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Taking the route: Psychoactive properties of culinary

Intoxication and toxicity can mimic psychiatric symptoms any substances that are not typically of as “substances of abuse” possess—when adequate- Mly dosed—clinically meaningful psychoactive properties. In addition to the more familiar effects of , psychostimulants, , , and , 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 screen might ask that patient if he (she) abuses spices. This might be particularly relevant when treating patients thought to have limited access to il- licit 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 © STOCKCREATIONS Patients may misuse culinary spices to achieve , or a James A. Bourgeois, OD, MD “natural high.” They may present with medical or psychiat- Clinical Professor Vice Chair, Clinical Affairs ric symptoms, including acute altered mental status, but the Department of /Langley Porter Psychiatric Institute psychoactive substances are not identified on routine toxicol- University of California San Francisco ogy studies. In addition, patients may not attribute their use San Francisco, California of spices for psychoactive effect to “,” because these Usha Parthasarathi, MBBS materials are legal and readily available. This may lead to Assistant Clinical Professor misdiagnosis of a systemic medical disorder or a primary psy- Ana Hategan, MD chiatric illness to explain the patient’s symptoms and initiat- Associate Clinical Professor ing a psychotropic agent and other psychiatric services when • • • • a program might be a more appropriate clini- Department of Psychiatry and Behavioural Neurosciences cal intervention. Michael G. DeGroote School of Medicine Some spices contain psychoactive compounds that can Faculty of Health McMaster University 1-7 alter CNS function (Table, page 22 ), might be abused for Hamilton, Ontario, Canada

Disclosures The authors report no financial relationships with any company whose products are mentioned Current Psychiatry in this article or with manufacturers of competing products. Vol. 13, No. 4 21 Table Classification of culinary spices with psychoactive effects Botanical basis Types Active ingredients Psychoactive effects Dried , , , , hallucinogenic or , Stimulant, sedative Stimulant, sedative Abuse Stimulant of spices Dried buds Sedative Arils Myristicin Stimulant, sedative Barks , Eugenol, Stimulant, sedative /cassia Roots and Calamus Stimulant, sedative , Stimulant, sedative Sedative 1,8-cineole, β-pinene Stimulant, sedative, hallucinogenic Asafetida , gum, , Sedative Clinical Point propenyl-isobutylsulfide, umbelliferone, vanillin Some spices contain Stigmas Picrocrocin, safranal Stimulant psychoactive Source: References 1-7 compounds that can alter CNS function, might be abused, recreational purposes, and can be toxic in nutmeg contains myristicin, a psychoactive an excessive amount. Internet resources, substance that is chemically similar to hal- and can be toxic including anonymous web-based commu- lucinogenic compounds such as . nications, and anecdotal materials about non- Its psychoactive effects could be attributed traditional recreational drugs, are available to to metabolic formation of de- anyone with Internet access.8 However, little rivatives from its core ingredients, elemicin, research has been conducted into the preva- myristicin, and safrole.11,12 lence of abuse (Box)9 and spices’ psychoactive Nutmeg and its active component, my- properties. The lack of toxicology detection risticin, produce central monoamine oxi- of spices in the medical setting presents a di- dase (MAO) inhibition as evidenced by agnostic challenge. the ability to lower the convulsive dose The psychoactive used in “natural of IV in mice and to increase high” products mainly are psychoactively brain 5-hydroxytryptamine concentra- inactive in their natural form, but or tions.13,14 Although myristicin’s potency is obtained from them might induce 1 not comparable to that of the more potent or more of 3 classifications of psychoactivity: MAO inhibitors such as • stimulant and iproniazid (which is not available in • sedative the United States), it seems adequate when • hallucinogenic. compared with its low toxicity.14 Nutmeg Many of these substances are considered is associated with a significant anti- to be , and some may be abused effect in mice, which seemed to to increase sexual function. be mediated by interaction with the adren- The following is a review of common spic- ergic, , and sys- Discuss this article at es that have been reported to possess poten- tems.13 Nutmeg is associated with sustained www.facebook.com/ tial psychoactive properties. increase in sexual activity in studies, CurrentPsychiatry with no evidence of adverse effects and toxicity, suggesting that nutmeg possesses Nutmeg clinically significant aphrodisiac activity.15 Nutmeg ( fragrans) is a common Psychoactive effects can be achieved by and easily accessible means of reaching ingesting 5 to 15 g of nutmeg.11 Acute - Current Psychiatry 22 April 2014 euphoria in adults.10 The aromatic oil of meg intoxication produces palpitations, dizziness, , and , Box mostly resolving within 24 hours, while effects of chronic abuse are reported to be Abuse of spices: similar to Cannabis use, including euphoria, Prevalence unknown giddiness, anxiety, fear, of impending pidemiology of the prevalence of abuse doom, detachment, confabulation, and hal- Eof culinary spices has been limited to lucinations.11,16 Urine drug screens are nega- case reports, case series, and estimates of population use based on registry-type data tive unless other psychoactive substances (eg, 17 cases of nutmeg intoxication were have been ingested.17 reported to a Texas control registry Suspected nutmeg intoxication or poison- between 1998 and 2004).9 Because abuse ing should be treated with supportive treat- of culinary spices does not have DSM-5 nomenclature—other than substance abuse ment. Use with caution because of not otherwise classified—population-based alternating periods of and obtunda- and clinical studies on prevalence are not tion during nutmeg intoxication.17 available. However, because individual cases may present—often in acute care setting— In case reports, myristicin poisoning for clinical attention, psychiatrists and other induced CNS neuromodulatory signs that medical specialists, such as emergency mimicked an hyperstimula- physicians, should consider the possibility of Clinical Point culinary spice abuse in cases of intoxication tion state.12,18 Fatal myristicin poisoning is that otherwise escape diagnostic classification. Treat suspected rare; 2 cases have been reported, 1 in com- bination with flunitrazepam (not available nutmeg intoxication in the United States).19,20 Nutmeg also has or poisoning with sedative properties and can cause GI symp- Standard treatment for alcohol intoxica- supportive measures; toms when ingesting excessive amounts.1,20,21 tion and withdrawal is indicated in cases use sedatives with Grover et al21 described no harmful effects on of suspected vanilla abuse. caution pressure and electrocardiogram; how- ever, Shah et al22 reported palpitations and dry mouth. Fennel The essential oil of fennel (Foeniculum vul- gare) can be neurotoxic and epileptogenic. Vanilla Skalli and colleagues recently reported a case Vanilla (species of the genus Vanilla) con- of seizure induction in a young woman after tains piperonal, also known as heliotropin.1 ingesting cakes containing fennel oil.26 Fennel Piperonal has aromatherapeutic qualities oil also has been reported to have significant that might elevate mood and well-being. interaction with the fluoroquinolone-type In the early 1990s, the Memorial Sloan- . Be aware of adverse effects associ- Kettering Center in New York City ated with fennel ingestion; question patients described heliotropin as a powerful aroma- if atypical seizures or reactions to antibiotics tool. Patients who were undergo- occur.27 ing an MRI in an environment scented with Spices such as fennel, , cinnamon, saf- heliotropin demonstrated a 63% reduction fron, and also contain psychoactive in anxiety compared with those who were substances that are chemically similar to my- not exposed to fragrance.23 The Smell and risticin, which can induce sedation, stimula- Treatment and Research Foundation tion, or hallucinations.7 in Chicago found that vanilla can promote .24 Short-term effects of vanillin—a major Black pepper component of vanilla—include a feeling of Piperine, which gives black pepper ( ni- relaxation and reduced stress; long-term use grum) its spiciness, enhances thermogenesis can produce an effect.1 There of lipid , accelerates energy me- are no reports of vanilla abuse to achieve tabolism, and increases and endor- these effects; however, patients might abuse phin production in the brain.28 Black pepper vanilla extract because of its alcohol content is reported to potentiate γ-aminobutyric acid Current Psychiatry (up to 35% ).25 A receptor subtypes,29 and could present Vol. 13, No. 4 23 possible applications for treating insomnia, agencies have warned against consuming epilepsy, and anxiety disorders. high amounts of cassia.34 There are no re- ports of side effects arising from the occa- sional use of cinnamon as a spice. Cloves In a study by Frydman-Marom et al,35 Non-culinary uses of (Syzygium aro- cinnamon extract (CEppt) was found to act maticum, a in the myrtle family) include on the CNS by inhibiting development of Abuse flavored cigarettes. However, in 2009 clove Alzheimer’s in animal models. of spices cigarettes were banned in the United States as part of a public policy to reduce the number of children who start .30 Eugenol, which Asarone constitutes as much as 90% of the essential oil Asarone is found in the family of extracted from cloves (and is responsible for spices that includes Acorus calamus. Asarone the aroma), can cause hepatotoxicity31 and is chemically similar to mescaline. Although palpitations32; it can be toxic in quantities as anecdotal reports indicate that A. calamus is low as 5 mL.33 Eugenol is present in other spic- a , research shows no evidence Clinical Point es, such as nutmeg and cinnamon, and has that it contains hallucinogenic substances.36 1 37 Compounds found in been reported to have sedative properties. Han et al reported an antidepressant ef- fect with the essential oil and asarones for ginger may interact the rhizomes of Acorus tatarinowii. In ani- with the serotonin Mace mal studies, asarone was found to reduce 5-HT1A receptor, Mace is made from the covering of nutmeg spontaneous motor activity, and even in low suggesting a () seeds. It has a strong aro- doses, reduced anxiety without decreasing ma resembling that of nutmeg. Whole mace acuity of .38 possible mechanism contains 4% to 14% of a volatile oil similar for reducing anxiety to that found in nutmeg. Because mace con- tains the same oils that make nutmeg psy- Ginger choactive1 in excessive amounts—although Ginger ( officinale) is regarded as a nutmeg seeds are more potent—be aware of sedative, general stimulant, and aphrodisi- the psychoactive potential of mace. ac.1,4,5 Its main constituents are phenolic com- pounds such as gingerols and shogaols, and such as zingiberene.4 Ginger Cinnamon is an inhibitor of synthetase, a Cassia cinnamon ( aromaticum) property shared by tricyclic .39 is spicier and tarter than Ceylon cinnamon Research indicates that 9 compounds (Cinnamomum zeylanicum), which has a more found in ginger may interact with the flowery aroma. The 2 types of cinnamon can serotonin 5-HT1A receptor, suggesting a be distinguished by their different chemical possible mechanism for reducing anxiety.40 A composition. Ceylon cinnamon contains eu- study by Nievergelt et al41 indicates that by genol and benzyl benzoate; cassia cinnamon binding to human serotonin receptors, - contains coumarin.3 Eugenol is reported to ger might influence GI function. Ginger ex- have sedative effects.1 Coumarin is a precur- tract contains a cholinergic and spasmogenic sor molecule in the synthesis of a number component, which provides a mechanistic of synthetic pharmaceuticals, insight for the prokinetic action of ginger.40 including coumadin. Because of the toxic component of coumarin, European health Turmeric Turmeric (Curcuma longa) has been investigat- ed for possible benefit in Alzheimer’s disease42; For more information, go to research into curcumin, the active substance of CurrentPsychiatry.com turmeric, is increasing. Although the original report was retracted after publication, cur- Current Psychiatry nutmeg, Parthasarathi 24 April 2014 was reported to selectively bind to hu- continued on page 30 continued from page 24 man receptors type 1 (CB1) with spices that may mimic 1) abuse of other nanomolar affinities and to function as an an- substances, 2) primary psychiatric illness, tagonist/inverse .43 However, Gertsch and 3) primary medical illness. When you et al44 found that curcumin did not interact encounter a patient with a new psychiat- functionally with the CB1 receptor, although ric symptom, consider inquiring about the this compound appears to share the ability of abuse of spices. the CB1 receptor inverse agonist. Patients might abuse more than 1 spice; Abuse a comprehensive screening approach might of spices therefore be useful. Caution patients that in- Galangal gesting these substance to excess can have Major constituents identified in the galan- harmful effects. Consider appropriate psy- gal (or galanga) and leaf oil were chopharmacotherapy for underlying psy- 1,8-cineole, and β-pinene and cam- chiatric symptoms to help patients who use phor.6 Galangal, a member of the ginger spices maladaptively to self-medicate psy- () family, interacts with MAO chiatric symptoms. inhibitors, H2 receptor antagonists, and pro- Consider abuse of culinary spices in clini- Clinical Point ton-pump inhibitors.1 , hallucino- cal presentations of psychiatric symptoms Physicians practicing genic, and stimulant properties have been that do not seem adequate for a diagnosis of a reported.1 An excessive amount can induce primary anxiety, mood, or psychotic disorder, in an environment diarrhea, dizziness, , and vomiting.1 or in cases atypical psychiatric presentations where street drugs that are—perhaps to your surprise—associat- are difficult to obtain ed with negative toxicology studies for com- (eg, prisons) should Saffron mon, more familiar substances of abuse. Stigma of saffron (a member of the family Physicians practicing in an environment consider monitoring Iridaceae) was found to be significantly more where street drugs are difficult to obtain for abuse of spices effective than and equally as effica- (eg, prisons) should consider monitoring cious as and in treat- for possible abuse of spices. Based on the ing . Saffron petal was found to be available, albeit limited, literature, it ap- significantly more effective than placebo and pears that most culinary spice–associated as effective as fluoxetine and saffron stigma intoxication can be managed: in a recent systematic review.45-48 • with an elevated level of clinical suspicion • by ruling out other causes of intoxication Asafetida • using targeted, empirical psychophar- Asafetida (Ferula assa-foetida), when combined macotherapy to manage symptoms with root, is used as a sedative to treat • with supportive care that includes close hyperactivity.2 The active ingredients of asafet- psychiatric follow-up. ida are the resin, endogenous gum, essential Consider comorbid abuse of other, more oil, propenyl-isobutylsulfide, umbelliferone, familiar substances of abuse in patients and vanillin. Several of the volatile constitu- who misuse spices. As with abuse, ents produce a sedative effect.2 Additive ef- the concept of “substance abuse” in clinical fects can occur between the hypotensive practice may need to be further expanded to property of asafetida and dopamine receptor include patients who abuse culinary spices. such as mesylate. Use Patients could be screened for psychiatric caution when combining asafetida in conjunc- illnesses known to increase the risk of sub- tion with a CNS depressant or a stimulant.2 stance abuse. These might include—but are not limited to: • comorbid psychotic disorders Recommendations for treating • mood disorders, particularly bipolar spice-abusers disorders Patients may present to psychiatry ser- • trauma- and stressor-related disor- vices with psychological and physiologi- ders, particularly posttraumatic stress Current Psychiatry 30 April 2014 cal evidence of intoxication with culinary disorder • personality disorders, particularly anti- social, borderline, and narcissistic per- Related Resources sonality disorders. • Srinivasan K. Role of spices beyond food flavoring: nu- traceuticals with multiple health effects. Food Reviews Pending the availability of population- International. 2005;21(2):167-188. based studies on abuse of culinary spices, • Parthasarathi U, Hategan A, Bourgeois JA. Out of the cup- the usual cautions regarding substance board and into the clinic: Nutmeg-induced mood disorder. Current Psychiatry. 2013;12(12):E1-E2. abuse seem to be appropriate when caring Drug Brand Names for these patients. Assessment for and man- Bromocriptine mesylate • Imipramine • Tofranil agement of comorbid psychiatric conditions Parlodel Iproniazid • Marsilid is essential in the comprehensive psychiatric Flunitrazepam • Rohypnol Tranylcypromine • Parnate care of patients who abuse substances. Fluoxetine • Prozac Last, general consideration of a 12-step recovery program appears warranted for 12. McKenna A, Nordt SP, Ryan J. Acute nutmeg poisoning. Eur these patients; the self-reflection and group J Emerg Med. 2004;11(4):240-241. support of such programs can be useful in 13. Dhingra D, Sharma A. Antidepressant-like activity of n-hexane extract of nutmeg (Myristica fragrans) seeds in helping patients control their use of these mice. J Med Food. 2006;9(1):84-89. substances. 14. Truitt EB Jr, Duritz G, Ebersberger EM. Evidence of Clinical Point inhibition by myristicin and nutmeg. Proc Soc Exp Biol Med. 1963;112:647-650. References 15. Tajuddin, Ahmad S, Latif A, et al. An experimental study Consider comorbid 1. O’Mahony Carey S. Psychoactive substances. A guide of sexual function improving effect of Myristica fragrans abuse of other, more to ethnobotanical plants and , synthetic chemicals, Houtt. (nutmeg). BMC Complement Altern Med. 2005;5:16. compounds and products. http://www.drugs.ie/ 16. Quin GI, Fanning NF, Plunkett PK. Nutmeg intoxication. J familiar substances resourcesfiles/guides/Psychoactive_substances_low_res. Accid Emerg Med. 1998;15(4):287-288. pdf. Accessed March 4, 2014. 17. Barceloux DG. Nutmeg (Myristica fragrans Houtt.) Dis of abuse in patients 2. Asafetida. Applied Health. http://www.appliedhealth. Mon. 2009;55(6):373-379. com/index.php?option=com_content&view=article&id= 18. Demetriades AK, Wallman PD, McGuiness A, et al. Low who misuse spices 108207. Accessed March 4, 2014. cost, high risk: accidental nutmeg intoxication. Emerg Med 3. Jayatilaka A, Poole SK, Poole CF, et al. Simultaneous micro J. 2005;22(3):223-225. steam distillation/ extraction for the isolation of 19. Weil A. The use of nutmeg as a psychotropic agent. Bull semivolatile compounds from cinnamon and their Narc. 1966;18(4):15-23. http://www.unodc.org/unodc/ separation by series coupled-column gas chromatography. en/data-and-analysis/bulletin/bulletin_1966-01-01_4_ Analytica Chimica Acta. 1995;302(2-3):147-162. page003.html. Accessed March 5, 2013. 4. Spices. History & Special Collections UCLA Louise M. 20. Stein U, Greyer H, Hentschel H. Nutmeg (myristicin) Darling Biomedical Library. http://unitproj.library.ucla. poisoning - report on a fatal case and a series of cases edu/biomed/spice/index.cfm?displayID=15. Accessed recorded by a poison information centre. Forensic Sci Int. March 4, 2014. 2001;118(1):87-90. 5. Ginger action and uses. Ginger extract. Gingerols. MDidea 21. Grover JK, Khandkar S, Vats V, et al. Pharmacological Web site. http://www.mdidea.com/products/new/ studies on Myristica fragrans—antidiarrheal, , new02108.html. Accessed March 4, 2014. and hemodynamic (blood pressure) parameters. 6. Raina VK, Srivastava SK, Syamasunder KV. The essential Methods Find Exp Clin Pharmacol. 2002;24(10):675-680. oil of ‘greater galangal’ [ (L.) Willd.] from the 22 Shah AM, Calello DP, Quintero-Solivan J, et al. The not-so- lower Himalayan region of . Flavour and Fragrance nice spice: a teenage girl with palpitations and dry mouth. Journal. 2002;17(5):358-360. Pediatr Emerg Care. 2011;27(12):1205-1207. 7. Wenk G. Psychoactive spices - Bon appetite! http://www. 23. Heliotropin. Polarized light microscopy digital image psychologytoday.com/blog/your-brain-food/201008/ gallery. http://micro.magnet.fsu.edu/primer/techniques/ psychoactive-spices-bon-appetite. Published August 4, polarized/gallery/pages/heliotropinsmall.html. Accessed 2010. Accessed March 4, 2014. March 5, 2014. 8. PM. Just a click away: recreational drug Web sites on 24. Gage E. Romancing the bean. Budget Travel. http://articles. the Internet. Pediatrics. 2002;109(6):e96. cnn.com/2007-09-11/travel/vanilla_1_vanilla-orchid- 9. Forrester MB. Nutmeg intoxication in Texas, 1998-2004. totonaca?_s=PM:TRAVEL. Published September 11, 2007. Hum Exp Toxicol. 2005;24(11):563-566. Updated September 16, 2012. Accessed March 5, 2014. 10. Abernethy MK, Becker LB. Acute nutmeg intoxication. Am J 25. Mazor S, DesLauriers CA, Mycyk MB. Adolescent ethanol Emerg Med. 1992;10(5):429-430. intoxication from vanilla extract ingestion: a case report. 11. Brenner N, Frank OS, Knight E. Chronic nutmeg . The Internet Journal of Family Practice. 2005;4(1). doi: J R Soc Med. 1993;86(3):179-180. 10.5580/bc. continued Bottom Line Presentation of culinary spice intoxication can parallel that of other medical or psychiatric illnesses, or other drugs of abuse. 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