeks later; there, a diagnosis of secondary anovulation is made and a workup for PCOS initiated.

Subsequent review of the medical record states that, during further follow-up with gynecology, Mrs. X no longer believes that she is pregnant.

CASE: Agitation

Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.

On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.

In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.

The authors’ observations

Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).^1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).³

Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,⁴ although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.

Table

DSM-IV-TR diagnostic criteria for delirium

Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.⁵ In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.⁶

EVALUATION: Confounding results

The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.

Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.

Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.⁷ After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.

The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.

Figure 1: Representative sample of triphasic waves

This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common

Figure 2: Mrs. M’s EEG results

This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines

The authors’ observations

Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.⁸

Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al⁹ described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.

Interpreting EEG

EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.^10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.^10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).

A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”¹³ The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”⁶

At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.

OUTCOME: Cause still unknown

By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.

Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.

The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.

The authors’ observations

We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).

We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”^9,12,14-16

This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.

Related Resources

• Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
• Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.

Drug Brand Names

• Clonazepam • Klonopin
• Docusate • Surfak
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Levothyroxine • Levoxyl, Synthtoid
• Venlafaxine XR • Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.

CASE: Agitation

Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.

On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.

In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.

The authors’ observations

Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).^1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).³

Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,⁴ although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.

Table

DSM-IV-TR diagnostic criteria for delirium

Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.⁵ In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.⁶

EVALUATION: Confounding results

The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.

Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.

Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.⁷ After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.

The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.

Figure 1: Representative sample of triphasic waves

This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common

Figure 2: Mrs. M’s EEG results

This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines

The authors’ observations

Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.⁸

Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al⁹ described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.

Interpreting EEG

EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.^10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.^10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).

A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”¹³ The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”⁶

At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.

OUTCOME: Cause still unknown

By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.

Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.

The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.

The authors’ observations

We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).

We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”^9,12,14-16

This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.

Related Resources

• Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
• Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.

Drug Brand Names

• Clonazepam • Klonopin
• Docusate • Surfak
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Levothyroxine • Levoxyl, Synthtoid
• Venlafaxine XR • Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.

CASE: Agitation

Mrs. M, age 39, presents to the emergency department (ED) with altered mental status. She is escorted by her husband and the police. She has a history of severe alcohol dependence, bipolar disorder (BD), anxiety, borderline personality disorder (BPD), hypothyroidism, and bulimia, and had gastric bypass surgery 4 years ago. Her husband called 911 when he could no longer manage Mrs. M’s agitated state. The police found her to be extremely paranoid, restless, and disoriented. Her husband reports that she shouted “the world is going to end” before she escaped naked into her neighborhood streets.

On several occasions Mrs. M had been admitted to the same hospital for alcohol withdrawal and dependence with subsequent liver failure, leading to jaundice, coagulopathy, and ascites. During these hospitalizations, she exhibited poor behavioral tendencies, unhealthy psychological defenses, and chronic maladaptive coping and defense mechanisms congruent with her BPD diagnosis. Specifically, she engaged in splitting of hospital staff, ranging from extreme flattery to overt devaluation and hostility. Other defense mechanisms included denial, distortion, acting out, and passive-aggressive behavior. During these admissions, Mrs. M often displayed deficits in recall and attention on Mini-Mental State Examination (MMSE), but these deficits were associated with concurrent alcohol use and improved rapidly during her stay.

In her current presentation, Mrs. M’s mental status change is more pronounced and atypical compared with earlier admissions. Her outpatient medication regimen includes lamotrigine, 100 mg/d, levothyroxine, 88 mcg/d, venlafaxine extended release (XR), 75 mg/d, clonazepam, 3 mg/d, docusate as needed for constipation, and a daily multivitamin.

The authors’ observations

Delirium is a disturbance of consciousness manifested by a reduced clarity of awareness (impairment in attention) and change in cognition (impairment in orientation, memory, and language).^1,2 The disturbance develops over a short time and tends to fluctuate during the day. Delirium is a direct physiological consequence of a general medical condition, substance use (intoxication or withdrawal), or both (Table).³

Delirium generally is a reversible mental disorder but can progress to irreversible brain damage. Prompt and accurate diagnosis of delirium is essential,⁴ although the condition often is underdiagnosed or misdiagnosed because of lack of recognition.

Table

DSM-IV-TR diagnostic criteria for delirium

Patients who have convoluted histories, such as Mrs. M, are common and difficult to manage and treat. These patients become substantially more complex when they are admitted to inpatient medical or surgical services. The need to clarify between delirium (primarily medical) and depression (primarily psychiatric) becomes paramount when administering treatment and evaluating decision-making capacity.⁵ In Mrs. M’s case, internal medicine, neurology, and psychiatry teams each had a different approach to altered mental status. Each team’s different terminology, assessment, and objectives further complicated an already challenging case.⁶

EVALUATION: Confounding results

The ED physicians offer a working diagnosis of acute mental status change, administer IV lorazepam, 4 mg, and order restraints for Mrs. M’s severe agitation. Her initial vital signs reveal slightly elevated blood pressure (140/90 mm Hg) and tachycardia (115 beats per minute). Internal medicine clinicians note that Mrs. M is not in acute distress, although she refuses to speak and has a small amount of dried blood on her lips, presumably from a struggle with the police before coming to the hospital, but this is not certain. Her abdomen is not tender; she has normal bowel sounds, and no asterixis is noted on neurologic exam. Physical exam is otherwise normal. A noncontrast head CT scan shows no acute process. Initial lab values show elevations in ammonia (277 μg/dL) and γ-glutamyl transpeptidase (68 U/L). Thyroid-stimulating hormone is 1.45 mlU/L, prothrombin time is 19.5 s, partial thromboplastin time is 40.3 s, and international normalized ratio is 1.67. The internal medicine team admits Mrs. M to the intensive care unit (ICU) for further management of her mental status change with alcohol withdrawal or hepatic encephalopathy as the most likely etiologies.

Mrs. M’s husband says that his wife has not consumed alcohol in the last 4 months in preparation for a possible liver transplant; however, past interactions with Mrs. M’s family suggest they are unreliable. The Clinical Institute Withdrawal Assessment (CIWA) protocol is implemented in case her symptoms are caused by alcohol withdrawal. Her vital signs are stable and IV lorazepam, 4 mg, is administered once for agitation. Mrs. M’s husband also reports that 1 month ago his wife underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure for portal hypertension. Outpatient psychotropics (lamotrigine, 100 mg/d, and venlafaxine XR, 75 mg/d) are restarted because withdrawal from these drugs may exacerbate her symptoms. In the ICU Mrs. M experiences a tonic-clonic seizure with fecal incontinence and bitten tongue, which results in a consultation from neurology and the psychiatry consultation-liaison service.

Psychiatry recommends withholding psychotropics, stopping CIWA, and using vital sign parameters along with objective signs of diaphoresis and tremors as indicators of alcohol withdrawal for lorazepam administration. Mrs. M receives IV haloperidol, 1 mg, once during her second day in the hospital for severe agitation, but this medication is discontinued because of concern about lowering her seizure threshold.⁷ After treatment with lactulose, her ammonia levels trend down to 33 μg/dL, but her altered mental state persists with significant deficits in attention and orientation.

The neurology service performs an EEG that shows no slow-wave, triphasic waves, or epileptiform activity, which likely would be present in delirium or seizures. See Figure 1 for an example of triphasic waves on an EEG and Figure 2 for Mrs. M's EEG results. Subsequent lumbar puncture, MRI, and a second EEG are unremarkable. By the fifth hospital day, Mrs. M is calm and her paranoia has subsided, but she still is confused and disoriented. Psychiatry orders a third EEG while she is in this confused state; it shows no pathologic process. Based on these examinations, neurology posits that Mrs. M is not encephalopathic.

Figure 1: Representative sample of triphasic waves

This EEG tracing is from a 54-year-old woman who underwent prolonged abdominal surgery for lysis of adhesions during which she suffered an intraoperative left subinsular stroke followed by nonconvulsive status epilepticus. The tracing demonstrates typical morphology with the positive sharp transient preceded and followed by smaller amplitude negative deflections. Symmetric, frontal predominance of findings seen is this tracing is common

Figure 2: Mrs. M’s EEG results

This is a representative tracing of Mrs. M’s 3 EEGs revealing an 8.5 to 9 Hz dominant alpha rhythm. There is superimposed frontally dominant beta fast activity, which is consistent with known administration of benzodiazepines

The authors’ observations

Mrs. M had repeated admissions for alcohol dependence and subsequent liver failure. Her recent hospitalization was complicated by a TIPS procedure done 1 month ago. The incidence of hepatic encephalopathy in patients undergoing TIPS is >30%, especially in the first month post-procedure, which raised suspicion that hepatic encephalopathy played a significant role in Mrs. M’s delirium.⁸

Because of frequent hospitalization, Mrs. M was well known to the internal medicine, neurology, and psychiatry teams, and each used different terms to describe her mental state. Internal medicine used the phrase “acute mental status change,” which covers a broad differential. Neurology used “encephalopathy,” which also is a general term. Psychiatry used “delirium,” which has narrower and more specific diagnostic criteria. Engel et al⁹ described the delirious patient as having “cerebral insufficiency” with universally abnormal EEG. Regardless of terminology, based on Mrs. M’s acute confusion, one would expect an abnormal EEG, but repeat EEGs were unremarkable.

Interpreting EEG

EEG is one of the few tools available for measuring acute changes in cerebral function, and an EEG slowing remains a hallmark in encephalopathic processes.^10,11 Initially, the 3 specialties agreed that Mrs. M’s presentation likely was caused by underlying medical issues or substances (alcohol or others). EEG can help recognize delirium, and, in some cases, elucidate the underlying cause.^10,12 It was surprising that Mrs. M’s EEGs were normal despite a clinical presentation of delirium. Because of the normal EEG findings, neurology leaned toward a primary psychiatric (“functional”) etiology as the cause of her delirium vs a general medical condition or alcohol withdrawal (“organic”).

A literature search in regards to sensitivity of EEG in delirium revealed conflicting statements and data. A standard textbook in neurology and psychiatry states that “a normal EEG virtually excludes a toxic-metabolic encephalopathy.”¹³ The American Psychiatric Association’s (APA) practice guidelines for delirium states: “The presence of EEG abnormalities has fairly good sensitivities for delirium (in one study, the sensitivity was found to be 75%), but the absence does not rule out the diagnosis; thus the EEG is no substitute for careful clinical observation.”⁶

At the beginning of Mrs. M’s care, in discussion with the neurology and internal medicine teams, we argued that Mrs. M was experiencing delirium despite her initial normal EEG. We did not expect that 2 subsequent EEGs would be normal, especially because the teams witnessed the final EEG being performed while Mrs. M was clinically evaluated and observed to be in a state of delirium.

OUTCOME: Cause still unknown

By the 6th day of hospitalization, Mrs. M’s vitals are normal and she remains hemodynamically stable. Differential diagnosis remains wide and unclear. The psychiatry team feels she could have atypical catatonia due to an underlying mood disorder. One hour after a trial of IV lorazepam, 1 mg, Mrs. M is more lucid and fully oriented, with MMSE of 28/30 (recall was 1/3), indicating normal cognition. During the exam, a psychiatry resident notes Mrs. M winks and feigns a yawn at the medical students and nurses in the room, displaying her boredom with the interview and simplicity of the mental status exam questions. Later that evening, Mrs. M exhibits bizarre sexual gestures toward male hospital staff, including licking a male nursing staff member’s hand.

Although Mrs. M’s initial confusion resolved, the severity of her comorbid psychiatric history warrants inpatient psychiatric hospitalization. She agrees to transfer to the psychiatric ward after she confesses anxiety regarding death, intense demoralization, and guilt related to her condition and her relationship with her 12-year-old daughter. She tearfully reports that she discontinued her psychotropic medications shortly after stopping alcohol 4 months ago. Shortly before her transfer, psychiatry is called back to the medicine floor because of Mrs. M’s disruptive behavior.

The team finds Mrs. M in her hospital gown, pursuing her husband in the hallway as he is leaving, yelling profanities and blaming him for her horrible experience in the hospital. Based on her demeanor, the team determines that she is back to her baseline mental state despite her mood disorder, and that her upcoming inpatient psychiatric stay likely would be too short to address her comorbid personality disorder. The next day she signs out of the hospital against medical advice.

The authors’ observations

We never clearly identified the specific etiology responsible for Mrs. M’s delirium. We assume at the initial presentation she had toxic-metabolic encephalopathy that rapidly resolved with lactulose treatment and lowering her ammonia. She then had a single tonic-clonic seizure, perhaps related to stopping and then restarting her psychotropics. Her subsequent confusion, bizarre sexual behavior, and demeanor on her final hospital days were more indicative of her psychiatric diagnoses. We now suspect that Mrs. M’s delirium was briefer than presumed and she returned to her baseline borderline personality, resulting in some factitious staging of delirium to confuse her 3 treating teams (a psychoanalyst may say this was a form of projective identification).

We felt that if Mrs. M truly was delirious due to metabolic or hepatic dysfunction or alcohol withdrawal, she would have had abnormal EEG findings. We discovered that the notion of “75% sensitivity” of EEG abnormalities cited in the APA guidelines comes from studies that include patients with “psychogenic” and “organic” delirium. Acute manias and agitated psychoses were termed “psychogenic delirium” and acute confusion due to medical conditions or substance issues was termed “organic delirium.”^9,12,14-16

This poses a circular reasoning in the diagnostic criteria and clinical approach to delirium. The fallacy is that, according to DSM-IV-TR, delirium is supposed to be the result of a direct physiological consequence of a general medical condition or substance use (criterion D), and cannot be due to psychosis (eg, schizophrenia) or mania (eg, BD). We question the presumptive 75% sensitivity of EEG abnormalities in patients with delirium because it is possible that when some of these studies were conducted the definition of delirium was not solidified or fully understood. We suspect the sensitivity would be much higher if the correct definition of delirium according to DSM-IV-TR is used in future studies. To improve interdisciplinary communication and future research, it would be constructive if all disciplines could agree on a single term, with the same diagnostic criteria, when evaluating a patient with acute confusion.

Related Resources

• Meagher D. Delirium: the role of psychiatry. Advances in Psychiatric Treatment. 2001;7:433-442.
• Casey DA, DeFazio JV Jr, Vansickle K, et al. Delirium. Quick recognition, careful evaluation, and appropriate treatment. Postgrad Med. 1996;100(1):121-4, 128, 133-134.

Drug Brand Names

• Clonazepam • Klonopin
• Docusate • Surfak
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lorazepam • Ativan
• Levothyroxine • Levoxyl, Synthtoid
• Venlafaxine XR • Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgment

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the U.S. Government. The authors are employees of the U.S. Government. This work was prepared as part of their official duties. Title 17 U.S.C. 105 provides that “Copyright protection under this title is not available for any work of the U.S. Government.” Title 17 U.S.C. 101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.