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PLANTS-SALVIA DIVINORUM

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Saliva diviornum is a member of the sage family and the principle active ingredient is salvinorin A, a neoclerodane diterpine, which acts as a potent hallucinogen that is a highly selective full agonist of the kappa-opioid receptor.

Specific Substances

    1) Salvia divinorum
    2) S. divinorum
    3) Salvinorin
    4) Salvinorin A
    5) Salvinorin B
    6) Diviner's sage
    7) Magic mint (slang term)
    8) ska Maria (slang term)
    9) ska Pastora (slang term)
    10) hojas de Maria
    11) hojas de la Pastora (slang term)
    12) heirba Maria (slang term)
    13) la Maria (slang term)
    14) Sally D (slang term)

Available Forms Sources

    A) FORMS
    1) The Salvia divinorum plant is prepared by using several methods. The leaves of the plant are either ingested by mastication and swallowing the juice from the leaves ("quid" a method of rolling up the fresh leaves and chewing on it), crushing the leaves to extract the juices and then swallowing the extract, or allowing the leaves to dry and smoking the leaves (Sheffler & Roth, 2003; Vortherms & Roth, 2006). Reportedly, the leaves are minimally absorbed and the sublingual and inhalation routes are preferred by users. The preferred method of use in the US and United Kingdom is smoking the dried and crushed leaves (Dalgarno, 2007).
    2) The active ingredient of Salvia divinorum is Salvinorin A, a neoclerodane diterpine, which acts as a potent hallucinogen that is a highly selective full agonist of the kappa-opioid receptor. As many as 5 other compounds (salvinorin B through E is thought to be inactive and Salvinorin F {status unknown}) have been extracted from the leaves of the plant, but do NOT appear to have the same hallucinogenic effects as Salvinorin A (Singh, 2007; Bucheler et al, 2005; Sheffler & Roth, 2003; Medana et al, 2006; Chavkin et al, 2004; Halpern, 2003). Salvinorin A appears to have similar activity and potency as mescaline (Valdes, 1994).
    3) S. divinorum is available as a natural dried plant material, fortified plant material and liquid extract. The leaves can sell for $15 to 120 per ounce, plants for $20 to 45, and liquid extract for $110 to 300 per ounce (Wolowich et al, 2006).
    4) Some Internet sources classify Salvinorin A as a dissociative agent, along with other agents such as phencyclidine (ie, PCP, angel dust), ketamine, dextromethorphan, ibogaine, and nitrous oxide (Wolowich et al, 2006).
    B) SOURCES
    1) S. divinorum can be found on the Internet or from local drug paraphernalia shops ("head shops") as a concentrated preparation of the leaf to produce salvia extract. This version of the plant produces less smoke and purportedly allows for a more powerful experience (Rosenbaum et al, 2012; Wolowich et al, 2006).
    a) The extract is sold in various strengths. Based on a users forum a strength of 1x has the potency of the natural product. Relative strengths have been described as 5x (ie, 5 times the potency of 1x), 10x, and 20x, respectively. However, a study of various products indicated that the concentration of several extracts were much lower than those claimed on the product label. Additional ingredients included caffeine and Vitamin E in some samples (Grundmann et al, 2007; Wolowich et al, 2006). Lack of standardization could lead to a potential risk among users.
    C) USES
    1) Salvia divinorum is a member of the mint (Lamiaceae) family and the leaves of the plant have been used for divination and shamanism by the Mazatecs of Mexico (Grundmann et al, 2007; Vortherms & Roth, 2006; Gonzalez et al, 2006). It is used by Mazatec curanderos (healers) for its hallucinogenic effects (Valdes, 1994). The leaves of the plant have sometimes been referred to as "ska pastora" or "ska Maria pastora" which means "leaves of the shepherdess" or "leaves of Mary the shepherdess" (Gonzalez et al, 2006). The hallucinatory effects are reportedly intense and last for up to an hour (Sheffler & Roth, 2003).
    2) In the past decade, S. divinorum has been used increasingly as a recreational drug among adolescents and young adults (Singh, 2007; Vortherms & Roth, 2006; Bucheler et al, 2005). Since the drug is not considered a "party-drug", it tends to appeal to individual experimentation. The plant has been described as a tool to aid in meditative introspection. It may also have role in assisting individuals in daily life to perform meditation or use it in healing rituals (Bucheler et al, 2005; Valdes, 1994).
    a) The availability of S. divinorum leaves and extracts through Internet sales has lead to the increased use of this plant, particularly in the US and Europe (Vortherms & Roth, 2006). In the US, the American Drug Enforcement Agency (DEA) has placed it on a list of drugs or chemicals "of concern"; no legal restrictions are currently in place (Rosenbaum et al, 2012; Bucheler et al, 2005). However, it has been outlawed in Australia, Finland, Denmark, Spain, Japan and Norway (Rosenbaum et al, 2012; Singh, 2007).
    3) Salvia divinorum may also have an antidepressant effect (Hanes, 2001; Grundmann et al, 2007). One woman with a history of depression reported a relief of symptoms after daily use (Hanes, 2001).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Salvia divinorum is a member of the mint (Lamiaceae) family and the leaves of the plant have been used for divination and shamanism by the Mazatec Indians. In the past decade, S. divinorum has been used increasingly as a recreational drug among adolescents and young adults. Since the drug is not considered a "party-drug", it tends to appeal to individual experimentation. It has been labeled by the DEA as a "drug of concern" even though it is not officially a scheduled drug. The drug can be ingested by chewing, swallowing or smoking. The leaves can be smoked in a similar method to marijuana (ie, "Sally D" cigarette).
    B) TOXICOLOGY: Salvia is a powerful dissociative intoxicant which has hallucinogenic properties. The active ingredient of Salvia divinorum is Salvinorin A, a neoclerodane diterpine, which acts as a potent hallucinogen that is a highly selective full agonist of the kappa-opioid receptor. As many as 5 other compounds (salvinorin B through E is thought to be inactive and Salvinorin F {status unknown}) have been extracted from the leaves of the plant, but do NOT appear to have the same hallucinogenic effects as Salvinorin A.
    C) EPIDEMIOLOGY: Exposure has occurred. It is readily available via the internet or sold at local head shops. Individuals may be more willing to use this agent because of its perceived lack of serious toxicity.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS reported following salvia recreational use have included: fatigue/tiredness, dizziness, physical exhaustion, grogginess, and mental slowness. Following salvia use individuals have complained of a lack of control over the experience and unpleasant side effects. After SMOKING Salvia divinorum some individuals complain of a feeling of being pushed or pulled that has been described as "Salvia gravity" in which users may feel pinned to the floor or ground after exposure.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Recreational use of saliva divinorum has produced psychoactive effects including hallucinations. No fatalities have been reported.
    2) DURATION: Intense very short-term hallucinogenic experience.
    3) INHALATION: Duration of effect has been described as less than a minute or between 1 and 5 minutes in individuals that smoked the extract. Others report up to 15 minutes to one hour following inhalation. Some have described that the "high" may last for up to 2 hours depending on potency.
    4) TRANSMUCOSAL ABSORPTION: Fresh leaves are rolled and masticated (quid method) and the juice is swallowed with reported effects developing within 3 to 5 minutes of ingestion and may last for up to 1 hour and recur for up to 4 hours. Reportedly, ingesting the leaves results in minimal absorption among some individuals.
    5) TYPICAL USER: Consumers of S. divinorum tend to be adolescents or young adults who desire individual experimentation that are seeking meditative introspection; it is not considered a party-drug.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Chills and shivering have been described after the use of S. divinorum.
    2) A reduction in body temperature has been reported in animal studies following exposure to salvinorin A.
    3) There have also been subjective complaints of hyperthermia among recreational users.

Laboratory Monitoring

    A) No routine laboratory studies are indicated. If mixed ingestion; obtain tests as necessary.
    B) Serum salvia levels are not clinically available or useful.
    C) Monitor vital signs including temperature in symptomatic individuals.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) SUMMARY
    1) The typical route of exposure is by inhalation. See the Inhalation overview for further treatment information.
    0.4.3) INHALATION EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Limited case reports are available in the literature. Adverse events are generally mild and resolve quickly. The duration of effects following inhalation or vaporization is 1 to 2 hours with some individuals reporting effects up to 4 hours after exposure. AGITATION: Minimize stimulation. Sedate patient with benzodiazepines as necessary; large doses may be required. A dimly lit, quiet environment with minimal stimulation, but with adequate observation should be provided during assessments. HALLUCINATIONS: Reassurance and a quiet environment may be helpful in patients who are experiencing hallucinations.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Serious adverse events are not anticipated and have not occurred with salvia divinorum alone.
    C) DECONTAMINATION
    1) PREHOSPITAL: GI absorption is minimal, gastric decontamination is NOT recommended. The typical route of exposure is inhalation.
    2) HOSPITAL: GI absorption is minimal. Gastric decontamination is unlikely to be necessary unless other agents have been ingested.
    D) ANTIDOTE
    1) There is no known antidote.
    E) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary following mild to moderate exposure; effects of saliva usually terminate quickly. Support airway as needed. Coingestion of other recreational agents or alcohol may require further monitoring.
    F) ENHANCED ELIMINATION
    1) Enhanced elimination is unlikely to be necessary.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Adults that are experiencing minimal symptoms may be monitored at home if a responsible, sober adult is present. In the event, of a pediatric exposure home care is not indicated for any type of exposure.
    2) OBSERVATION CRITERIA: Patients with more than minimal symptoms (agitation, hallucinations) and children with any exposure should be sent to a healthcare facility for evaluation and observed for 4 to 6 hours as indicated.
    3) ADMISSION CRITERIA: Due to a short duration of effects (an average of 1 to 2 hours for most individuals) it is unlikely that patients would require hospital admission following S. divinorum exposure. Patients with significant persistent central nervous system toxicity (i.e., agitation or anxiety) or persistent hallucinogenic effects should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Patients should be referred for substance abuse counseling as appropriate.
    H) TOXICOKINETICS
    1) The active compound is trans-neoclerodane diterpene known as salvinorin A. It is a psychotropic terpenoid, and its psychotropic effects appear to be the result of kappa-opioid receptor (KOR) stimulation. It is a selective, full, and very efficacious agonist for KOR. Neutropic effects mediated by KOR include analgesia, sedation, dysphoria, and perceptual distortions. Salvinorin A is well absorbed by the respiratory tract, and minimally absorbed by the gastrointestinal system based on animal studies conducted in mice. Unlike classic hallucinogens such as LSD, psilocybin or mescaline, it does not interact with 5-hydroxytryptamine 2A-receptors and shows no affinity to mu- and delta-opioid receptors. Salvinorin A also does not interact with binding-sites for norepineprhine, dopamine, glutamine, and GABA-transporters. In an animal study with non-human primates administered an intravenous 0.032 mg/kg bolus of salvinorin A, the distribution phase was nearly complete within 5 minutes of administering the bolus and the overall elimination half-life was 37.9 and 80.0 minutes in male and female primates, respectively.
    I) DIFFERENTIAL DIAGNOSIS
    1) Other drugs of abuse (eg, LSD, psilocybin or mescaline) that may produce hallucinogenic effects. Coingestion of other agents (eg, alcohol or cannabis) that may prolong the effects of salvia divinorum.

Range Of Toxicity

    A) TOXICITY: A toxic dose has not been established. Profound hallucinations have been reported at doses of 200 to 500 micrograms after vaporization or inhalation of salvinorin A. Doses higher than 1 mg have commonly resulted in out-of-body experiences. It has been shown that taking it orally has resulted in little or no response in some individuals due to poor GI absorption. Individuals may become unaware of their surroundings and develop uncontrollable delirium following doses of greater than 500 micrograms.
    B) RECREATIONAL USE: Based on products sold over the Internet or paraphernalia shops ("head shops"), the extract is available in strengths of 5, 10, or 20 times the original salvinorin A concentration. Adulteration with caffeine and vitamin E have been found in some products. Serious adverse effects are rare at usual recreational doses.

Clinical Effects

Summary Of Exposure

    A) USES: Salvia divinorum is a member of the mint (Lamiaceae) family and the leaves of the plant have been used for divination and shamanism by the Mazatec Indians. In the past decade, S. divinorum has been used increasingly as a recreational drug among adolescents and young adults. Since the drug is not considered a "party-drug", it tends to appeal to individual experimentation. It has been labeled by the DEA as a "drug of concern" even though it is not officially a scheduled drug. The drug can be ingested by chewing, swallowing or smoking. The leaves can be smoked in a similar method to marijuana (ie, "Sally D" cigarette).
    B) TOXICOLOGY: Salvia is a powerful dissociative intoxicant which has hallucinogenic properties. The active ingredient of Salvia divinorum is Salvinorin A, a neoclerodane diterpine, which acts as a potent hallucinogen that is a highly selective full agonist of the kappa-opioid receptor. As many as 5 other compounds (salvinorin B through E is thought to be inactive and Salvinorin F {status unknown}) have been extracted from the leaves of the plant, but do NOT appear to have the same hallucinogenic effects as Salvinorin A.
    C) EPIDEMIOLOGY: Exposure has occurred. It is readily available via the internet or sold at local head shops. Individuals may be more willing to use this agent because of its perceived lack of serious toxicity.
    D) WITH THERAPEUTIC USE
    1) ADVERSE EFFECTS reported following salvia recreational use have included: fatigue/tiredness, dizziness, physical exhaustion, grogginess, and mental slowness. Following salvia use individuals have complained of a lack of control over the experience and unpleasant side effects. After SMOKING Salvia divinorum some individuals complain of a feeling of being pushed or pulled that has been described as "Salvia gravity" in which users may feel pinned to the floor or ground after exposure.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. Recreational use of saliva divinorum has produced psychoactive effects including hallucinations. No fatalities have been reported.
    2) DURATION: Intense very short-term hallucinogenic experience.
    3) INHALATION: Duration of effect has been described as less than a minute or between 1 and 5 minutes in individuals that smoked the extract. Others report up to 15 minutes to one hour following inhalation. Some have described that the "high" may last for up to 2 hours depending on potency.
    4) TRANSMUCOSAL ABSORPTION: Fresh leaves are rolled and masticated (quid method) and the juice is swallowed with reported effects developing within 3 to 5 minutes of ingestion and may last for up to 1 hour and recur for up to 4 hours. Reportedly, ingesting the leaves results in minimal absorption among some individuals.
    5) TYPICAL USER: Consumers of S. divinorum tend to be adolescents or young adults who desire individual experimentation that are seeking meditative introspection; it is not considered a party-drug.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Chills and shivering have been described after the use of S. divinorum.
    2) A reduction in body temperature has been reported in animal studies following exposure to salvinorin A.
    3) There have also been subjective complaints of hyperthermia among recreational users.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) ANIMAL DATA: Rectal body temperature was reduced in mice following the administration of salvinorin A, similar to other kappa-opioid receptor agonists (Ansonoff et al, 2006).
    2) Chills and shivering have been described by individuals during or immediately following the use of S. divinorum (Bucheler et al, 2005).
    3) There have also been subjective complaints of hyperthermia among recreational users of S. divinorum (Dalgarno, 2007).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) CARDIAC FINDING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES
    1) In a retrospective review of Salvia species exposures reported to the California Poison Control System from 1998 to 2008, there were 37 intentional exposures to S. divinorum, of which 18 (49%) were S. divinorum only exposures. Tachycardia was reported in 2 patients and one patient developed palpitations following acute exposure to S. divinorum alone. Overall, no serious adverse events were observed with the isolated use of S. divinorum; however, the relatively common use of coingestants (i.e., alcohol, marijuana, ecstasy, GHB) increased toxicity (Vohra et al, 2011).
    b) ANIMAL STUDIES
    1) Studies in animals have shown that S. divinorum can effect blood pressure, and may influence the ischemic tolerance of the myocardium, and the induction of cardiac dysrhythmias (Bucheler et al, 2005).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DEPRESSIVE DISORDER
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A woman reported significant improvement in her depressive mood following the regular use of S. divinorum (Hanes, 2001).
    b) The potential for use as an antidepressant remains unknown (Dalgarno, 2007; Siebert, 2004).
    B) DIZZINESS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective review of Salvia species exposures reported to the California Poison Control System from 1998 to 2008, there were 37 intentional exposures to S. divinorum, of which 18 (49%) were S. divinorum only exposures. Dizziness was reported in one patient following acute exposure to S. divinorum alone. Overall, no serious adverse events were observed with the isolated use of S. divinorum; however, the relatively common use of coingestants (i.e., alcohol, marijuana, ecstasy, GHB) increased toxicity (Vohra et al, 2011).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) DIURESIS
    1) WITH POISONING/EXPOSURE
    a) Diuresis and increased sweating have been described following the use of S. divinorum, which may be related to its role as a potent agonist of cerebral kappa-opioid receptors (KOR) (Bucheler et al, 2005).
    b) CASE SERIES: In a retrospective review of Salvia species exposures reported to the California Poison Control System from 1998 to 2008, there were 37 intentional exposures to S. divinorum, of which 18 (49%) were S. divinorum only exposures. Diaphoresis was reported in one patient following acute exposure to S. divinorum alone. Overall, no serious adverse events were observed with the isolated use of S. divinorum; however, the relatively common use of coingestants (i.e., alcohol, marijuana, ecstasy, GHB) increased toxicity (Vohra et al, 2011).
    B) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective review of Salvia species exposures reported to the California Poison Control System from 1998 to 2008, there were 37 intentional exposures to S. divinorum, of which 18 (49%) were S. divinorum only exposures. Flushing was reported in three patients following acute exposure to S. divinorum alone. Overall, no serious adverse events were observed with the isolated use of S. divinorum; however, the relatively common use of coingestants (i.e., alcohol, marijuana, ecstasy, GHB) increased toxicity (Vohra et al, 2011).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) TREMOR
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Somatic reactions reported following repeated inhalation of S. divinorum in a 19-year-old man included muscle tremor, prickling of the skin, and fever-like hot flashes. Effects usually occurred almost immediately following inhalation and resolved within 30 minutes (Bucheler et al, 2005).

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPOGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective review of Salvia species exposures reported to the California Poison Control System from 1998 to 2008, there were 37 intentional exposures to S. divinorum, of which 18 (49%) were S. divinorum only exposures. Hypoglycemia was reported in one patient following acute exposure to S. divinorum alone. Overall, no serious adverse events were observed with the isolated use of S. divinorum; however, the relatively common use of coingestants (i.e., alcohol, marijuana, ecstasy, GHB) increased toxicity (Vohra et al, 2011).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No routine laboratory studies are indicated. If mixed ingestion; obtain tests as necessary.
    B) Serum salvia levels are not clinically available or useful.
    C) Monitor vital signs including temperature in symptomatic individuals.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Serum salvia levels are not clinically available or useful. Specific laboratory levels are not routinely indicated. If mixed ingestion; obtain laboratory studies as indicated.

Methods

    A) GC-MS
    1) Salvinorin A has been detected by using gas chromatography-mass spectrometry (GC-MS) (Grundmann et al, 2007; Giroud et al, 2000) following the methanolic extract of cultivated S. divinorum plant (Giroud et al, 2000).
    2) Using a GC-MS method following extraction from biological matrices, salvinorin A was detected in plasma, urine, saliva, and sweat. The limit of detection was 5 ng/mL and the limit of quantification was 15 ng/mL.
    a) This is currently very little human data. Samples were to be collected and analyzed in 2 volunteers after smoking 75 mg of dried leaves; however, GC-MS was only able to detect Salvinorin A in urine and sweat, because both individuals refused to have blood samples drawn due to intense hallucinations (Grundmann et al, 2007).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Due to a short duration of effects (an average of 1 to 2 hours for most individuals) it is unlikely that patients would require hospital admission following S. divinorum exposure. Patients with significant persistent central nervous system toxicity (i.e., agitation or anxiety) or persistent hallucinogenic effects should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Adults that are experiencing minimal symptoms may be monitored at home if a responsible, sober adult is present. In the event, of a pediatric exposure home care is not indicated for any type of exposure.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Patients should be referred for substance abuse counseling as appropriate.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with more than minimal symptoms (agitation, hallucinations) and children with any exposure should be sent to a healthcare facility for evaluation and observed for 4 to 6 hours as indicated.
    6.3.3) DISPOSITION/INHALATION EXPOSURE
    6.3.3.1) ADMISSION CRITERIA/INHALATION
    A) Due to a short duration of effects (an average of 1 to 2 hours for most individuals) it is unlikely that patients would require hospital admission following S. divinorum exposure. Patients with significant persistent central nervous system toxicity (i.e., agitation or anxiety) or persistent hallucinogenic effects should be admitted.
    6.3.3.2) HOME CRITERIA/INHALATION
    A) Adults that are experiencing minimal symptoms may be monitored at home if a responsible, sober adult is present. In the event, of a pediatric exposure home care is not indicated for any type of exposure.
    6.3.3.3) CONSULT CRITERIA/INHALATION
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear. Patients should be referred for substance abuse counseling as appropriate.
    6.3.3.5) OBSERVATION CRITERIA/INHALATION
    A) Patients with more than minimal symptoms (agitation, hallucinations) and children with any exposure should be sent to a healthcare facility for evaluation and observed for 4 to 6 hours as indicated.

Monitoring

    A) No routine laboratory studies are indicated. If mixed ingestion; obtain tests as necessary.
    B) Serum salvia levels are not clinically available or useful.
    C) Monitor vital signs including temperature in symptomatic individuals.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) GI absorption is minimal, gastric decontamination is not recommended.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. The typical route of exposure is inhalation. See the Inhalation treatment section for further information.

Inhalation Exposure

    6.7.2) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Adverse effects are generally mild and of short duration. There is NO known antidote. No routine labs or diagnostic studies are indicated. Assess neurologic function frequently. Monitor vital signs including temperature in symptomatic patients.
    a) To treat agitation, provide a quiet, dimly lit environment to minimized stimulation. Oral or intravenous benzodiazepines may be used as needed. Based on limited reports in the literature, the duration of effects following inhalation or vaporization are from 1 to 2 hours and may extend to 4 hours in some individuals.
    b) Salvinorin A has been shown to be a selective and very efficacious agonist for kappa opioid receptors (KOR); therefore, opioid antagonists like naloxone or naltrexone which have reduced affinity to KOR may not be useful antidotes (Bucheler et al, 2005). However, there are some anecdotal reports that naloxone can block the effects of salvinorin A in humans (Roth et al, 2004).
    c) The potency of this agent could lead to inadvertent overdose. Hallucinogenic effects have been detected at doses as low as 200 to 500 micrograms after vaporization or inhalation of Salvinorin A (Valdes, 1994).
    B) PSYCHOMOTOR AGITATION
    1) Benzodiazepines are generally effective in controlling agitation and combativeness. Sedate patient with benzodiazepines as necessary; large doses may be required.
    2) INDICATION
    a) If patient is severely agitated, sedate with IV benzodiazepines.
    3) DIAZEPAM DOSE
    a) ADULT: 5 to 10 mg IV initially, repeat every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) CHILD: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    4) LORAZEPAM DOSE
    a) ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed (Manno, 2003).
    b) CHILD: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    5) Extremely large doses of benzodiazepines may be required in patients with severe intoxication in order to obtain adequate sedation. Titrate dose to clinical response and monitor for hypotension, CNS and respiratory depression, and the need for endotracheal intubation.
    6) CHLORDIAZEPOXIDE: ADULT DOSE: 50 to 100 mg, may be an alternative in an uncooperative patient (Kulig, 1990; Strassman, 1984).
    7) PSYCHOLOGIC ASSISTANCE may be helpful in "talking down" some patients who are undergoing a "bad trip". Reassurance by a psychiatrist, psychologist, or a trusted friend may be helpful in ameliorating the acute anxiety state (Ellenhorn, 1997; Gilman et al, 1996).
    8) HALOPERIDOL: May be given at doses of 5 to 10 mg IM or 10 to 20 mg orally, administered hourly as necessary in cases of extreme agitation or hallucinosis (Kulig, 1990; Leikin et al, 1989; Strassman, 1984; Miller et al, 1992).
    C) PSYCHOTIC DISORDER
    1) Based on limited data, some recreational users of salvia have reported episodes of hallucinations and effects similar to other hallucinogens (ie, LSD). Evaluate patient. Provide a calm and reassuring environment may be all that is required due to the rapid absorption of salvia and short duration of clinical effects.
    D) FLASHBACKS
    1) Benzodiazepines may be indicated in cases of acute anxiety.
    E) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Range Of Toxicity

Summary

    A) TOXICITY: A toxic dose has not been established. Profound hallucinations have been reported at doses of 200 to 500 micrograms after vaporization or inhalation of salvinorin A. Doses higher than 1 mg have commonly resulted in out-of-body experiences. It has been shown that taking it orally has resulted in little or no response in some individuals due to poor GI absorption. Individuals may become unaware of their surroundings and develop uncontrollable delirium following doses of greater than 500 micrograms.
    B) RECREATIONAL USE: Based on products sold over the Internet or paraphernalia shops ("head shops"), the extract is available in strengths of 5, 10, or 20 times the original salvinorin A concentration. Adulteration with caffeine and vitamin E have been found in some products. Serious adverse effects are rare at usual recreational doses.

Minimum Lethal Exposure

    A) A minimum lethal exposure has not been determined.

Maximum Tolerated Exposure

    A) Profound hallucinogenic effects have been detected at doses as low as 200 to 500 micrograms after vaporization or inhalation of salvinorin A that last about one hour (Valdes, 1994; Giroud et al, 2000). Individuals may become unaware of their surroundings and develop uncontrollable delirium following doses of greater than 500 micrograms (Imanshahidi & Hosseinzadeh, 2006). Doses higher than 1 mg have commonly resulted in out-of-body experiences (Wolowich et al, 2006; Bucheler et al, 2005). In comparison, hallucinogenic effects can be produced by LSD at doses of 50 to 250 mcg, mescaline at 100 mg, and psilocybin at 5 mg (Wolowich et al, 2006; Gonzalez et al, 2006).
    B) The quickest and most intense method of exposure is sublingual or inhalation by smoking or vaporization (Wolowich et al, 2006).
    C) It has been shown that taking salvia orally has resulted in little or no response in some individuals (Valdes et al, 2001); however mastication allows absorption across the buccal mucosa.
    D) CASE SERIES: In a retrospective review of Salvia species exposures reported to the California Poison Control System from 1998 to 2008, there were 37 intentional exposures to S. divinorum, of which 18 (49%) were S. divinorum only exposures. Most cases were young males between the ages of 15 to 24 who were commonly exposed by smoking (n=14) the plant. Of these cases, 13 (72%) had evidence of psychotomimetic or neuromotor disturbances. The most common clinical events included: confusion or disorientation, hallucinations, giddiness or dizziness, flushed sensation, and tachycardia. Mydriasis (n=2) and hypoglycemia (n=1) were also observed. Overall, no serious adverse events were reported with the isolated use of S. divinorum; however, the relatively common use of coingestants (i.e., alcohol, marijuana, ecstasy, GHB) increased toxicity (Vohra et al, 2011). The authors reported that a dose-response relationship could not be established in this case series.
    E) CASE REPORTS: Two young men developed psychotic symptoms following the chronic use of Salvia divinorum along with cannabis and other drugs of abuse. Mania also occurred in one patient. Once clinically improved, the patients subjectively thought that salvia was the possible cause of their symptoms (El-Khoury & Sahakian, 2015).
    1) CASE REPORT: A 19-year-old man, with a prior brief history of psychotic symptoms 2 years earlier, developed an acute onset of psychotic and manic symptoms within days of consuming unknown quantities of Salvia divinorum and cannabis. He was brought to the hospital by his family for treatment and was started on a combination of olanzapine and valproic acid used as a mood stabilizer. He did well until he gradually stopped taking the medications. He had an abrupt onset of symptoms which included persecutory and grandiose delusions with some episodes of elevated mood (ie, restlessness, overactivity, increased libido, sexual disinhibition). During this event, treatment included lithium, carbamazepine and olanzapine to regulate his mood. Due to sedative effects, olanzapine was tapered and gradually stopped and replaced with aripiprazole. Although his psychotic symptoms stopped, he had a loss of motivation and partial global impairment in executive functioning that was persistent (El-Khoury & Sahakian, 2015).
    2) CASE REPORT: A 24-year-old man with no history of psychotic disorders developed paranoid persecutory delusions, social avoidance and restlessness after a 12 month history of daily cannabis use, twice weekly cocaine use and smoking Salvia divinorum 2 to 3 times a week. A routine urine analysis was negative for most substances of abuse (ie, opiates, cocaine, THC, amphetamines). Initial treatment included risperidone and alprazolam. The following day he developed neck dystonia and was admitted to a psychiatric care unit and started on olanzapine that was continued for 2 months with resolution of symptoms. However, he showed signs of depression and was started on sertraline. About 3 months after treatment, the patient restarted his use of cocaine (twice a week), cannabis (8 joints twice weekly) and Saliva divinorum (up to 8 cigarettes twice weekly). He did not report any psychotic symptoms but depressive symptoms continued and the patient was gradually switched to venlafaxine and aripiprazole (El-Khoury & Sahakian, 2015).
    F) MAZTEC CULTURE
    1) In the Maztec culture, doses of 5 to 80 pairs of leaves are used to produce the hallucinatory effects; taking fewer than 20 pairs of leaves may produce little or no effect. The effects are enhanced when taken in a quiet and low lit environment, which can produce visions that last 1 to 2 hours (Valdes, 1994).
    G) ANIMAL STUDIES
    1) In toxicity studies, mice were given doses of 1 g/kg of salvinorin A and were observed for a week with no obvious clinical effects noted. It was determined that salvinorin A was not absorbed in the gastrointestinal tract when ingested, since it does not dissolve in aqueous solutions (Valdes, 1994).
    2) CHRONIC EXPOSURE: In another study, mice were given 400, 800, 1600, 3200, and 6400 mcg/kg of salvinorin A daily for 2 weeks and developed no histologic evidence of toxicity in the spleen, blood, brain, liver, kidneys, or bone marrow (Imanshahidi & Hosseinzadeh, 2006).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) The plant's active compound has been identified as trans-neoclerodane diterpene known as salvinorin A. It is a psychotropic terpenoid (Wolowich et al, 2006), and its psychotropic effects appear to be the result of kappa-opioid receptor (KOR) stimulation. Neutropic effects mediated by KOR include analgesia, sedation, dysphoria, and perceptual distortions; it may also have a role in relieving depression (Bucheler et al, 2005; Hanes, 2001).
    1) Salvinorin A is a selective, full, and very efficacious agonist for KOR. Unlike classic hallucinogens such as LSD, psilocybin or mescaline, it does not interact with 5-hydroxytryptamine 2A-receptors and shows no affinity to mu- and delta-opioid receptors. Salvinorin A also does not interact with binding-sites for norepineprhine, dopamine, glutamine, and GABA-transporters (Bucheler et al, 2005).

References

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