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and Dependence 111 (2010) 250–256

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Drug and

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Use patterns and self-reported effects of divinorum: An internet-based survey

Matthew J. Baggott a,b,∗, Earth Erowid c, Fire Erowid c, Gantt P. Galloway b, John Mendelson b a Helen Wills Neuroscience Institute, University of California - Berkeley, Berkeley, CA, USA b and Pharmacology Research Laboratory, California Pacific Medicial Center Research Institute, San Francisco, CA, USA c Erowid Center, Grass Valley, CA, USA article info abstract

Article history: Background: There is growing use of (SD), a psychoactive that produces Received 30 October 2009 -like effects through a kappa receptor (KOR) mechanism. Little is known about KOR Received in revised form 4 May 2010 effects in humans and about users of SD. Accepted 6 May 2010 Objectives: To characterize the reasons, methods, and reported consequences of SD use. Methods: Individuals reading SD-related pages of a drug-information website were invited to anony- mously complete an online questionnaire if they had used SD. Keywords: Results: Participants (N = 500) were 92.6% male and 23.4 ± 8.7 (mean ± s.d.) years old. They had used a Salvia divinorum Hallucinogen median of six times (range 1–250). 80.6% probably or definitely would use SD again. Most participants Kappa opioid (92.6%) typically smoked or vaporized SD product. When smoked, the drug’s main effects were estimated Patterns of use to last 14.1 ± 12.8 (range 0.5–120) minutes. When asked to compare SD effects to other methods of alter- Subjective effects ing consciousness, the most common answer was that SD was unique (38.4%). 25.8% reported persisting (≥24 h) positive effects (often described as increased sense of well-being) on at least one occasion. 4.4% reported persisting negative effects (most often anxiety). Conclusions: SD is typically smoked, acute effects are brief, and persistent adverse effects are uncommon. In addition to acute hallucinogenic effects, SD may produce subacute increases in subjective well-being. Such a subacute effect would be unusual for a drug that is used non-medically, as withdrawal from other typically either does not affect mood or causes . Findings from this convenience sample should be confirmed and extended using surveys of random samples and controlled clinical studies. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction et al., 2005; Kovacs et al., 2005; Mitchell et al., 2005; Zapata and Shippenberg, 2006). Variations in the genes encoding the KOR and Pharmacological manipulations of the kappa opioid recep- two ligands have been associated with a risk for alcohol dependence tor (KOR) system have been proposed as novel treatments for (Xuei et al., 2006). In addition, a KOR agonist reduces convul- depression and drug and alcohol dependence (Carroll et al., 2005; sion severity in animals susceptible to ethanol withdrawal seizures Gaveriaux-Ruff and Kieffer, 2002; Kieffer and Gaveriaux-Ruff, (Beadles-Bohling and Wiren, 2006). 2002). KOR antagonists show antidepressant-like effects and atten- Despite this acknowledged therapeutic potential, few clinical uate behavioral responses to stress (Mague et al., 2003), while KOR studies have employed KOR and little is known about their stimulation modulates the reward system by reducing effects in humans. One apparent reason is that, at high doses, KOR release in the nucleus accumbens, and by generating aversive states agonists such as , , and produce (Aldrich and Vigil-Cruz, 2003; Spanagel et al., 1990). KOR manip- sensory effects such as visual and auditory distortions and feel- ulations modulate ethanol consumption in rodents, and ethanol- ings of depersonalization (Chappell et al., 1993; Martin et al., 1965; and -induced alteration in brain dopamine levels (Chefer Pfeiffer et al., 1986; Walsh et al., 2001). At lower doses, KOR ago- nists also produce decreased body temperature, diuresis, sedation, stupor, and difficulty concentrating (Ashton et al., 1989; Chappell et al., 1993; Kramer et al., 2000; Martin et al., 1965; Pfeiffer et al., ∗ Corresponding author at: Addiction and Pharmacology Research Laboratory, 1986; Reece et al., 1994; Rimoy et al., 1994; Walsh et al., 2001). California Pacific Medical Center Research Institute, 7th Floor, St Luke’s Hospital, Cardiovascular effects from kappa agonists are reportedly minimal 3555 Cesar Chavez Street, San Francisco, CA 94110, USA. Tel.: +1 415 641 3370; fax: +1 415 641 3380. (Rimoy et al., 1994; Walsh et al., 2001). Selective KOR antagonists E-mail address: [email protected] (M.J. Baggott). are not available for use in clinical trials at present.

0376-8716/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.drugalcdep.2010.05.003 M.J. Baggott et al. / Drug and Alcohol Dependence 111 (2010) 250–256 251

Salvia divinorum (SD) is a hallucinogenic plant that has been Table 1 traditionally used for and healing in the zone of Estimated duration of Salvia divinorium effects when smoked or vaporized. Mexico (Johnson, 1939), and was first collected by Westerners in Estimated duration of effects when smoked or vaporized (min) 1955 (Epling and Jativa, 1962). In the , a 2008 gov- SD extract (N = 296) SD (N = 180) (N =6) ernment report estimated that 1.8 million people had tried SD, with most initiating use in the last two years ( Mean 14.1 15.7 27.5 St. Dev. 12.8 14.8 16.1 and Mental Health Services Administration, 2008). SD use has been Median 10 10 21 reported in college students in the United States (Khey et al., 2008; Mode 10 5 N/A Lange et al., 2008) and is also occurring in Europe (Pavarin, 2006) Min 0 0 13 and Japan (Tsujikawa et al., 2008). At least in a sample of Italian Max 120 90 50 youth attending concerts, SD users appear to have fewer medical, legal, or social impairments than do individuals who consume other found any of the survey questions difficult to understand, and whether they had recreational drugs (Pavarin, 2006). previously completed this survey. The putative primary psychoactive agent in SD is a structurally When participants finished the survey, they clicked a button on the bottom novel KOR agonist named salvinorin A (Ortega et al., 1982; Valdés et of the page affirming that their responses were complete. Their responses were al., 1984). Consistent with KOR agonist activity, users describe SD in then anonymously stored in an electronic database. If participants did not click this button, none of their responses were stored. The automatically collected web-server lay literature as hallucinogenic: it produces perceptual distortions, activity log counted the number of times the announcement was read, the number pseudo-, and a profoundly altered sense of self and of times the information sheet was read, and the number of times the survey was environment, including out-of-body (Aardvark, 1998; completed. Erowid, 2008; Siebert, 1994b; Turner, 1996). SD therefore appears Data from a participant were excluded from analysis if: (1) data were incom- to have the potential to elucidate the role of the KOR receptor sys- plete; (2) the participant reported having previously completed the survey; (3) the participant reported he or she was not fluent in English or had difficulty understand- tem in health and disease (Butelman et al., 2004; Chavkin et al., ing the questions; or (4) another response was submitted from the same computer 2004; Roth et al., 2002). (IP address) within ten minutes. The survey ended when 500 participants completed Aside from books and web sites providing information to poten- the survey and met inclusion and exclusion criteria. tial users (Aardvark, 1998; Erowid, 2008; Ott, 1993; Pendell, 1995; Data were analyzed using R (R Development Core Team, 2007). Siebert, 2009; Sociedad, 1998; Turner, 1996), there is very lit- tle published information on users’ experiences with the drug 3. Results (Gonzalez et al., 2006; Lange et al., 2009). For that reason, study- ing SD users appears to be a novel method for understanding the We collected a total of 520 responses (40.1% of those viewing the effects of high and repeated exposure to a KOR agonist in humans. survey), of which 500 met inclusion/exclusion criteria. Participants We therefore conducted an anonymous web-based survey of SD were primarily (92.6%) male. The mean age was 23.4 ± 8.7 years use. Participants were asked to report basic demographic and drug- (range 13–68), with 20.2% under 18 years of age. 77.4% lived in the effect information as well has when, how, and why they had used United States. SD. 3.1. Usage patterns 2. Methods Participants reported a mean (±standard deviation) lifetime use We recruited anonymous participants from a popular drug-information web site ± that does not take a position against drug use (www.erowid.org). Individuals visiting of SD products to be 13.3 22.9 (median 6; range 1–250) days the web site’s pages relating to SD saw an announcement about the questionnaire, (Fig. 1). The number of days SD was used in the last 30 and 365 which appeared as a hyperlink reading, “Survey for people who have used Salvia days was 1.5 ± 2.6 (median 1; range 0–24) and 7.5 ± 11.6 (median divinorum”. Prospective participants who clicked on this link then read an informa- 3; range 0–110), respectively. Most individuals (92.6%) typically tion sheet describing the study and its potential risks. Prospective participants from Australia were asked not to participate due to legal restrictions on SD in that country. smoked or vaporized the SD products, with 61.4% of this subset Participants went on to fill out a 39-item survey, requiring approximately 20 min. using a concentrated extract and 37.3% using a dried leaf. 4.2% Data were collected from Jul 24, 2003–Aug 20, 2003. The study was approved by the reported they had used purified salvinorin A, which has occasion- California Pacific Medical Center Institutional Review Board (IRB). The IRB endorsed ally been sold over the web. inclusion of subjects less than 18 years of age but did not require parental consent. Those SD products (N = 482) reported holding the We note that this it was not possible to anonymously verify participants’ ages, and ± that SD was completely unregulated at the time of this survey (except in Australia, inhaled product 23.5 14.9 (median 20; range 2–203) seconds as noted). before exhaling. A single episode of use was estimated to include an Questions were either multiple-choice with a free-response ‘other’ option, or average of 3.4 ± 3.1 (median 3; range 1–40) inhalations. The main fully free-response. Participants were required to select a single response for most effects of the SD leaf or extract were estimated to last 14.9 ± 13.7 questions. (Questions for which multiple responses could be selected are noted in (median 10; range 0–120) minutes when used in this manner Section 3.) Categories for scoring free responses were created by the first author after reviewing all responses. The free responses were then independently cat- (Table 1). egorized by two research technicians, with discrepancies resolved by the first Those who chewed or otherwise buccally absorbed the SD prod- author. ucts reported keeping it in their mouth for 18.4 ± 21 (median 15; Participants were asked their age, gender, whether they were fluent in English, range 0–240) minutes before spitting or swallowing. This was and whether they lived in the United States. Days of SD use in the last 30 days, ± year, and lifetime were obtained, along with usual , patterns repeated 2.1 6.2 (median 1; range 0–80) times in a single episode of use, and preparations before using. Because research with lysergic acid diethy- of use. When used in this manner, effects were estimated to last lamide (LSD) suggests that retrospective memory of hallucinogenic states is often 30.5 ± 34.3 (median 25; range 0–240) minutes. inaccurate (Linton et al., 1964), we did not attempt to elicit detailed descriptions 38.6% of participants reported they usually had an uninebriated of peak SD effects. Instead, we asked participants to describe any other methods of companion present when they used SD. altered consciousness that produced effects similar to SD. Participants were then asked to specify, in free-response format, the effects they liked most and least, and to select from a list of possible after-effects drawn from anecdotal reports of SD 3.2. Reasons for use or discontinuation effects and clinical studies with KOR and mu agonists. Reports of positive and negative effects that lasted 24 h or more were also obtained. To assess Motivations for use endorsed by participants were: to explore possible dependence liability, we asked participants whether they believed they were addicted to SD, as well as which DSM-IV dependence criteria that they felt altered consciousness (86.2%), curiosity (76.6%), spiritual or mysti- applied to them (Abel et al., 1996). Finally, participants reported whether they had cal reasons (74.0%), personal growth or self-understanding (69.2%), 252 M.J. Baggott et al. / Drug and Alcohol Dependence 111 (2010) 250–256

Fig. 1. Histograms and distribution functions for previous use of Salvia divinorum products. contemplation or (52.0%), relaxation or enjoyment example, one participant wrote, “[t]he feeling of warmth it sends (35.6%), to get high (31.2%), to increase enjoyment of other activities through my body is very similar to how I feel doing . The clarity (20.6%), to help a mainly psychological problem (11.0%), and to help of a satori—a flash of intuitive wisdom in meditation ....” a mainly physical problem (0.8%) (multiple motivations could be When asked to list their favorite aspects of SD use in free endorsed). 80.6% reported they would probably or definitely use SD text, most described the altered state of consciousness, with many again. Reasons frequently endorsed by those who probably or def- specifically mentioning insights or altered understanding of things initely would not use SD products again (N = 33, 6.6%) were “didn’t (20.6%), perceptual changes (19.4%), alterations of sense of self and like effects” (36.4%), “prefer other methods of altering conscious- environment (such as out-of-body experiences or merging with ness” (30.3%), and “effects were too mild” (24.2%) (multiple reasons objects in the environment) (19.2%), increased calmness and sub- could be endorsed). jective well-being afterwards (7.2%). Less commonly, participants mentioned the short duration of effects (9.0%) and the legality of 3.3. Acute SD effects SD (5.4%). Effects endorsed as occurring after peak intoxication are sum- When asked for a free-text response comparing SD effects to marized in Table 3. other methods of altering consciousness, the most common answer was that SD was unique (38.4%; Table 2). A representative answer 3.4. Effects lasting more than 24 h was “Nothing on this planet is like SD; no drug, no amount of med- itation can make you feel like SD makes you feel.” Less commonly, In a free-response answer, 129 (25.8%) participants reported SD was also compared to meditation/yoga/ (23.2%), seroton- positive effects lasting 24 h or more after use. Of these 129 partic- ergic (17.7%), dreaming (7.1%), NMDA antagonists ipants, 60 (46.5%) reported improved mood and “antidepressant- and other (6.8%), and marijuana (6.5%). Comparisons like effects”. For example, one participant wrote “I an to meditation seemed based on somatic and cognitive effects. For antidepressant effect that begins some time (12–24 h) after taking salvia; it may linger for 3–5 days.” Another noted “I feel my bat- Table 2 teries have been recharged and am given renewed strength to take Comparison of Salvia divinorium to other methods of altering consciouness. on life’s challenges.” The term ‘afterglow’ was sometimes used to

Comparison made by participants %a describe this effect. We conducted a multiple logistic regression to determine if per- SD is unique 38.4 sistent positive effects were predicted by gender, willingness to use SD is like meditation/yoga/trances 23.2 SD is like serotonergic hallucinogens (e.g. LSD) 17.7 SD again, use mainly to help a psychological problem, and prefer- SD is like dreaming 7.1 ence for less intense effects. This confirmed that people were more SD is like NMDA antagonists (e.g. ) and other anesthetics 6.8 likely to report positive effects if they expressed greater likelihood SD is like 6.5 of using SD again (OR 2.05, 95%CI: 1.34–3.17, p = 0.001) and if they a Each response could fit more than one category; thus, total does not equal 100%. had used SD for help with a psychological problem (OR 2.01, 95%CI: M.J. Baggott et al. / Drug and Alcohol Dependence 111 (2010) 250–256 253

Table 3 Reported Salvia divinorum after-effects.

After-effect %a After-effect %

Increased insight 47.0 Yawning 11.8 Improved mood 44.8 Anxiety 9.4 Calmness 42.2 Difficulty sleeping 7.8 Increased connection with universe or nature 39.8 Chills or gooseflesh 7.0 Weird thoughts 36.4 Increased urine production 6.4 Things seeming unreal 32.4 Body felt cold 6.4 Floating feeling 32.0 Watery eyes 5.4 Increased sweating 28.2 Decreased connection with universe or nature 5.4 Body felt warm or hot 25.2 Irritability 5.0 Mind racing 23.2 Worsened mood 4.0 Lightheadedness 22.2 Decreased self-confidence 2.4 Increased self-confidence 21.6 1.8 Improved concentration 19.4 Runny nose or sneezing 1.8 Drowsiness 18.8 Muscle cramps or aches 1.8 18.6 Decreased insight 1.8 Lack of coordination 18.0 Decreased sweating 1.6 Feeling like someone or something else 14.0 Decreased urine production 0.6 Heart racing 13.2 Diarrhea 0.2 Bothered by noises 12.2 0.0 Difficulty concentrating 12.0

a Participants could endorse more than one response.

1.11–3.62, p = 0.020). There was no effect of gender or preference When asked about effects persisting over a shorter time frame, a for intense effects. There were also no significant interactions. greater percentage of participants reported similar positive expe- Serious adverse events were rare in this young population. riences, with 44.8% of the entire sample reporting improved mood In a free response answer, only 4.4% reported persisting (24 h and 42.6% reporting a feeling of calmness. Improved mood or or more) negative effects – most often anxiety – on one or antidepressant effects lasting 24 h or more after SD use is con- more occasions. Three participants (0.6%) provided free-response sistent with a published case report of a 26-year-old women answers regarding professional help they had sought for an who reports complete remission of depressive symptoms fol- SD-related problem. One went to a priest to discuss Catholi- lowing 0.5–0.75 g of sublingually administered SD three cism, while a second visited a therapist. The single participant times per week (Hanes, 2001). However, systemic administration who reported seeking emergency treatment had used multiple of SD (0.125–2.0 mg/kg) triggered depressive-like symptoms in substances (dimethyltryptamine, , SD, metham- rats, with increased immobility in the forced swim test and ele- phetamine, , “etc.”) and described what might vated intracranial self-stimulation (ICSS) thresholds (Carlezon et have been . al., 2006). Animal studies indicate that KOR antagonists, rather than agonists such as SD, have antidepressant-like effects in the forced 3.5. Abuse liability swim test (Mague et al., 2003; Pliakas et al., 2001) and the learned helplessness paradigm (Newton et al., 2002). There was little evidence of dependence in our survey popula- A study in mice provides potential evidence of rapid down- tion. At some point, 0.6% (3 people) felt addicted to or dependent regulation of kappa signaling pathways. Pretreatment with the upon SD, while 1.2% (6) reported strong cravings for SD. The DSM- kappa agonist U50,488 affected cocaine-induced conditioned IV-R psychiatric diagnostic system in the United States classifies place-preference in a time-dependent manner, impairing place people as drug dependent based on seven criteria. Of the three preference when U50,488 preceded cocaine administration by who reported feelings of addiction or dependence on SD, only one 15 min and enhancing place preference when U50,488 preceded endorsed any DSM-IV criteria (strong cravings and using more cocaine administration by 60 min (McLaughlin et al., 2006). These SD than planned). When asked about these signs and symptoms findings suggest that the effects reported by our participants, if individually, 2 additional respondents (0.4%) reported three depen- confirmed, may be due to SD-induced downregulation of KOR path- dence criteria. None of these individuals reported more than 2 of ways. 13 after-effects characteristic of mu- (such as Most of our participants smoked SD products. This was also seen increased sweating, gooseflesh, worsened mood, and diarrhea). with the 32 users studied by Gonzalez et al. (2006), for whom smok- ing was the preferred route of administration for 78%, with the 4. Discussion remaining 22% preferring a combination of smoking and sublingual. According to the Erowid’s Salvia Frequently Asked Questions (FAQ) There is growing interest in the therapeutic potential of KOR document, several inhalations, each held for 30 s or so, are often manipulations, as well as growing use of the KOR agonist S. divi- employed in rapid succession (Erowid, 2008; Gruber, 1999). This norum. However, little is known about the effects of selective is consistent with our sample, where users estimated they usually KOR agonists in humans or the characteristics of SD users. We took a median of 3 inhalations, holding each lungful for a median used an anonymous questionnaire to measure the usage patterns, of 20 s. demographics, and experiences of non-medical users of SD. To our In our study, effects reportedly persisted for a median of 10 min knowledge, this is the first study attempting to collect data on after administration by smoking. Our results are comparable to the effects persisting beyond the acute intoxication. reported effects of SD in online documents and in the Gonzalez et A notable finding was that 25.8% of our participants reported al. (2006) report, in which 60% of participants estimated the dura- positive effects lasting more than 24 h after SD use; of these par- tion of effects to be between 1 and 5 min when smoked. When ticipants, 46.5% reported improved mood. In a free-text response, the SD product was chewed or buccally absorbed, effects report- 7.2% reported that this was the effect they liked best about SD. edly persisted for a median of 25 min. This appears shorter than 254 M.J. Baggott et al. / Drug and Alcohol Dependence 111 (2010) 250–256 the Siebert’s (2009) estimate that “effects begin in 10–15 min, and in the other). There is a case report of persistent severe psychiatric quickly develop to a peak level that lasts 20–40 min. The effects then disturbances, including déjà vu, paranoia, and cognitive impair- gradually diminish over an additional 30 min to an hour.” Our par- ment, in a patient with a history of SD use, although the time since ticipants’ estimates may be shorter because users were estimating SD use was unclear and marijuana was used several hours before the duration of peak intoxication only, or because earlier estimates the onset of symptoms (Singh, 2007). To date, there is only a sin- were drawn from smaller samples. gle case report describing a significant acute medical complication In a study of the of intravenous SD in 4 rhesus of SD exposure (Paulzen and Grunder, 2008). In this case a young monkeys, 0.032 mg/kg SD was rapidly distributed (t1/2 for distri- woman had a psychotic episode, and a subsequent prolonged and ± ± bution 0.95 0.20 min), with an elimination t1/2 of 56.6 24.8 min complicated hospital course, after smoking marijuana to which SD (Schmidt et al., 2005). If human elimination is as slow as that in had been added without her knowledge. However, many of her the monkey, then substantial hysteresis is likely, suggesting rapid complications appear secondary to medical intervention and not single-dose tolerance to SD. More recently, the half-life of SD in to SD or marijuana. baboon brains has been estimated to be 8 min (Hooker et al., 2008). Although not documented by our survey, online documents Rapid elimination is consistent with the brief effects noted in non- describe minor bruises, cuts, and burns obtained when intoxicated human primates (Butelman et al., 2008; Schmidt et al., 2005) and users fell or dropped smoking apparatuses on themselves (Erowid, in our survey. Rapid elimination helps explain the overwhelming 2008). In addition, it has been reported that very intoxicated users preponderance of smoking as a route of administration, as rapid of SD sometimes walk around in an agitated delirious state (Salvia absorption makes it more likely that intoxicating concentrations Authors, 2009; Siebert, 1994a). Similar, but less profound, disori- will be present at the KOR and users can rapidly re-administer doses entation has been seen in individual participants in clinical studies as effects wane. using high-dose kappa agonists (Walsh et al., 2001). It may there- Most participants in our survey reported that SD effects were fore be a point of concern that only 38.6% of participants usually had unique (38.4%), with many comparing it to yoga/meditation/ an uninebriated friend monitor them while they used SD. Thus, SD (23.2%) and serotonergic hallucinogens (17.7%). SD was also com- use is likely not without risk, despite the paucity of adverse effects pared to serotonergic hallucinogens by participants in the Gonzalez reported in our sample and in previous reports. SD may cause infre- et al. report. Comparisons between drug effects may be influenced quent but serious adverse events that were not detected due to the by marketing of SD (websites sometimes compare SD to cannabis limited sample size. and hallucinogens (Dennehy et al., 2005)) and may be limited by Similar caveats apply to the questions of SD dependence. To our the experience of our participants, who likely have varying levels knowledge, SD dependence has not been reported. Our failure to of exposure to methods of altering consciousness. Given that we detect it in our sample must be regarded with caution given both did not ask participants detailed questions about their experiences our sample’s self-selected nature and the lack of validation of self- with other drugs or for specific comparisons between SD and other report as a means of assessing dependence. Dependence is a serious drugs, we are limited in our ability to characterize the subjective complication, and even a low incidence that would not be reliably effects of SD. detected with this sample size could be a matter of serious concern. Nonetheless, the reported effects of SD in our sample are gen- Our sample was young, with 20.2% under 18 years. It is possible erally consistent with KOR agonists’ known clinical effects, such as that uncontrolled inebriants appeal to those with greater difficulty sedation, difficulty concentrating (Ashton et al., 1989; Chappell et obtaining more controlled substances, although only 5.4% of par- al., 1993; Kramer et al., 2000; Martin et al., 1965; Pfeiffer et al., 1986; ticipants stated that legality was their favorite aspect of SD. Reece et al., 1994; Rimoy et al., 1994; Walsh et al., 2001), auditory Our participants were predominantly male (92.6%). A prepon- and visual distortions, and feelings of depersonalization (Chappell derance of male SD users was also noted in the two surveys of US et al., 1993). In addition to the hallucinogen-like effects, Gonzalez college students (Khey et al., 2008; Lange et al., 2008). Although et al. (2006) noted that 44% of their 32 participants reported expe- sex differences in effects of SD (Butelman et al., 2008) and other riencing some degree of adverse symptoms immediately after the kappa opioid agonists (Barrett et al., 2002; Craft and Bernal, 2001; acute effects of SD. Common symptoms in their sample included Gear et al., 1996; Negus et al., 2002) have been noted in humans tiredness (12.5%) and dizziness (9.4%). Similarly, our participants and animals, the gender imbalance may also reflect other factors, reported drowsiness (18.8%) and dizziness (18.6%). such as differences in willingness to participate in an online survey. Our participants also reported many positively experi- Genetic or neuroendocrine differences may also contribute to this enced symptoms. Some of these also appeared consistent with gender effect (Mogil et al., 2003; Negus and Mello, 1996). hallucinogen-like effects, such as increased insight (47.0%) and The principal limitation of this study is our use of a web-based increased sense of connection with the universe or nature convenience sample, which is unlikely to be representative of all (39.8%). SD users. A criticism of web-based surveys is that they are known In our survey of 500 users, the only individual who had sought to suffer from the “volunteer effect”—i.e., people are more likely treatment from a physician for a putatively SD-related complica- to elect to contribute to a topic that affects or has affected them tion had also consumed several other drugs. While few serious (Eysenbach and Wyatt, 2002). It should be noted that the web site adverse events were reported by our participants, it must be from which the sample was drawn does not advocate against drug emphasized that the of new drugs is often only detected use. Because we recruited from a drug-information web site, our as use spreads to greater numbers of people. Early adopters of sample is likely to over-represent individuals with an interest in novel hallucinogens may be better-educated and more concerned drugs. Similarly, people who have had good experiences with SD about their health than typical drug users. Thus, the relative lack of may also be overrepresented. SD and KOR agonists have a reputa- adverse effects may reflect user, rather than drug, characteristics. tion for anxiogenic effects (Pfeiffer et al., 1986; Walsh et al., 2001). The toxicity of SD appears low. A statewide review of 10 years of Accordingly, it may be hypothesized that this sample – 80.6% of poison control center records in California revealed 37 cases related whom reported willingness to use SD again – may disproportion- to SD, with 18 reportedly involving no other substances (Vohra ately represent those who find the acute effects of SD tolerable. The et al., 2009). Signs and symptoms were generally consistent with design of the current survey does not permit evaluation of these adverse hallucinogen effects (e.g. disorientation, agitation), and limitations. vital-signs abnormalities were documented in two cases of isolated In summary, we report on usage patterns and experiences of SD exposure ( in one, and tachycardia and a convenience sample of 500 users of the KOR-agonist-containing M.J. Baggott et al. / Drug and Alcohol Dependence 111 (2010) 250–256 255 hallucinogenic plant S. divinorum. Users typically smoke this plant Chavkin, C., Sud, S., Jin, W., Stewart, J., Zjawiony, J.K., Siebert, D.J., Toth, B.A., Hufeisen, or an extract, leading to brief but intense hallucinogenic effects. We S.J., Roth, B.L., 2004. Salvinorin A, an active component of the hallucinogenic sage Salvia divinorum is a highly efficacious kappa-opioid receptor agonist: structural did not find evidence of a dependence syndrome or other serious and functional considerations. J. Pharmacol. Exp. Ther. 308, 1197–1203. adverse events in our sample. However, a number of participants Chefer, V.I., Czyzyk, T., Bolan, E.A., Moron, J., Pintar, J.E., Shippenberg, T.S., 2005. reported increased well-being and calmness occurring minutes to Endogenous kappa-opioid receptor systems regulate mesoaccumbal dopamine dynamics and vulnerability to cocaine. J. Neurosci. 25, 5029–5037. days after the acute inebriation. This subacute effect appears to be Craft, R.M., Bernal, S.A., 2001. Sex differences in opioid antinociception: kappa and novel for a drug that is used non-medically, as these drugs more ‘mixed action’ agonists. Drug Alcohol Depend. 63, 215–228. typically have dysphoric withdrawal effects. Further research on Dennehy, C.E., Tsourounis, C., Miller, A.E., 2005. Evaluation of herbal dietary sup- SD users may help clarify the role of the KOR system in health and plements marketed on the internet for recreational use. Ann. Pharmacother. 39, 1634–1639. disease, as well as the therapeutic potential of manipulating this Epling, C., Jativa, M., 1962. A new species of salvia from Mexico, vol. 20. Botanical system. Museum Leaflets Harvard University, pp. 75–76. Erowid, 2008. Erowid Salvia divinorum (Ska Pastora) Vault. www.erowid. org//salvia. (Accessed on 22.12.08). Role of funding source Eysenbach, G., Wyatt, J., 2002. Using the Internet for surveys and health research. J. Med. Internet Res. 4, E13. Funding for this study was provided by NIH Grant DA018179. Gaveriaux-Ruff, C., Kieffer, B.L., 2002. Opioid receptor genes inactivated in mice: the Baggott was supported by a Beckley Foundation grant. The NIDA highlights. Neuropeptides 36, 62–71. Gear, R.W., Gordon, N.C., Heller, P.H., Paul, S., Miaskowski, C., Levine, J.D., 1996. Gen- and Beckley Foundation had no further role in study design; in the der difference in response to the kappa-opioid . Neurosci. collection, analysis and interpretation of data; in the writing of the Lett. 205, 207–209. report; or in the decision to submit the paper for publication. Gonzalez, D., Riba, J., Bouso, J.C., Gomez-Jarabo, G., Barbanoj, M.J., 2006. Pattern of use and subjective effects of Salvia divinorum among recreational users. Drug Alcohol Depend. 85, 157–162. Contributors Gruber, J.W., 1999. High performance liquid chromatographic quantification of salvi- norin A from tissues of Salvia divinorum Epling & Játiva-M. Phytochem. Anal. 10, Authors Baggott and Mendelson designed the study and wrote 22–25. the protocol. Authors E. Erowid and F. Erowid designed the Hanes, K.R., 2001. Antidepressant effects of the herb Salvia divinorum: a case report. J. Clin. Psychopharmacol. 21, 634–635. study and programmed the computerized questionnaire. Galloway Hooker, J.M., Xu, Y., Schiffer, W., Shea, C., Carter, P., Fowler, J.S., 2008. Pharmacoki- undertook statistical analysis. Baggott wrote the first draft of the netics of the potent hallucinogen, salvinorin A in primates parallels the rapid manuscript. All authors contributed to and have approved the final onset and short duration of effects in humans. NeuroImage 41, 1044–1050. Johnson, J., 1939. The elements of Mazatec witchcraft. Göteborgs Etnografiska manuscript. Museum Etnologiska Stud. 9, 119–149. Khey, D.N., Miller, B.L., Griffin, O.H., 2008. Salvia divinorum use among a college Conflict of interest student sample. Baywood, 297–306. Kieffer, B.L., Gaveriaux-Ruff, C., 2002. Exploring the opioid system by gene knockout. Prog. Neurobiol. 66, 285–306. The authors declare that they have no conflicts of interest. Kovacs, K.M., Szakall, I., O’Brien, D., Wang, R., Vinod, K.Y., Saito, M., Simonin, F., Kieffer, B.L., Vadasz, C., 2005. Decreased oral self-administration of alcohol in kappa-opioid receptor knock-out mice. Alcohol Clin. Exp. Res. 29, 730– Acknowledgements 738. Kramer, H.J., Uhl, W., Ladstetter, B., Backer, A., 2000. Influence of , a new kappa-opioid receptor agonist, on tubular water absorption and vasopressin We would like to thank the participants for providing informa- secretion in man. Br. J. Clin. Pharmacol. 50, 227–235. tion about their Salvia divinorum use and Danielle Hubbard and Lange, J.E., Daniel, J., Homer, K., Reed, M.B., Clapp, J.D., 2009. Salvia divinorum: effects Jeremy Coyle for assistance in preparing the manuscript. and use among YouTube users. Drug Alcohol Depend. 108 (1), 138–140. 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