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Clinical Toxicology
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Opioid receptors and legal highs: Salvia divinorum and
Kavita M. Babu a; Christopher R. McCurdy b; Edward W. Boyer ac
Division of Medical Toxicology, Department of Emergency Medicine, University of
Massachusetts Medical School, Worcester, Massachusetts, USA
Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi,
University, Mississippi, USA
Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA

Online Publication Date: 01 February 2008
To cite this Article: Babu, Kavita M., McCurdy, Christopher R. and Boyer, Edward
W. (2008) 'Opioid receptors and legal highs: Salvia divinorum and Kratom', Clinical
Toxicology, 46:2, 146 - 152
To link to this article: DOI: 10.1080/15563650701241795


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Keywords Salvia divinorum. USA Salvia divinorum and Mitragyna speciosa (“Kratom”). School of Pharmacy. University of Mississippi. seeds. Department of Emergency Medicine. online Address correspondence to Kavita M. while others unscheduled psychoactive dietary supplements whose seem to encourage experimentation.and delta. BOYER3 Opioid receptors and legal highs 1 Division of Medical Toxicology. 7-hydroxymitragynine. MCCURDY2. 7–9). Harvard Medical School. USA. and tips for successful cultivation are available Massachusetts Medical School. USA 3 Division of Medical Toxicology. Whole Toxicology. Boston. will not sell Salvia divinorum or other psychoactive natural . Massachusetts. Clinical Toxicology (2008) 46. Massachusetts. Dietary supplements Introduction Salvia divinorum Toxicologists and poison control specialists play an Salvia divinorum is a perennial herb classified as a member important role in the identification of emerging trends in of the mint family (see Figure 1).opioid receptors. Other names for Salvia substance abuse. Worcester. divinorum include “Diviner’s Sage. Mitragynine. divinorum has been recognized for its hallucinogenic prop- poison control center or visits to the emergency depart. has been reported to be more potent than morphine. Salvia divinorum contains the highly selective kappa. Several features make Salvia divinorum attractive to young drug users.” and cologic monitoring may fail or lag in detection of “Magic Mint. plant material or extracts of salvinorin A Received 11 October 2006. the traditional methods of toxi. Mitragynine. The purpose of this article is to familiarize toxicologists and poison control specialists with these emerging psychoactive dietary supplements. accepted 22 January 2007. Division of Medical vendors. While several vendors state that they Massachusetts 01655. Babu. First. Department of Emergency Medicine. Many divinorum and Mitragyna speciosa (“Kratom”) are two websites advertise it as a “legal” hallucinogen. Some users ingest Salvia divinorum for ment. and monitoring of widely accessed sites Indians to create religious visions. University of plants. Mississippi. and even university campus stores (6). 55 Lake Avenue North. can provide insight into emerging substance abuse trends Salvia divinorum is one of the most widely marketed recre- that escape conventional methods of observation. explaining their use by chronic narcotics users to ameliorate opioid withdrawal symptoms. University. Salvinorin A. the major alkaloid identified from Kratom. this compound produces visual hallucinations and synesthesia. use of Salvia divinorum and Kratom represents an emerging trend that escapes traditional methods of toxicologic monitoring. two unscheduled dietary supplements whose active agents are opioid receptor agonists. erties for centuries. The Internet has long been recognized as a source of shamanistic purposes. advertising a combina- popularity has grown significantly in the past few years. has been reported as a partial opioid agonist producing similar effects to morphine. Salvia ational botanicals available via the Internet (1). and EDWARD W. Both Kratom alkaloids are reported to activate supraspinal mu. Despite their widespread Internet availability. CHRISTOPHER R. In a recent study of innovative adolescent methods of observation to predict emergent trends of drug users. via the Internet (4. An interesting minor alkaloid of Kratom. record stores. Inc. ISSN: 1556-3650 print / 1556-9519 online DOI: 10. E-mail: kavita_babu@yahoo. 146–152 Downloaded By: [CDL Journals Account] At: 20:30 5 March 2008 Copyright © Informa Healthcare USA. However.” “Mystic Sage. University of Massachusetts Medical School. replicating its original use by Mazatec drug information.opioid receptor agonist salvinorin A.1080/15563650701241795 ARTICLE LCLT Opioid receptors and legal highs: Salvia divinorum and Kratom KAVITA M. substances of abuse that do not typically provoke calls to a S. may be purchased from “head” shops. University of Massachusetts Medical School. Department of Emergency Medicine. USA 2 Department of Medicinal Chemistry. had used the Internet to obtain information about Salvia divinorum (5). Salvia divinorum and specialists in poison information with Salvia is being used recreationally by both adults and adolescents divinorum and Kratom. have discrete psychoactive effects that have contributed to their increasing popularity. 25% of the surveyed adolescents stated that they substance use. tion of dried leaves and extracts of salvinorin A as “the fresh- The purpose of this article is to familiarize toxicologists man selection” or the “starter pack” (2–4) . Massachusetts.” While more than 500 species of Salvia exist. and to illustrate the need for novel internationally. Worcester. Children’s Hospital. Worcester. Kratom.

products to minors.). correctly rely solely upon poison control center data in recognizing report that Salvia divinorum does not trigger any positive trends in emerging recreational substances.212 and Figure 3) (18). and lack of detectability combine to make tion. Christopher McCurdy. Salvia divinorum. or request information/educational tion (15).. thus differ- (F. there were 2. and “Maria Pastora” revealed a total of 90 exposures (see Figure 2) (17).org. Erowid and E. incorrect coding by specialists in poison informa- legality. Opioid receptors and legal highs 147 Downloaded By: [CDL Journals Account] At: 20:30 5 March 2008 40 35 30 Number of calls 25 20 15 10 5 0 2002 2003 2004 2005 Year * No calls reported between 2000 and 2002 Fig. Exposures do not necessarily represent a poisoning Little formal epidemiologic data are available for Salvia or overdose.erowid. 12 October 2006). Third. Ten percent of Pharmacology these patients were subsequently admitted for observation. Ease of access. naturally-occurring agonist of the kappa opioid Salvia divinorum index grew disproportionately relative to receptor (KOR). ethnographic investigations suggest accuracy of every report made to member centers. Salvia divinorum was listed as or healthcare professionals report an actual or potential a “Drug or Chemical of Concern” in 2004 by the National exposure to a substance ( described 463 and 424 The active component of Salvia divinorum is salvinorin A. or a Drug Intelligence Center and Drug Enforcement topical exposure. Additional a marked increase in the use of Salvia divinorum (16). In contrast. materials. Addi. lack of significant acute toxicity and lack of user contact Salvia divinorum a desirable hallucinogen to adolescents and with the health care system. an ingestion. ing sharply from other hallucinogens with related neuropsy- sonal communication.erowid. and Missouri (14). etc. Image courtesy of Dr. salvinorin A demonstrates no 1. The average age among intentional users was 21. Further limitations of AAPCC young adults who wish to experiment with drugs yet avoid data as described by the AAPCC follow: “The American discovery of their substance use. online data indicate the inability of clinicians and epidemiologists to drug encyclopedias.628 daily visits to the Salvia divinorum index on 3/1 and 9/1 apparent binding affinity for the 5-HT2A receptor. founders of www. Potential factors contributing to the disproportionately low potential adolescent users may be influenced by the availabil. substance. The AAPCC is not able to completely verify the divinorum use. Association of Poison Control Centers (AAPCC. tion logged by the country’s 61 Poison Control Centers Possession and cultivation of Salvia divinorum and salvinorin (PCCs). Fig. many websites lack clear mechanisms to other substances indexed on the website. A search of the AAPCC data the complete incidence of national exposures to any set from 2000 to 2005 using keywords “Salvia divinorum” substance(s)” (16). Second. a daily visits to the Erowid Salvia divinorum index on 3/1/2000 psychotropic diterpene that produces hallucinations (see and 9/1/2000. Case records in this database are from self-reported A is therefore illegal for human consumption in Delaware.Erowid.aapcc. per. 1. The kappa. AAPCC call data: Salvia divinorum (2000–2005)*. from the AAPCC should not be construed to represent tion of Poison Control Centers.g. with a 30:1 female predominance. However.5 years. number of contacts with the AAPCC regarding Salvia divi- ity of anecdotal Internet instructions that suggest evidence norum include failure of clinicians to recognize use of this supporting Salvia divinorum’s safety (13). however. Instead. hits to the selective. These preliminary prevent sales to persons younger than 18.receptor exists in both the spinal . an maintains the national database of informa- has prompted legislation to criminalize Salvia divinorum. http:// Concern regarding Salvia divinorum use by adolescents www. respectively. data from www. Erowid. 2. calls: they reflect only information provided when the public Louisiana. While some of this chiatric effects (18). such as www. exposures may go unreported to PCCs and data referenced tional information was obtained from the Americal Associa. results on qualitative urine drug screens (10–12). safety. salvinorin A is a highly increase may reflect the growth of the Internet. By 2005.

aversion.31). like hearing colors or smelling sounds (27). like driving (30). Two hundred micrograms are thought to be uncommon. and CSF. and persist for up to one hour neuropsychiatric effects produced by Salvia divinorum are (27). perhaps not result in respiratory depression. suggesting that the compound would not be addic- nation half-life was significantly longer in the females. study demonstrated a weak aversive effect of salvinorin A in the elimination half-life was 56.6 ± 24. administration of salvinorin A is not described in humans. that this natural product could be used as a probe to ascertain urine. but its role in diseases of perception. naloxone (a non-specific opioid receptor antagonist) may although it has been performed in an animal model (28). users have described psychotomimesis. ex vivo study demonstrated that salvinorin A is converted to salvinorin B via ester hydrolysis by blood esterases (29). The exact mechanism of salvinorin A demonstrated complete reversal of the analgesic effects of metabolism is unknown. However. diuresis and spinal analgesia. which last up to 20 to 30 minutes (27). The absence of reports describ- ing acute or chronic Salvia divinorum toxicity implies either its relative safety or failure of clinicians to recognize Salvia cord and brain. Salvia divinorum and salvinorin A may be administered via buccal or pulmonary routes and the onset and duration of effect varies with route of administration. while doses of 10 mg failed to To date. raphy (HPLC) and Liquid Chromatography Mass Spectrome- The mechanism by which the KOR produces hallucina. of salvinorin A or B in human blood after use. no reports currently exist in the literature gesting that elimination kinetics may vary with gender (28). High Performance Liquid Chromatog- of GI transit. Symptoms severe doses of Salvia divinorum required to produce hallucinations enough to require treatment in the emergency department depend on route of administration. Babu et al. an animal model demonstrated that salvinorin B Abuse liability never reached detectable levels after intravenous injection of salvinorin A. . the selec- effects. One salvinorin A in mice (19). no cases of Salvia divinorum toxicity or deaths produce hallucinations after ingestion (27). sug. there is interest in the therapeutic potential human volunteers who had smoked Salvia divinorum (31). whether in extract or leaf form. Indeed. Salvinorin A has been limiting long term. on tolerance or withdrawal to the effects of salvinorin A. Inhalation (of either vaporized salvinorin A extract or relatively mild. Sweating. Gas chromatography/ mass spectrometry the molecular basis of a number of psychiatric conditions identified salvinorin A in urine and saliva obtained from two (26). tive kappa opioid receptor antagonist. the physiological and within seconds to minutes. and may be rapidly cleared in vivo (28). Salvia divinorum produces synes- H H O thesia as its characteristic psychotropic effect. Additionally. suggesting enzymatic deactivation or significant first. pass metabolism (27). and psychoactive effects can occur In comparison to other hallucinogens. no studies have validated a method for the detection agent (26). as are pathways of elimination. Side effects are not described. but agitated delirium and confusion are smoked dried leaves) produces psychoactive effects within reported (30.12). The selectivity of salvinorin A for the KOR suggests quantifying salvinorin A added to samples of primate blood. Hallucinogenic effects are typically O O brief. chills. Threshold also attributed to Salvia divinorum (13). analysis of salvinorin A and B in plant matter and in ex vivo including schizophrenia and depression. reverse the physiological and psychiatric effects of Ingestion of salvinorin A produces no psychoactive salvinorin A at the kappa opioid receptor. has been postulated animal studies (12). 3. After Addiction to Salvia divinorum has not been described. Salvinorin A is Management rapidly absorbed through the buccal mucosa. One intravenous administration of salvinorin A to four primates. hallucinations after inhalation. and depressant effects (19–24). Structure of salvinorin A. many users O O report a confusion of the senses. Downloaded By: [CDL Journals Account] At: 20:30 5 March 2008 O Clinical effects and toxicity Hallucinations occur rapidly after administration and are O O typically very vivid (27). try (LC-MS) protocols have been applied to the quantitative tions is unknown. Theoretically. sedation. The intravenous from overdose have been reported (30). frequent use.M. However. animals. 148 K. Stimulation of the kappa. of salvinorin A as a novel antidepressant. The elimi. lasting only one to two hours. One study demonstrated the feasibility of (25). through lack of insight (30). Additionally. demonstrated to have pharmacological activity consistent with Routine drug screens do not detect the presence of known KOR agonists including analgesia.8 minutes. norbinaltorphine. inhibition salvinorin A (10. or antipsychotic To date. but individuals may be susceptible to trauma Fig. tive (23). and diuresis have been seconds.receptor produces divinorum use by patients. but does aversive effects with Salvia divinorum exposure. and the greatest risk may be of salvinorin A has been described as the threshold dose for trauma in the context of complex activity.

The . Many abusers of opioid analgesics develop withdrawal symptoms during periods of intentional opioid abstinence. Erowid. and is available through more than fifty online vendors (38). is a tree native to swampy regions of Asia and Africa (32) (see Figures 4 and 5).org on both 3/1/2000 Fig. and 9/1/2000. Kratom is an economical alternative to other opioid-replacement medications (such as buprenorphine). A search of the AAPCC data set for Kratom revealed a total of two reported exposures between 2000 and 2005. Mitragyna speciosa. While this increase may simply reflect the growth of the Internet. and was criminalized in Australia in 2005.39). and is responsible for the substance’s opioid effects (see Figure 6) (40. In Thailand. Kratom is widely used by this online community to mitigate opioid withdrawal symptoms. Kratom has long been considered unusual in its dual proper- ties as a stimulant and sedative. mitragynine is structurally simi- Fig. personal communication. and can be obtained without a prescription (9. both supraspinal opioid mu. Kratom was used in Thailand and Malaysia by manual laborers to enhance productivity. while its use by women was considered unusual (34).” The patients were aged 17 and 20 (36). The wide availability of Kratom on the Internet reflects extensive demand for this product.and delta. the use of Kratom was historically associated with working class men.receptors (42). reports of the use of Kratom to modu- late opioid withdrawal symptoms increasingly appeared on an Internet bulletin board that offers advice to individuals regarding the purchase of online pharmaceuticals in 2005 (37. Kratom has been illegal in Thailand since 1946. there were less than 50 hits to the Kratom index on www. there were 219 hits to the Kratom index on 3/1. Mitragynine displays in vitro activity at Image courtesy of Dr. Image courtesy of Dr.erowid. 4. By 2005. and 189 hits on 9/1 (F. 12 October 2006). and for its euphoric (also called “coca-like”) effect at low doses (33). founders of www. Erowid and E. An indole alkaloid.41). no national drug abuse survey currently monitors Kratom use in the United States (35). Mitragyna speciosa. Opioid receptors and legal highs 149 Downloaded By: [CDL Journals Account] At: 20:30 5 March 2008 Kratom (Mitragyna speciosa) Kratom. and its use to treat pain and opium withdrawal was described as early as the nineteenth century (32). however.38). or Mitragyna speciosa Korth. Kratom has opioid-like effects. At higher doses. At $10 to $40 per ounce of plant material. using the keyword “Mitragyna speciosa.erowid. Pharmacology Mitragynine is the most prevalent of the more than twenty alkaloids that have been isolated from Kratom. Christopher lar to yohimbine. In contrast. Christopher McCurdy. Kratom is not currently scheduled in the United States. 5.

Anorexia. as well as season addicts (34. which are very bitter. antidote should be considered for patients who present with Studies on 7-hydroxymitragynine have demonstrated that this respiratory depression after Kratom use. No cases of death due to Kratom have been administration (45). (40). as well as its amelioration of opiate withdrawal by obtaining an accurate history. clinical effects.34). required. in addition to alkaloid may be more potent than morphine. Animal studies suggest that mitragynine reported in the United States. This effect has also been witnessed in animal models pharmacokinetics.34. potential toxicity and opiate effects predominating at higher doses in humans abuse potential of these products. N N N N 46). be involved in activation or inhibition of other receptor Animal literature provides conflicting results regarding the systems. myalgias. Kratom leaves contain approximately 0. may stimulate post-synaptic alpha-2 adrenergic receptors. Dose-dependent neuropsychiatric effects may occur within five to ten minutes after consumption. Additionally. or a visit to the Emergency Department. Given the safety profile and potential benefits of 7-hydroxymitragynine. diarrhea and presence of other alkaloids in the leaves themselves (33). efficacy of opioid receptor antagonists in reversing Kratom Additional alkaloids isolated from Kratom. However. yawning. vomiting. the doses required to produce stimulation. Further study of the (33.48). 150 K. Abuse liability smoked or brewed into tea (46). antinociceptive and antidiarrheal OH properties of mitragynine have been described as clinically H H similar to codeine. which accounts for the analgesia activity of metabolites has been reported. and long-term effects of Salvia divinorum and Kratom is analgesia and toxicity in human remain poorly defined. Fig. possess antinociceptive effects in naloxone use in the emergency department setting. and last for up to one hour (33. and respiratory No diagnostic testing for the presence of mitragynine or its depression. mitragynine doses Conclusions as high as 920 mg/kg have been delivered without apparent clinical effect (47). even after oral supportive care. In animal models. Kratom leaves. . this animal models and a high affinity for opioid receptors (44). the development of hyperpigmentation mitragynine content of Kratom leaves is variable and may be over the cheeks has been described in long-term Kratom dependent on geographic origin of trees. The chemical similarity Reports of toxicity secondary to mitragynine are rare between the Kratom alkaloids and other biologically active (33. Nausea. Management there are no reports of mitragynine being screened for affinity at these specific receptors. The arthralgias (34).receptor mediates analgesia. Also. In the mouse model.48).34). and diarrhea have been commonly H described among Kratom users.34). this may be in part due to the irritability. mitragynine has been shown to compounds suggests that mitragynine and its congeners may cause less respiratory depression than other narcotics (46). and twenty Addiction to Kratom has been described in older reports (48). Downloaded By: [CDL Journals Account] At: 20:30 5 March 2008 OCH3 OCH3 The antitussive. with occasional reports of O O O O nystagmus and tremor (33). and their use is increasing in the United States. leaves of Kratom contain approximately 17 mg of mitragy. The symptoms include lower mitragynine doses.M. The diagnosis is established mitragynine. Mitragynine has also been postulated to be involved in the activation of descending noradrenergic and serotonergic pathways in the spinal cord (43). Babu et al. symptoms. Structures of Mitragynine and 7-Hydroxymitragynine. Salvia divinorum and Kratom are both widely available over the Internet. Little is descriptions exist of stimulant effects at lower doses. These products escape traditional methods of toxi- Clinical effects and toxicity cological monitoring.2% mitragynine by weight. rhinorrhea. as use of Salvia divinorum or Kratom are unlikely to prompt a call to the poison control The clinical effects of Kratom are dose-dependent. consistent center. can be chewed. an opioid abstinence syndrome has been nine (33. toxicity (47). Chewing of leaves produces greater effect at reported after chronic Kratom use. 6. euphoria. tolerance has also been described (34. Diagnosis mu. and/or block stimulation of 5-HT2A receptors (44). hyper- pgimentation and psychosis have been described in chronic O O users (34). weight loss. including effects (49). However. and known about the clinical effects. toxicokinetics.

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