Sriram Ramaswamy, MD

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

[embed:render:related:node:249151]

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

[embed:render:related:node:249151]

Approximately 1 in 200 individuals will be diagnosed with schizophrenia in their lifetime.¹ DSM-5 criteria for the diagnosis of schizophrenia require the presence of ≥2 of 5 symptoms: delusions, hallucinations, disordered speech, grossly disorganized (or catatonic) behavior, and negative symptoms such as flat affect or avolition.² Multiple studies have found increased rates of cannabis use among patients with schizophrenia. Because cognitive deficits are the chief predictor of clinical outcomes and quality of life in individuals with schizophrenia, the cognitive effects of cannabis use among these patients are of clinical significance.³ As legislation increasingly allows for the sale, possession, and consumption of cannabis, it is crucial to provide clinicians with evidence-based recommendations for treating patients who regularly use cannabis (approximately 8% of the adult population³). In this article, we analyze several peer-reviewed studies to investigate the impact of cannabis use on the onset and development of schizophrenia.

A look at substance-induced psychosis

Schizophrenia is associated with several structural brain changes, and some of these changes may be influenced by cannabis use (Box⁴). The biochemical etiology of schizophrenia is poorly understood but thought to involve dopamine, glutamate, serotonin, and gamma-aminobutyric acid. Certain positive symptoms, such as hallucinations, are uniquely human and difficult to study in animal models.⁵ Psychoactive substance use, especially cannabis, is frequently comorbid with schizophrenia. Additionally, certain individuals may be more predisposed to substance-induced psychosis than others based on genetic variation and underlying brain structure changes.⁴ Substance-induced psychosis is a psychotic state following the ingestion of a psychoactive substance or drug withdrawal lasting ≥48 hours.⁶ The psychoactive effects of cannabis have been associated with an exacerbation of existing schizophrenia symptoms.⁷ In 1998, Hall⁷ proposed 2 hypotheses to explain the relationship between cannabis and psychosis. The first was that heavy consumption of cannabis triggers a specific type of cannabis psychosis.⁷ The second was that cannabis use exacerbates existing schizophrenia, making the symptoms worse.⁷ Hall⁷ concluded that there was a complicated interaction among an individual’s vulnerability to their stressors, environment, and genetics.

Box

Cannabis, COMT, and homocysteine

Great advances have been made in our ability to examine the association between genetics and metabolism. One example of this is the interaction between the catechol-O-methyltransferase (COMT) gene and the active component of cannabis, delta-9-tetra­hydrocannabinol (THC). COMT codes for an enzyme that degrades cortical dopamine. The Val158Met polymorphism of this gene increases COMT activity, leading to increased dopamine catabolism, and thus decreased levels of extracellular dopamine, which induces an increase in mesolimbic dopaminergic activity, thereby increasing susceptibility to psychosis.³

In a study that genotyped 135 patients with schizophrenia, the Val158Met polymorphism was present in 29.63% of participants.³ Because THC can induce episodes of psychosis, individuals with this polymorphism may be at a higher risk of developing schizophrenia. Compared to Met carrier control participants with similar histories of cannabis consumption, those with the Val158Met polymorphism demonstrated markedly worse performance on tests of verbal fluency and processing speed.³ This is clinically significant because cognitive impairments are a major prognostic factor in schizophrenia, and identifying patients with this polymorphism could help personalize interventions for those who consume cannabis and are at risk of developing schizophrenia.

A study that evaluated 56 patients with first-episode schizophrenia found that having a history of cannabis abuse was associated with significantly higher levels of homocysteine as well as lower levels of high-density lipoprotein and vitamin B12.⁸ Homocysteine is an agonist at the glutamate binding site and a partial antagonist at the glycine co-agonist site in the N-methyl-D-aspartate receptor, which suggests that homocysteine may contribute to hypofunctioning of glutamate transmission; this is implicated in the development of schizophrenia. These increases in homocysteine are also found in siblings of patients with schizophrenia, which indicates a possible association between the methylenetetrahydrofolate (MTHFR) gene and schizophrenia.⁸

The C677T polymorphism in MTHFR may predict the risk of developing metabolic syndrome in patients taking second-generation antipsychotics.⁸ Elevations in homocysteine by as little as 5 μmol/L may increase schizophrenia risk by 70% compared to controls, possibly due to homocysteine initiating neuronal apoptosis, catalyzing dysfunction of the mitochondria, or increasing oxidative stress.⁸ There is a positive correlation between homocysteine levels and severity of negative symptoms (P = .006) and general psychopathology (P = .008) of schizophrenia when analyzed using the Positive and Negative Syndrome Scale.⁸ Negative symptoms such as blunted affect, apathy, anhedonia, and loss of motivation significantly impact the social and economic outcomes of patients diagnosed with schizophrenia.

Research paints a mixed picture

A Danish study analyzed the rates of conversion to schizophrenia or bipolar disorder (BD) among 6,788 individuals who received a diagnosis of substance-induced psychosis from 1994 to 2014.⁶ Ten comparison participants were selected for each case participant, matched on sex and year/month of birth. Participants were followed until the first occurrence of schizophrenia or BD, death, or emigration from Denmark. Substances implicated in the initial psychotic episode included cannabis, alcohol, opioids, sedatives, cocaine, amphetamines, hallucinogens, and combinations of substances.

Continue to: The overall conversion rate...

The overall conversion rate over 20 years was 32.2% (95% CI, 29.7 to 34.9), with 26.0% developing schizophrenia vs 8.4% developing BD.⁶ Of the substances involved, cannabis was the most common, implicated in 41.2% (95% CI, 36.6 to 46.2) of cases.⁶ One-half of male patients converted within 2.0 years and one-half of female patients converted within 4.4 years after a cannabis-induced psychosis.⁶

This study had several limitations. It could not account for any short-term psychotic symptoms experienced by the general population, especially after cannabis use. Such patients might not seek treatment. Thus, the results might not be generalizable to the general population. The study did not evaluate if conversion rates differed based on continued substance use following the psychosis episode, or the amount of each substance taken prior to the episode. Dose-dependence was not well elucidated, and this study only looked at patients from Denmark and did not account for socioeconomic status.⁶

Another Danish study looked at the influences of gender and cannabis use in the early course of the disease in 133 patients with schizophrenia.⁹ These researchers found that male gender was a significant predictor of earlier onset of dysfunction socially and in the workplace, as well as a higher risk of developing negative symptoms. However, compared to gender, cannabis use was a stronger predictor of age at first psychotic episode. For cannabis users, the median age of onset of negative symptoms was 23.7, compared to 38.4 for nonusers (P < .001).⁹

Cannabis use is significantly elevated among individuals with psychosis, with a 12-month prevalence of 29.2% compared to 4.0% among the general population of the United States.¹⁰ In a study that assessed 229 patients with a schizophrenia spectrum disorder during their first hospitalization and 6 months, 2 years, 4 years, and 10 years later, Foti et al¹⁰ found that the lifetime rate of cannabis use was 66.2%. Survival analysis found cannabis use doubled the risk of the onset of psychosis compared to nonusers of the same age (hazard ratio [HR] = 1.97; 95% CI, 1.48 to 2.62, P < .001), even after adjusting for socioeconomic status, age, and gender (HR = 1.34; 95% CI, 1.01 to 1.77, P < .05).¹⁰ Additionally, Foti et al¹⁰ found significant positive correlations between psychotic symptoms and cannabis use in patients with schizophrenia over the course of 10 years. An increase in symptoms was associated with a higher likelihood of cannabis use, and a decrease in symptoms was correlated with a lower likelihood of use (adjusted odds ratio = 1.64; 95% CI, 1.12 to 2.43, P < .0125).¹⁰

Ortiz-Medina et al¹¹ conducted a meta-analysis of 22 studies of 15 cohorts from healthy populations and 12 other cohort follow-up studies that evaluated the onset of psychotic symptoms in individuals who used cannabis. Most studies found associations between cannabis use and the onset of symptoms of schizophrenia, and most determined cannabis was also a major risk factor for other psychotic disorders. Analyses of dose-dependence indicated that repeated cannabis use increased the risk of developing psychotic symptoms. This risk is increased when an individual starts using cannabis before age 15.¹¹ Age seemed to be a stronger predictor of onset and outcome than sex, with no significant differences between men and women. One study in this review found that approximately 8% to 13% cases of schizophrenia may have been solely due to cannabis.¹¹ The most significant limitation to the studies analyzed in this review is that retrospective studies utilize self-reported questionnaires.

Continue to: Other researchers have found...

Other researchers have found it would take a relatively high number of individuals to stop using cannabis to prevent 1 case of schizophrenia. In a study of data from England and Wales, Hickman et al¹² evaluated the best available estimates of the incidence of schizophrenia, rates of heavy and light cannabis use, and risk that cannabis causes schizophrenia to determine the number needed to prevent (NNP) 1 case of schizophrenia. They estimated that it would require approximately 2,800 men age 20 to 24 (90% CI, 2,018 to 4,530) and 4,700 men age 35 to 39 (90% CI, 3,114 to 8,416) who heavily used cannabis to stop their consumption to prevent 1 case of schizophrenia.¹² For women with heavy cannabis use, the mean NNP was 5,470 for women age 25 to 29 (90% CI, 3,640 to 9,839) and 10,870 for women age 35 to 39 (90% CI, 6,786 to 22,732).¹² For light cannabis users, the NNP was 4 to 5 times higher than the NNP for heavy cannabis users. This suggests that clinical interventions aimed at preventing dependence on cannabis would be more effective than interventions aimed at eliminating cannabis use.

Medical cannabis and increased potency

In recent years, the use of medical cannabis, which is used to address adverse effects of chemotherapy as well as neuropathic pain, Parkinson’s disease, and epilepsy, has been increasing.¹³ However, there is a lack of well-conducted randomized clinical trials evaluating medical cannabis’ efficacy and safety. As medical cannabis continues to gain public acceptance and more states permit its legal use, patients and physicians should be fully informed of the known adverse effects, including impaired attention, learning, and motivation.¹³

Several studies have drawn attention to the dose-dependence of many of cannabis’ effects. Since at least the 1960s, the concentration of THC in cannabis has increased substantially, thus increasing its potency. Based on 66,747 samples across 8 studies, 1 meta-analysis estimated that THC concentrations in herbal cannabis increased by 0.29% (P < .001) each year between 1970 and 2017.¹⁴ Similarly, THC concentrations in cannabis resins were found to have increased by 0.57% (P = .017) each year between 1975 and 2017.¹⁴ Cannabis products with high concentrations of THC carry an increased risk of addiction and mental health disorders.¹⁴

Identifying those at highest risk

Despite ongoing research, scientific consensus on the relationship of cannabis to schizophrenia and psychosis has yet to be reached. The disparity between the relatively high prevalence of regular adult use of cannabis (8%⁷)and the low incidence of cannabis-induced psychosis suggests that cannabis use alone is unlikely to lead to episodes of psychosis in individuals who are not predisposed to such episodes. Sarrazin et al¹⁵ evaluated 170 patients with schizophrenia, 31 of whom had cannabis use disorder. They found no significant difference in lifetime symptom dimensions between groups, and proposed that cannabis-associated schizophrenia should not be categorized as a distinct clinical entity of schizophrenia with specific features.¹⁵

Policies that encourage follow-up of patients after episodes of drug-induced psychosis may mitigate the adverse social and economic effects of schizophrenia. Currently, these policies are not widely implemented in health care institutions, possibly because psychotic symptoms may fade after the drug’s effects have dissipated. Despite this, these patients are at high risk of developing schizophrenia and self-harm. New-onset schizophrenia should be promptly identified because delayed diagnosis is associated with worse prognosis.⁶ Additionally, identifying genetic susceptibilities to schizophrenia—such as the Val158Met polymorphisms—in individuals who use cannabis could help clinicians manage or slow the onset or progression of schizophrenia.³ Motivational interviewing strategies should be used to minimize or eliminate cannabis use in individuals with active schizophrenia or psychosis, thus preventing worse outcomes.

Bottom Line

Identifying susceptibilities to schizophrenia may guide interventions in patients who use cannabis. Several large studies have suggested that cannabis use may exacerbate symptoms and worsen the prognosis of schizophrenia. Motivational interviewing strategies aimed at minimizing cannabis use may improve outcomes in patients with schizophrenia.

Related Resources

• Khokhar JY, Dwiel LL, Henricks AM, et al. The link between schizophrenia and substance use disorder: a unifying hypothesis. Schizophr Res. 2018;194:78-85. doi:10.1016/j. schres.2017.04.016
• Otite ES, Solanky A, Doumas S. Adolescents, THC, and the risk of psychosis. Current Psychiatry. 2021;20(12):e1-e2. doi:10.12788/cp.0197

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Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

CP01607034_t1.PNG

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

CP01607034_t2.PNG

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

CP01607026_t3.PNG

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

CP01607034_t1.PNG

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

CP01607034_t2.PNG

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

CP01607026_t3.PNG

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

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Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

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What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

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Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.