Usha Parthasarathi, MBBS

Conducting clinical research with patients in an acute inpatient psychi­atric setting raises possible ethical dif­ficulties, in part because of concern about patients’ ability to give informed consent to participate in research.

We propose the acronym CHECK (for capacity, heredity, ethics, coercion-free, and knowledge) to provide researchers with guid­ance on the process of addressing informed consent in an acute inpatient setting.

Capacity. Ensure that the patient has the decisional capacity to:

• understand disclosed information about proposed research
• appreciate the impact of participation and nonparticipation
• reason about risks and benefits of participation
• communicate a consistent choice.¹

The standards for disclosing informa­tion to a potential participant are higher for research than in clinical practice, because patients must understand and accept ran­domization, placebo control, blinding, and possible exposure to non-approved treat­ment interventions—yet there is a balance regarding how much information is neces­sary for consent in a given situation.²

Be mindful that the severity of the patient’s psychiatric illness can impair understanding and insight that might pre­clude giving informed consent (eg, major depression can produce a slowing of intel­lectual processes; mania can display dis­tractibility; schizophrenia can compromise decisional capacity because of disorga­nized thinking or delusions; and neuro­cognitive disorders can affect the ability to process information).

The MacArthur Competence Assessment Tool for Clinical Research, designed as an aid to assessing capacity, has the most empirical support, although other instru­ments might be equally or better suited to some situations.¹

Heredity. When undertaking human genetic and genomic research, create a precise, robust consent process. Genome sequencing studies can reveal information about the health of patients and their families, provoking discussion about appropriate protections for such data. Informed consent should include:

• how the data will be used now and in the future
• the extent to which patients can control future use of the data
• benefits and risks of participation, including the potential for unknown future risks
• what information, including incidental findings, will be returned to the patient
• what methods will be used to safe­guard genetic testing data.³

Ethics. Researchers are bound by a code of ethics:

• Patients have the right to decline par­ticipation in research and to withdraw at any stage without prejudice; exclusion rec­ognizes the need to protect those who may be incapable of exercising that right.² Avoid research with dissenting patients, whether or not they are considered capable.² Do not rou­tinely invite treatment-refusing patients to participate in research projects, other than in extraordinary circumstances; eg, treatment refusing patients who have been adjudicated as “incompetent,” in which case the court-appointed surrogate decision-maker could be approached for informed consent. You should routinely seek a legal opinion in such a circumstance.

• Unless the research is examining inter­ventions for acute and disabling psychiatric illness, consent should not be sought until patients are well enough to make an informed decision. However, clinical assessment is always needed (despite psychiatric illness category) because it cannot be assumed that psychiatric patients are unable to make such a decision (eg, in some cases, substance abuse should not automatically eliminate a partici­pant, as long as the patient retains adequate cognitive status for informed consent).

• Capacity for consent is not “all-or-nothing,” but is specific to the research para­digm. In cases of impaired decisional capacity, researchers can obtain informed consent by obtaining agreement of family, legal represen­tative, or caregiver; therefore, research with assenting adults, who are nonetheless incapa­ble, is unlikely to be regarded as unethical.²

Coercion-free. Avoid covert pressures:
• Ensure that consent is given freely without coercion or duress. This is impor­tant if the participant has a physician-patient relationship with a member of the research team. Exercise caution when research meth­ods involve physical contact. Such contact, in incapable patients—even those who assent— could create a medico-legal conflict (eg, tak­ing a blood sample specific for research purposes without consent could result in a charge of battery).² When in doubt, seek a legal opinion before enrolling decisionally incapable patients (and/or those adjudicated as incompetent) in research trials.

• Consider that participation be initi­ated by a third party (eg, an approach from a staff member who is not part of their care team and not involved in the research to ask if the potential participant has made a deci­sion that he wants to have communicated to the researcher⁴).

• Require that a family member, legal representative, or caregiver be present at the time of consent with decisionally incapaci­tated patients.

Knowledge. The participant must be given adequate information about the project. Understand consent as an ongoing process occurring within a specific context:

• Give participants a fair explanation of the proposed project, the risks and ben­efits that might ensue, and, when applicable, what appropriate procedures may be offered if the participant experiences discomfort. If a study is to be blinded, patients must under­stand and appreciate that they could receive no benefit at all.

• Consider the importance of using appropriate language, repeating informa­tion, ensuring adequate time for ques­tions and answers, and providing written material to the patient.² Avoid leaving the patient alone with an information sheet to avoid coercion, because this risks deny­ing patients the opportunity to participate because they lack the occasion to receive information and ask questions.⁴ Rather, go over the research consent document item by item with the patient in an iterative pro­cess, encouraging questions. Ensure private individual discussion between study team members and the patient to address ques­tions related to the study.⁴

• Reapproach patients to discuss or revisit consent as needed, because their capacity to provide informed consent may vary over time. This is especially important in CNS ill­nesses, in which the level of cognitive func­tion is variable. An item such as “consent status” for each encounter can be added to the checklist.

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

Conducting clinical research with patients in an acute inpatient psychi­atric setting raises possible ethical dif­ficulties, in part because of concern about patients’ ability to give informed consent to participate in research.

We propose the acronym CHECK (for capacity, heredity, ethics, coercion-free, and knowledge) to provide researchers with guid­ance on the process of addressing informed consent in an acute inpatient setting.

Capacity. Ensure that the patient has the decisional capacity to:

• understand disclosed information about proposed research
• appreciate the impact of participation and nonparticipation
• reason about risks and benefits of participation
• communicate a consistent choice.¹

The standards for disclosing informa­tion to a potential participant are higher for research than in clinical practice, because patients must understand and accept ran­domization, placebo control, blinding, and possible exposure to non-approved treat­ment interventions—yet there is a balance regarding how much information is neces­sary for consent in a given situation.²

Be mindful that the severity of the patient’s psychiatric illness can impair understanding and insight that might pre­clude giving informed consent (eg, major depression can produce a slowing of intel­lectual processes; mania can display dis­tractibility; schizophrenia can compromise decisional capacity because of disorga­nized thinking or delusions; and neuro­cognitive disorders can affect the ability to process information).

The MacArthur Competence Assessment Tool for Clinical Research, designed as an aid to assessing capacity, has the most empirical support, although other instru­ments might be equally or better suited to some situations.¹

Heredity. When undertaking human genetic and genomic research, create a precise, robust consent process. Genome sequencing studies can reveal information about the health of patients and their families, provoking discussion about appropriate protections for such data. Informed consent should include:

• how the data will be used now and in the future
• the extent to which patients can control future use of the data
• benefits and risks of participation, including the potential for unknown future risks
• what information, including incidental findings, will be returned to the patient
• what methods will be used to safe­guard genetic testing data.³

Ethics. Researchers are bound by a code of ethics:

• Patients have the right to decline par­ticipation in research and to withdraw at any stage without prejudice; exclusion rec­ognizes the need to protect those who may be incapable of exercising that right.² Avoid research with dissenting patients, whether or not they are considered capable.² Do not rou­tinely invite treatment-refusing patients to participate in research projects, other than in extraordinary circumstances; eg, treatment refusing patients who have been adjudicated as “incompetent,” in which case the court-appointed surrogate decision-maker could be approached for informed consent. You should routinely seek a legal opinion in such a circumstance.

• Unless the research is examining inter­ventions for acute and disabling psychiatric illness, consent should not be sought until patients are well enough to make an informed decision. However, clinical assessment is always needed (despite psychiatric illness category) because it cannot be assumed that psychiatric patients are unable to make such a decision (eg, in some cases, substance abuse should not automatically eliminate a partici­pant, as long as the patient retains adequate cognitive status for informed consent).

• Capacity for consent is not “all-or-nothing,” but is specific to the research para­digm. In cases of impaired decisional capacity, researchers can obtain informed consent by obtaining agreement of family, legal represen­tative, or caregiver; therefore, research with assenting adults, who are nonetheless incapa­ble, is unlikely to be regarded as unethical.²

Coercion-free. Avoid covert pressures:
• Ensure that consent is given freely without coercion or duress. This is impor­tant if the participant has a physician-patient relationship with a member of the research team. Exercise caution when research meth­ods involve physical contact. Such contact, in incapable patients—even those who assent— could create a medico-legal conflict (eg, tak­ing a blood sample specific for research purposes without consent could result in a charge of battery).² When in doubt, seek a legal opinion before enrolling decisionally incapable patients (and/or those adjudicated as incompetent) in research trials.

• Consider that participation be initi­ated by a third party (eg, an approach from a staff member who is not part of their care team and not involved in the research to ask if the potential participant has made a deci­sion that he wants to have communicated to the researcher⁴).

• Require that a family member, legal representative, or caregiver be present at the time of consent with decisionally incapaci­tated patients.

Knowledge. The participant must be given adequate information about the project. Understand consent as an ongoing process occurring within a specific context:

• Give participants a fair explanation of the proposed project, the risks and ben­efits that might ensue, and, when applicable, what appropriate procedures may be offered if the participant experiences discomfort. If a study is to be blinded, patients must under­stand and appreciate that they could receive no benefit at all.

• Consider the importance of using appropriate language, repeating informa­tion, ensuring adequate time for ques­tions and answers, and providing written material to the patient.² Avoid leaving the patient alone with an information sheet to avoid coercion, because this risks deny­ing patients the opportunity to participate because they lack the occasion to receive information and ask questions.⁴ Rather, go over the research consent document item by item with the patient in an iterative pro­cess, encouraging questions. Ensure private individual discussion between study team members and the patient to address ques­tions related to the study.⁴

• Reapproach patients to discuss or revisit consent as needed, because their capacity to provide informed consent may vary over time. This is especially important in CNS ill­nesses, in which the level of cognitive func­tion is variable. An item such as “consent status” for each encounter can be added to the checklist.

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

Conducting clinical research with patients in an acute inpatient psychi­atric setting raises possible ethical dif­ficulties, in part because of concern about patients’ ability to give informed consent to participate in research.

We propose the acronym CHECK (for capacity, heredity, ethics, coercion-free, and knowledge) to provide researchers with guid­ance on the process of addressing informed consent in an acute inpatient setting.

Capacity. Ensure that the patient has the decisional capacity to:

• understand disclosed information about proposed research
• appreciate the impact of participation and nonparticipation
• reason about risks and benefits of participation
• communicate a consistent choice.¹

The standards for disclosing informa­tion to a potential participant are higher for research than in clinical practice, because patients must understand and accept ran­domization, placebo control, blinding, and possible exposure to non-approved treat­ment interventions—yet there is a balance regarding how much information is neces­sary for consent in a given situation.²

Be mindful that the severity of the patient’s psychiatric illness can impair understanding and insight that might pre­clude giving informed consent (eg, major depression can produce a slowing of intel­lectual processes; mania can display dis­tractibility; schizophrenia can compromise decisional capacity because of disorga­nized thinking or delusions; and neuro­cognitive disorders can affect the ability to process information).

The MacArthur Competence Assessment Tool for Clinical Research, designed as an aid to assessing capacity, has the most empirical support, although other instru­ments might be equally or better suited to some situations.¹

Heredity. When undertaking human genetic and genomic research, create a precise, robust consent process. Genome sequencing studies can reveal information about the health of patients and their families, provoking discussion about appropriate protections for such data. Informed consent should include:

• how the data will be used now and in the future
• the extent to which patients can control future use of the data
• benefits and risks of participation, including the potential for unknown future risks
• what information, including incidental findings, will be returned to the patient
• what methods will be used to safe­guard genetic testing data.³

Ethics. Researchers are bound by a code of ethics:

• Patients have the right to decline par­ticipation in research and to withdraw at any stage without prejudice; exclusion rec­ognizes the need to protect those who may be incapable of exercising that right.² Avoid research with dissenting patients, whether or not they are considered capable.² Do not rou­tinely invite treatment-refusing patients to participate in research projects, other than in extraordinary circumstances; eg, treatment refusing patients who have been adjudicated as “incompetent,” in which case the court-appointed surrogate decision-maker could be approached for informed consent. You should routinely seek a legal opinion in such a circumstance.

• Unless the research is examining inter­ventions for acute and disabling psychiatric illness, consent should not be sought until patients are well enough to make an informed decision. However, clinical assessment is always needed (despite psychiatric illness category) because it cannot be assumed that psychiatric patients are unable to make such a decision (eg, in some cases, substance abuse should not automatically eliminate a partici­pant, as long as the patient retains adequate cognitive status for informed consent).

• Capacity for consent is not “all-or-nothing,” but is specific to the research para­digm. In cases of impaired decisional capacity, researchers can obtain informed consent by obtaining agreement of family, legal represen­tative, or caregiver; therefore, research with assenting adults, who are nonetheless incapa­ble, is unlikely to be regarded as unethical.²

Coercion-free. Avoid covert pressures:
• Ensure that consent is given freely without coercion or duress. This is impor­tant if the participant has a physician-patient relationship with a member of the research team. Exercise caution when research meth­ods involve physical contact. Such contact, in incapable patients—even those who assent— could create a medico-legal conflict (eg, tak­ing a blood sample specific for research purposes without consent could result in a charge of battery).² When in doubt, seek a legal opinion before enrolling decisionally incapable patients (and/or those adjudicated as incompetent) in research trials.

• Consider that participation be initi­ated by a third party (eg, an approach from a staff member who is not part of their care team and not involved in the research to ask if the potential participant has made a deci­sion that he wants to have communicated to the researcher⁴).

• Require that a family member, legal representative, or caregiver be present at the time of consent with decisionally incapaci­tated patients.

Knowledge. The participant must be given adequate information about the project. Understand consent as an ongoing process occurring within a specific context:

• Give participants a fair explanation of the proposed project, the risks and ben­efits that might ensue, and, when applicable, what appropriate procedures may be offered if the participant experiences discomfort. If a study is to be blinded, patients must under­stand and appreciate that they could receive no benefit at all.

• Consider the importance of using appropriate language, repeating informa­tion, ensuring adequate time for ques­tions and answers, and providing written material to the patient.² Avoid leaving the patient alone with an information sheet to avoid coercion, because this risks deny­ing patients the opportunity to participate because they lack the occasion to receive information and ask questions.⁴ Rather, go over the research consent document item by item with the patient in an iterative pro­cess, encouraging questions. Ensure private individual discussion between study team members and the patient to address ques­tions related to the study.⁴

• Reapproach patients to discuss or revisit consent as needed, because their capacity to provide informed consent may vary over time. This is especially important in CNS ill­nesses, in which the level of cognitive func­tion is variable. An item such as “consent status” for each encounter can be added to the checklist.

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Many substances that are not typically thought of as “substances of abuse” possess—when adequate­ly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of alcohol, psychostimulants, opioids, Cannabis, and hallucinogens, you may encounter psychiatric phenomena resulting from abuse of more obscure substances, including culinary spices.

The clinician treating a patient in an apparent intoxicated state who has a negative drug screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il­licit substances or those with ready access to large amounts of spices, such as prisoners, young patients, and those working in the food service industry.

Abuse of spices can be a problematic diagnosis
Patients may misuse culinary spices to achieve euphoria, or a “natural high.” They may present with medical or psychiat­ric symptoms, including acute altered mental status, but the psychoactive substances are not identified on routine toxicol­ogy studies. In addition, patients may not attribute their use of spices for psychoactive effect to “drugs,” because these materials are legal and readily available. This may lead to misdiagnosis of a systemic medical disorder or a primary psy­chiatric illness to explain the patient’s symptoms and initiat­ing a psychotropic agent and other psychiatric services when a substance abuse program might be a more appropriate clini­cal intervention.

Some spices contain psychoactive compounds that can alter CNS function (Table^1-7), might be abused for recreational purposes, and can be toxic in an excessive amount. Internet resources, including anonymous web-based communications, and anecdotal materials about non-traditional recreational drugs, are available to anyone with Internet access.⁸ However, little research has been conducted into the preva­lence of abuse (Box)⁹ and spices’ psychoactive properties. The lack of toxicology detection of spices in the medical setting presents a di­agnostic challenge.

The psychoactive plants used in “natural high” products mainly are psychoactively inactive in their natural form, but extracts or alkaloids obtained from them might induce 1 or more of 3 classifications of psychoactivity:
   • stimulant
   • sedative
   • hallucinogenic.

Many of these substances are considered to be aphrodisiac, and some may be abused to increase sexual function.

The following is a review of common spic­es that have been reported to possess poten­tial psychoactive properties.

Nutmeg
Nutmeg (Myristica fragrans) is a common and easily accessible means of reaching euphoria in adults.¹⁰ The aromatic oil of nutmeg contains myristicin, a psychoactive substance that is chemically similar to hal­lucinogenic compounds such as mescaline. Its psychoactive effects could be attributed to metabolic formation of amphetamine de­rivatives from its core ingredients, elemicin, myristicin, and safrole.^11,12

Nutmeg and its active component, my­risticin, produce central monoamine oxi­dase (MAO) inhibition as evidenced by the ability to lower the convulsive dose of IV tryptamine in mice and to increase brain 5-hydroxytryptamine concentra­tions.^13,14 Although myristicin’s potency is not comparable to that of the more potent MAO inhibitors such as tranylcypromine and iproniazid (which is not available in the United States), it seems adequate when compared with its low toxicity.¹⁴ Nutmeg extract is associated with a significant anti­depressant effect in mice, which seemed to be mediated by interaction with the adren­ergic, dopaminergic, and serotonergic sys­tems.¹³ Nutmeg is associated with sustained increase in sexual activity in animal studies, with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses clinically significant aphrodisiac activity.¹⁵

Psychoactive effects can be achieved by ingesting 5 to 15 g of nutmeg.¹¹ Acute nut­meg intoxication produces palpitations, dizziness, anxiety, and hallucinations, mostly resolving within 24 hours, while effects of chronic abuse are reported to be similar to Cannabis use, including euphoria, giddiness, anxiety, fear, sense of impending doom, detachment, confabulation, and hal­lucinations.^11,16 Urine drug screens are nega­tive unless other psychoactive substances have been ingested.¹⁷

Suspected nutmeg intoxication or poison­ing should be treated with supportive treat­ment. Use sedatives with caution because of alternating periods of delirium and obtunda­tion during nutmeg intoxication.¹⁷

In case reports, myristicin poisoning induced CNS neuromodulatory signs that mimicked an anticholinergic hyperstimula­tion state.^12,18 Fatal myristicin poisoning is rare; 2 cases have been reported, 1 in com­bination with flunitrazepam (not available in the United States).^19,20 Nutmeg also has sedative properties and can cause GI symp­toms when ingesting excessive amounts.^1,20,21 Grover et al²¹ described no harmful effects on blood pressure and electrocardiogram; how­ever, Shah et al²² reported palpitations and dry mouth.

Vanilla
Vanilla (species of the genus Vanilla) con­tains piperonal, also known as heliotropin.¹ Piperonal has aromatherapeutic qualities that might elevate mood and well-being. In the early 1990s, the Memorial Sloan- Kettering Cancer Center in New York City described heliotropin as a powerful aroma­therapy tool. Patients who were undergo­ing an MRI in an environment scented with heliotropin demonstrated a 63% reduction in anxiety compared with those who were not exposed to fragrance.²³ The Smell and Taste Treatment and Research Foundation in Chicago found that vanilla can promote sexual arousal.²⁴

Short-term effects of vanillin—a major component of vanilla—include a feeling of relaxation and reduced stress; long-term use can produce an antidepressant effect.¹ There are no reports of vanilla abuse to achieve these effects; however, patients might abuse vanilla extract because of its alcohol content (up to 35% ethanol).²⁵

Fennel
The essential oil of fennel (Foeniculum vul­gare) can be neurotoxic and epileptogenic. Skalli and colleagues recently reported a case of seizure induction in a young woman after ingesting cakes containing fennel oil.²⁶ Fennel oil also has been reported to have significant interaction with the fluoroquinolone-type antibiotics. Be aware of adverse effects associ­ated with fennel ingestion; question patients if atypical seizures or reactions to antibiotics occur.²⁷

Spices such as fennel, dill, cinnamon, saf­fron, and anise also contain psychoactive substances that are chemically similar to my­risticin, which can induce sedation, stimula­tion, or hallucinations.⁷

Black pepper
Piperine, which gives black pepper (Piper ni­grum) its spiciness, enhances thermogenesis of lipid metabolism, accelerates energy me­tabolism, and increases serotonin and endor­phin production in the brain.28 Black pepper is reported to potentiate γ-aminobutyric acid A receptor subtypes,²⁹ and could present possible applications for treating insomnia, epilepsy, and anxiety disorders.

Cloves
Non-culinary uses of clove (Syzygium aro­maticum, a tree in the myrtle family) include flavored cigarettes. However, in 2009 clove cigarettes were banned in the United States as part of a public policy to reduce the number of children who start smoking.³⁰ Eugenol, which constitutes as much as 90% of the essential oil extracted from cloves (and is responsible for the aroma), can cause hepatotoxicity³¹ and palpitations³²; it can be toxic in quantities as low as 5 mL.³³ Eugenol is present in other spic­es, such as nutmeg and cinnamon, and has been reported to have sedative properties.¹

Mace
Mace is made from the covering of nutmeg (Myristica fragrans) seeds. It has a strong aro­ma resembling that of nutmeg. Whole mace contains 4% to 14% of a volatile oil similar to that found in nutmeg. Because mace con­tains the same oils that make nutmeg psy­choactive1 in excessive amounts—although nutmeg seeds are more potent—be aware of the psychoactive potential of mace.

CinnamonCassia cinnamon (Cinnamomum aromaticum) is spicier and tarter than Ceylon cinnamon (Cinnamomum zeylanicum), which has a more flowery aroma. The 2 types of cinnamon can be distinguished by their different chemical composition. Ceylon cinnamon contains eu­genol and benzyl benzoate; cassia cinnamon contains coumarin.³ Eugenol is reported to have sedative effects.¹ Coumarin is a precur­sor molecule in the synthesis of a number of synthetic anticoagulant pharmaceuticals, including coumadin. Because of the toxic component of coumarin, European health agencies have warned against consuming high amounts of cassia.³⁴ There are no re­ports of side effects arising from the occa­sional use of cinnamon as a spice. 

In a study by Frydman-Marom et al,³⁵ cinnamon extract (CEppt) was found to act on the CNS by inhibiting development of Alzheimer’s disease in animal models.

Asarone
Asarone is found in the Asarum family of spices that includes Acorus calamus. Asarone is chemically similar to mescaline. Although anecdotal reports indicate that A. calamus is a hallucinogen, research shows no evidence that it contains hallucinogenic substances.³⁶ Han et al³⁷ reported an antidepressant ef­fect with the essential oil and asarones for the rhizomes of Acorus tatarinowii. In ani­mal studies, asarone was found to reduce spontaneous motor activity, and even in low doses, reduced anxiety without decreasing acuity of perception.³⁸

Ginger
Ginger (Zingiber officinale) is regarded as a sedative, general stimulant, and aphrodisi­ac.^1,4,5 Its main constituents are phenolic com­pounds such as gingerols and shogaols, and sesquiterpenes such as zingiberene.⁴ Ginger is an inhibitor of thromboxane synthetase, a property shared by tricyclic antidepressants.³⁹

Research indicates that 9 compounds found in ginger may interact with the serotonin 5-HT1A receptor, suggesting a possible mechanism for reducing anxiety.⁴⁰ A study by Nievergelt et al⁴¹ indicates that by binding to human serotonin receptors, gin­ger might influence GI function. Ginger ex­tract contains a cholinergic and spasmogenic component, which provides a mechanistic insight for the prokinetic action of ginger.⁴⁰

Turmeric
Turmeric (Curcuma longa) has been investigat­ed for possible benefit in Alzheimer’s disease⁴²; research into curcumin, the active substance of turmeric, is increasing. Although the original report was retracted after publication, cur­cumin was reported to selectively bind to hu­man cannabinoid receptors type 1 (CB1) with nanomolar affinities and to function as an an­tagonist/inverse agonist.⁴³ However, Gertsch et al⁴⁴ found that curcumin did not interact functionally with the CB1 receptor, although this compound appears to share ability of the CB1 receptor inverse agonist.

Galangal
Major constituents identified in the galan­gal (or galanga) rhizome and leaf oil were 1,8-cineole, and β-pinene and cam­phor.6 Galangal, a member of the ginger (Zingiberaceae) family, interacts with MAO inhibitors, H2 receptor antagonists, and pro­ton-pump inhibitors.¹ Anxiolytic, hallucino­genic, and stimulant properties have been reported.1 An excessive amount can induce diarrhea, dizziness, nausea, and vomiting.¹

Saffron
Stigma of saffron (a member of the family Iridaceae) was found to be significantly more effective than placebo and equally as effica­cious as fluoxetine and imipramine in treat­ing depression. Saffron petal was found to be significantly more effective than placebo and as effective as fluoxetine and saffron stigma in a recent systematic review.^45-48

Asafetida
Asafetida (Ferula assa-foetida), when combined with valerian root, is used as a sedative to treat hyperactivity.² The active ingredients of asafet­ida are the resin, endogenous gum, essential oil, propenyl-isobutylsulfide, umbelliferone, and vanillin. Several of the volatile constitu­ents produce a sedative effect.² Additive ef­fects can occur between the hypotensive property of asafetida and dopamine receptor agonists such as bromocriptine mesylate. Use caution when combining asafetida in conjunc­tion with a CNS depressant or a stimulant.² 

Recommendations for treating spice-abusers
Patients may present to psychiatry ser­vices with psychological and physiologi­cal evidence of intoxication with culinary spices that may mimic 1) abuse of other substances, 2) primary psychiatric illness, and 3) primary medical illness. When you encounter a patient with a new psychiat­ric symptom, consider inquiring about the abuse of spices.

Patients might abuse more than 1 spice; a comprehensive screening approach might therefore be useful. Caution patients that in­gesting these substance to excess can have harmful effects. Consider appropriate psy­chopharmacotherapy for underlying psy­chiatric symptoms to help patients who use spices maladaptively to self-medicate psy­chiatric symptoms.

Consider abuse of culinary spices in clini­cal presentations of psychiatric symptoms that do not seem adequate for a diagnosis of a primary anxiety, mood, or psychotic disorder, or in cases atypical psychiatric presentations that are—perhaps to your surprise—associat­ed with negative toxicology studies for com­mon, more familiar substances of abuse.

Physicians practicing in an environment where street drugs are difficult to obtain (eg, prisons) should consider monitoring for possible abuse of spices. Based on the available, albeit limited, literature, it ap­pears that most culinary spice–associated intoxication can be managed:
   • with an elevated level of clinical suspicion
   • by ruling out other causes of intoxication
   • using targeted, empirical psychophar­macotherapy to manage symptoms
   • with supportive care that includes close psychiatric follow-up.

Consider comorbid abuse of other, more familiar substances of abuse in patients who misuse spices. As with inhalant abuse, the concept of “substance abuse” in clinical practice may need to be further expanded to include patients who abuse culinary spices. Patients could be screened for psychiatric illnesses known to increase the risk of sub­stance abuse. These might include—but are not limited to:
   • comorbid psychotic disorders
   • mood disorders, particularly bipolar disorders
   • trauma- and stressor-related disor­ders, particularly posttraumatic stress disorder
   • personality disorders, particularly anti­social, borderline, and narcissistic personality disorders.

Pending the availability of population-based studies on abuse of culinary spices, the usual cautions regarding substance abuse seem to be appropriate when caring for these patients. Assessment for and man­agement of comorbid psychiatric conditions is essential in the comprehensive psychiatric care of patients who abuse substances.

Last, general consideration of a 12-step recovery program appears warranted for these patients; the self-reflection and group support of such programs can be useful in helping patients control their use of these substances. 

Bottom Line
Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. Consideration and questioning for abuse of spices is necessary to ascertain the psychoactive effects of these substances when used surreptitiously. Management should follow substance abuse treatment protocols: inquiry into patterns of problematic use and readiness to change, assessment and management of psychiatric comorbidity, and referral to a recovery program.
 

Related Resources
• Srinivasan K. Role of spices beyond food flavoring: nu­traceuticals with multiple health effects. Food Reviews International. 2005;21(2):167-188.
• Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup­board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2.

Drug Brand Names
Bromocriptine mesylate • Parlodel         Imipramine • Tofrani
Flunitrazepam • Rohypnol                     Iproniazid • Marsilid
Fluoxetine • Prozac                               Tranylcypromine • Parnate

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

Clinicians often are unaware of a patient’s misuse or abuse of easily accessible substances such as spices, herbs, and natural supplements. This can lead to misdiagnosed severe psychiatric disorders and, more alarmingly, unnecessary use of long-term psychotropics and psychiatric services.

Excessive ingestion of nutmeg (Myristica fragrans) can produce psychiatric symptoms because it contains myristicin, a psychoactive substance, in its aromatic oil.¹ It is structurally similar to other hallucinogenic compounds such as mescaline. The effects of nutmeg could be attributed to metabolic formation of amphetamine derivatives from its core ingredients: elemicin, myristicin, and safrole.^1-3 However, neither amphetamine derivatives nor core ingredients are detected in the urine of patients suspected of abusing nutmeg, which makes diagnosis challenging.

We present a case of nutmeg abuse leading to psychotic depression.

Nutmeg and depression

Mr. D, age 50, is admitted to our inpatient psychiatric unit with severe dysphoria, hopelessness, persecutory delusions, suicidal ideation, and a sense of impending doom for the third time in 2 years. At previous admissions, he was diagnosed with bipolar disorder.

During his first admission, Mr. D reported an intentional overdose by water intoxication; laboratory studies revealed  hyponatremia, liver dysfunction, abnormal cardiac markers, increased creatine kinase, and leukocytosis with neutrophilia. With supportive treatment, all parameters returned to the normal range within 7 days.

At his third admission, Mr. D describes an extensive history of nutmeg abuse. He reports achieving desirable psychoactive effects such as excitement, euphoria, enhanced sensory perceptions, and racing thoughts within a half hour of ingesting 1 teaspoon (5 g) of nutmeg; effects lasted for 6 hours. He reports that consuming 2 teaspoons (10 g) produced a “stronger” effect, and that 1 tablespoon (15 g) was associated with severe dysphoria, fear, psychosis, suicidal ideation, and behavior, which led to his psychiatric admissions. He denies any other substance use.

Urine drug screen and other routine laboratory investigations are negative. Symptoms resolve spontaneously within 3 days and he is managed without pharmacotherapy. The diagnosis is revised to substance-induced mood disorder with psychotic features. We provide psychoeducation about nutmeg’s psychoactive effects, and Mr. D is motivated to stop abusing nutmeg. Three years later he remains in good health.

Effects of nutmeg

Acute nutmeg intoxication produces anxiety, fear, and hallucinations, and generally is self-limited, with most symptoms resolving within 24 hours.² Chronic effects of nutmeg abuse resemble those of marijuana abuse (Table 1). Acute and long-term physical effects are listed in Table 2. 

Be alert for presentations of a ‘natural high’

Nutmeg, other spices, and herbs can be used by persons looking for a ”natural high”; as we saw with Mr. D, nutmeg abuse can present as a mood disorder resembling bipolar disorder. An acute, atypical presentation of mood changes or suicidal ideation should prompt you to investigate causes other than primary mood or psychotic disorders, and should include consideration of the effects of atypical drugs—and spices—of abuse.

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

Clinicians often are unaware of a patient’s misuse or abuse of easily accessible substances such as spices, herbs, and natural supplements. This can lead to misdiagnosed severe psychiatric disorders and, more alarmingly, unnecessary use of long-term psychotropics and psychiatric services.

Excessive ingestion of nutmeg (Myristica fragrans) can produce psychiatric symptoms because it contains myristicin, a psychoactive substance, in its aromatic oil.¹ It is structurally similar to other hallucinogenic compounds such as mescaline. The effects of nutmeg could be attributed to metabolic formation of amphetamine derivatives from its core ingredients: elemicin, myristicin, and safrole.^1-3 However, neither amphetamine derivatives nor core ingredients are detected in the urine of patients suspected of abusing nutmeg, which makes diagnosis challenging.

We present a case of nutmeg abuse leading to psychotic depression.

Nutmeg and depression

Mr. D, age 50, is admitted to our inpatient psychiatric unit with severe dysphoria, hopelessness, persecutory delusions, suicidal ideation, and a sense of impending doom for the third time in 2 years. At previous admissions, he was diagnosed with bipolar disorder.

During his first admission, Mr. D reported an intentional overdose by water intoxication; laboratory studies revealed  hyponatremia, liver dysfunction, abnormal cardiac markers, increased creatine kinase, and leukocytosis with neutrophilia. With supportive treatment, all parameters returned to the normal range within 7 days.

At his third admission, Mr. D describes an extensive history of nutmeg abuse. He reports achieving desirable psychoactive effects such as excitement, euphoria, enhanced sensory perceptions, and racing thoughts within a half hour of ingesting 1 teaspoon (5 g) of nutmeg; effects lasted for 6 hours. He reports that consuming 2 teaspoons (10 g) produced a “stronger” effect, and that 1 tablespoon (15 g) was associated with severe dysphoria, fear, psychosis, suicidal ideation, and behavior, which led to his psychiatric admissions. He denies any other substance use.

Urine drug screen and other routine laboratory investigations are negative. Symptoms resolve spontaneously within 3 days and he is managed without pharmacotherapy. The diagnosis is revised to substance-induced mood disorder with psychotic features. We provide psychoeducation about nutmeg’s psychoactive effects, and Mr. D is motivated to stop abusing nutmeg. Three years later he remains in good health.

Effects of nutmeg

Acute nutmeg intoxication produces anxiety, fear, and hallucinations, and generally is self-limited, with most symptoms resolving within 24 hours.² Chronic effects of nutmeg abuse resemble those of marijuana abuse (Table 1). Acute and long-term physical effects are listed in Table 2. 

Be alert for presentations of a ‘natural high’

Nutmeg, other spices, and herbs can be used by persons looking for a ”natural high”; as we saw with Mr. D, nutmeg abuse can present as a mood disorder resembling bipolar disorder. An acute, atypical presentation of mood changes or suicidal ideation should prompt you to investigate causes other than primary mood or psychotic disorders, and should include consideration of the effects of atypical drugs—and spices—of abuse.

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

Clinicians often are unaware of a patient’s misuse or abuse of easily accessible substances such as spices, herbs, and natural supplements. This can lead to misdiagnosed severe psychiatric disorders and, more alarmingly, unnecessary use of long-term psychotropics and psychiatric services.

Excessive ingestion of nutmeg (Myristica fragrans) can produce psychiatric symptoms because it contains myristicin, a psychoactive substance, in its aromatic oil.¹ It is structurally similar to other hallucinogenic compounds such as mescaline. The effects of nutmeg could be attributed to metabolic formation of amphetamine derivatives from its core ingredients: elemicin, myristicin, and safrole.^1-3 However, neither amphetamine derivatives nor core ingredients are detected in the urine of patients suspected of abusing nutmeg, which makes diagnosis challenging.

We present a case of nutmeg abuse leading to psychotic depression.

Nutmeg and depression

Mr. D, age 50, is admitted to our inpatient psychiatric unit with severe dysphoria, hopelessness, persecutory delusions, suicidal ideation, and a sense of impending doom for the third time in 2 years. At previous admissions, he was diagnosed with bipolar disorder.

During his first admission, Mr. D reported an intentional overdose by water intoxication; laboratory studies revealed  hyponatremia, liver dysfunction, abnormal cardiac markers, increased creatine kinase, and leukocytosis with neutrophilia. With supportive treatment, all parameters returned to the normal range within 7 days.

At his third admission, Mr. D describes an extensive history of nutmeg abuse. He reports achieving desirable psychoactive effects such as excitement, euphoria, enhanced sensory perceptions, and racing thoughts within a half hour of ingesting 1 teaspoon (5 g) of nutmeg; effects lasted for 6 hours. He reports that consuming 2 teaspoons (10 g) produced a “stronger” effect, and that 1 tablespoon (15 g) was associated with severe dysphoria, fear, psychosis, suicidal ideation, and behavior, which led to his psychiatric admissions. He denies any other substance use.

Urine drug screen and other routine laboratory investigations are negative. Symptoms resolve spontaneously within 3 days and he is managed without pharmacotherapy. The diagnosis is revised to substance-induced mood disorder with psychotic features. We provide psychoeducation about nutmeg’s psychoactive effects, and Mr. D is motivated to stop abusing nutmeg. Three years later he remains in good health.

Effects of nutmeg

Acute nutmeg intoxication produces anxiety, fear, and hallucinations, and generally is self-limited, with most symptoms resolving within 24 hours.² Chronic effects of nutmeg abuse resemble those of marijuana abuse (Table 1). Acute and long-term physical effects are listed in Table 2. 

Be alert for presentations of a ‘natural high’

Nutmeg, other spices, and herbs can be used by persons looking for a ”natural high”; as we saw with Mr. D, nutmeg abuse can present as a mood disorder resembling bipolar disorder. An acute, atypical presentation of mood changes or suicidal ideation should prompt you to investigate causes other than primary mood or psychotic disorders, and should include consideration of the effects of atypical drugs—and spices—of abuse.

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