Salvia divinorum

# Research Output: Salvia divinorum

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## Botanical Identity

**Accepted binomial:** *Salvia divinorum* Epling & Játiva [Ref 19]

**Family:** Lamiaceae (mint family)

**Genus/Section:** *Salvia* L., subgenus *Calosphace*, section *Dusenostachys* (placement contested — see molecular phylogenetics below)

**First formal description:** Epling C & Játiva-M C, *Botanical Museum Leaflets* 20(3): 75–76 (1962) [Ref 4, Ref 19]. The type specimen was collected by R. Gordon Wasson and Albert Hofmann during their 1962 expedition to the Sierra Mazateca of Oaxaca, Mexico [Ref 4].

**Native range:** Sierra Mazateca, Oaxaca, Mexico. The species occurs in humid, shaded cloud-forest ravines and stream margins at elevations primarily between 300–1,800 m. Its native range is extremely restricted — confined to a small area of the Sierra Mazateca [Ref 5, Ref 19].

**Distribution:** Mexico Southwest only (POWO classification: subtropical biome) [Ref 19]. Not known to occur naturally outside this region.

**Cultivation status:** Both wild-harvested and cultivated. *S. divinorum* rarely sets viable seed outside its native habitat and is propagated almost entirely vegetatively (stem cuttings); all material in cultivation worldwide derives from a small number of clonal lineages introduced in the 1960s–1980s [Ref 4, Ref 5]. Cultivated plants are grown globally as ornamentals and for recreational/research use.

**Morphology:** Perennial, rhizomatous herb growing to 1+ metre in height. Hollow, square stems characteristic of Lamiaceae. Large, ovate, slightly serrated leaves. White flowers with violet calyces; blooms rarely under cultivation. Peltate glandular trichomes are the primary site of salvinorin A biosynthesis and accumulation [Ref 39].

**Molecular phylogenetics:** Jenks et al. (2011 [Ref 18]) sequenced ITS, trnL-trnF, and psbA-trnH DNA regions of 52 species representing major lineages of subgenus *Calosphace*. Results showed *S. divinorum* should NOT be classified within section *Dusenostachys* as previously assumed, and it is NOT an interspecific hybrid (contradicting an earlier hypothesis). The closest known relative is *S. venulosa*, a rare endemic of Colombia [Ref 18].

**Misidentification risk:** Not known to closely resemble toxic species under normal horticultural conditions. However, enhanced-extract products sold online sometimes mislabel concentration levels (see Alkaloid Profile). Other *Salvia* species (e.g., common sage *S. officinalis*) have no significant psychoactive properties.

**Discrepancies with seed data:** The brief listed no seed data for family, genus/species, or native range. All botanical data above is sourced from primary publications and the POWO taxonomy database [Ref 19]. There are no contradictions to resolve.

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## Alkaloid / Cannabinoid Profile

*S. divinorum* is classified as a plant article — its active constituent is a diterpenoid, not an alkaloid or cannabinoid. The correct chemical class is neoclerodane diterpenoid.

### Primary Active Constituent: Salvinorin A

**PubChem CID:** 128563 [database lookup confirmed]
**Molecular formula:** C₂₃H₂₈O₈
**Molecular weight:** 432.5 g/mol
**IUPAC name:** methyl (2S,4aR,6aR,7R,9S,10aS,10bR)-9-acetyloxy-2-(furan-3-yl)-6a,10b-dimethyl-4,10-dioxo-2,4a,5,6,7,8,9,10a-octahydro-1H-benzo[f]isochromene-7-carboxylate
**InChIKey:** OBSYBRPAKCASQB-AGQYDFLVSA-N

Salvinorin A is a neoclerodane diterpenoid — notably, it contains **no nitrogen atom**, making it structurally unique among potent opioid receptor ligands, which typically require a basic nitrogen for receptor engagement. It is the first reported naturally occurring, non-nitrogenous kappa-opioid receptor (KOR) agonist (Roth et al. 2002 [Ref 1]).

**Historical isolation:** Salvinorin A was first reported as "salvinorin" by Ortega et al. (1982) [unverifiable — pre-digital publication; cited in Casselman 2014 [Ref 4]] and independently isolated and named "divinorin A" by Valdes et al. (1984) [unverifiable; cited in Casselman 2014 [Ref 4]]. The two compounds were subsequently confirmed to be identical.

### Quantified Concentrations in Plant Material

Chambers et al. (2023 [Ref 36]) using DART-HRMS on commercially available products:
- **Raw/dried leaf material:** average 1.54 mg/g (range across published studies: 0.89–7.8 mg/g)
- **Enhanced leaf extracts (commercial):** 13.0–53.2 mg/g (e.g., "5×" extract: 13.0 mg/g; "50×" extract: 53.2 mg/g; "60×" extract: 29.3 mg/g)
- **Important caveat:** Labeled potency multipliers do NOT reliably correspond to actual salvinorin A concentrations. Similar inconsistencies have been documented in Japan, the US, Portugal, and Mexico [Ref 36]. The number on a label (e.g., "20×") is not a validated dosing guide.

### Preparation and Concentration Ratios

Salvinorin A is heat-stable enough to survive combustion/vaporization. When leaves are smoked or vaporized, salvinorin A is the active agent delivered to the respiratory mucosa. When leaves are ingested orally, salvinorin A is rapidly hydrolyzed by gastrointestinal esterases to **salvinorin B** (the primary metabolite), which is pharmacologically inactive at KOR (Brito-da-Costa et al. 2021 [Ref 2]).

### Minor Constituents

*S. divinorum* contains additional minor neoclerodane diterpenoids including salvinorin B through J, and divinatorins A–F. These have been identified by analytical studies (cited in Grundmann et al. 2007 [Ref 25]) but occur at trace concentrations and do not contribute meaningfully to the plant's psychoactive profile. Salvinorin B (the primary metabolite of salvinorin A) is produced by ester hydrolysis and is inactive [Ref 2].

**FLAG for generation agent:** No published HPLC quantification study comparing salvinorin concentrations across cultivars/genotypes was identified in this search. Variability exists (range 0.89–7.8 mg/g in published literature) but cultivar-level data are not available. Note this absence.

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## History & Ethnobotany

### Indigenous Traditional Use

*S. divinorum* has been used for centuries by the Mazatec people of the Sierra Mazateca, Oaxaca, Mexico, where it is known by several names including *ska María pastora* ("leaves/herb of Mary the Shepherdess"), *yerba de la pastora*, *hierba de la Virgen*, and *hojas de María Pastora* [Ref 5, Ref 37]. The Mazatec use the plant in divinatory healing ceremonies (*veladas*), where a *curandera* (healer) or patient consumes the plant to enter a visionary state for diagnostic spiritual healing or treatment [Ref 4, Ref 37].

Traditional preparation methods documented by Diaz (2013 [Ref 37]), from field research conducted 1973–1983:
1. **Fresh leaf quid:** Crushed or rolled fresh leaves held in the mouth; slow buccal absorption; produces a more gradual, milder experience
2. **Water infusion/decoction:** Crushed fresh leaves mixed with water and drunk; effects reported as milder still, consistent with GI hydrolysis reducing bioavailability
3. **Direct chewing:** Leaves chewed slowly with juice held in the mouth

Diaz (2013 [Ref 37]) documented that the traditional water potion produced "short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and increased visual and auditory imagery, but not actual hallucinations" — considerably milder than the smoked preparation's intense effects.

**FLAG: Traditional-use section relies substantially on Diaz 2013 (Ref 37), which is a retrospective report from 1973–1983 field observations without contemporaneous publication. This section should be flagged for human editorial review of ethnographic sources.**

### Western Scientific History

- **1938–1962:** R. Gordon Wasson, ethnomycologist, documented Mazatec ritual use during multiple Mexico expeditions. He and Albert Hofmann (discoverer of LSD) collected the first flowering *S. divinorum* specimen in 1962 [Ref 4].
- **1962:** Epling & Játiva publish formal botanical description in *Botanical Museum Leaflets* [Ref 19].
- **1982:** Ortega et al. first isolate salvinorin from the leaves [unverifiable].
- **1984:** Valdes et al. independently isolate "divinorin A" (= salvinorin A) [unverifiable].
- **1994:** Siebert publishes first systematic pharmacological investigation documenting that inhalation produces psychoactive effects [unverifiable by API — not found in PubMed; cited in Casselman 2014 [Ref 4] and Zawilska 2013 [Ref 5]].
- **1990s–2000s:** Plant gains popularity as a legal alternative to classical hallucinogens; internet sales begin; international awareness grows [Ref 5, Ref 23].
- **2002:** Roth et al. (PNAS) establish kappa-opioid receptor agonism as mechanism (776 citations) [Ref 1]. This is the landmark mechanistic discovery.
- **2004:** Chavkin et al. confirm salvinorin A as a full agonist at human KOR [Ref 35].
- **Mid-2000s:** Wave of US state-level scheduling; international bans follow [Ref 20, Ref 30].
- **2009:** DEA lists as Drug of Concern (no formal scheduling initiated) [Ref 20].
- **2011–2016:** Multiple human controlled studies at Johns Hopkins, Yale, UC San Diego [Ref 3, Ref 10, Ref 11, Ref 12, Ref 14].
- **2016:** UK Psychoactive Substances Act bans all legal highs including *S. divinorum* [Ref 30].
- **2020s:** Growing research interest in salvinorin analogues for therapeutic applications (pain, addiction, GI disease) [Ref 39, Ref 41].

---

## Neuroscience & Mechanism

### Primary Receptor Target

Salvinorin A is a **selective full agonist at the kappa-opioid receptor (KOR/κ-opioid receptor)** with no clinically significant activity at the serotonin 5-HT₂A receptor, the canonical target of classical psychedelics (Roth et al. 2002 [Ref 1]; Maqueda et al. 2016 [Ref 10]). This was definitively confirmed in humans: naltrexone (opioid receptor antagonist) fully blocked salvinorin A's subjective, cardiovascular, and neuroendocrine effects, whereas ketanserin (5-HT₂A antagonist) did not [Ref 10].

Key receptor characteristics:
- **Highly selective:** no significant activity at a battery of 50 receptors, transporters, and ion channels tested by Roth et al. [Ref 1]
- **Full agonist efficacy** at cloned human KOR (Chavkin et al. 2004 [Ref 35])
- **β-arrestin-biased signaling:** Salvinorin A displays pronounced β-arrestin-biased signaling that distinguishes it from endogenous dynorphins and classical KOR agonists, producing rapid receptor desensitization (Ganado et al. 2026 [Ref 9])
- **Non-nitrogenous:** unique scaffold enabling different binding epitope from classical opioids; binds residues in TM II and VII of KOR rather than TM III aspartate [Ref 39]

### CNS Mechanism

Kappa-opioid receptor systems are powerful counter-modulatory mechanisms to dopaminergic function (Butelman & Kreek 2015 [Ref 6]):

1. **Thalamocortical disruption:** Primary mechanism for hallucinogenic/dissociative effects. KOR activation in thalamocortical circuits produces the profound perceptual alterations [Ref 9].
2. **Mesolimbic dopaminergic suppression:** Salvinorin A decreases extracellular dopamine in the nucleus accumbens (NAc) without affecting serotonin (Carlezon et al. 2006 [Ref 34]; Zhang et al. 2005). This dopaminergic suppression explains the aversive/dysphoric quality and low abuse potential.
3. **Fragmentation of large-scale brain networks** (functional connectivity disruption; Ganado et al. 2026 [Ref 9]).
4. **Neuroendocrine effects:** Dose-related increases in prolactin and cortisol in humans (Ranganathan et al. 2012 [Ref 12]).

The endogenous KOR ligands (dynorphins) are involved in the stress response and counter-modulate dopaminergic reward. This system explains salvinorin A's unique profile: intense hallucinogenic/dissociative effects WITHOUT the euphoria and reward typical of serotonergic psychedelics or opioids [Ref 6, Ref 9].

### Pharmacokinetics by Preparation Route

**Smoked/Vaporized (primary recreational and research route):**
- Onset: ~2 minutes (peak effects at 2 min, the first time point measured in Johnson 2011 [Ref 3])
- Duration: ~15–20 minutes (definite subjective effects absent at ~20 minutes [Ref 3])
- Dose range studied in humans: 0.375–21 μg/kg inhaled (Johnson 2011 [Ref 3]); EUDA reports 200–500 μg as typical doses for vivid effects [Ref 29]
- Absorption: rapid respiratory mucosa absorption; near-immediate CNS distribution

**Traditional Quid / Fresh Leaf Buccal Preparation:**
- Onset: approximately 15–30 minutes (traditional use reports from Diaz 2013 [Ref 37]; Casselman 2014 [Ref 4])
- Duration: reported 30–90 minutes in traditional contexts [Ref 37]
- Effects: milder, more gradual than smoked; characterized by dysphoria, tactile and proprioceptive sensations, depersonalization rather than full hallucinations [Ref 37]
- Absorption: buccal mucosal absorption bypassing GI hydrolysis, but less efficient than inhalation
- **FLAG:** No published controlled pharmacokinetic study of the buccal quid preparation exists. Traditional-use data and Diaz's field observations are the primary source for this preparation's onset/duration profile.

**Sublingual:**
- Mendelson et al. (2011 [Ref 14]): placebo-controlled trial of sublingual salvinorin A — **no psychoactive effects** were produced. Authors concluded sublingual bioavailability is negligible under the conditions tested.

**Oral (swallowed):**
- Inactive: rapid esterase hydrolysis to inactive salvinorin B in the gastrointestinal tract (Brito-da-Costa et al. 2021 [Ref 2])
- No controlled human data exist for oral administration

**Pharmacokinetic Parameters (animal data — rat, i.p., Teksin et al. 2009 [Ref 15]):**
- Plasma half-life: 75 minutes
- Brain half-life: 36 minutes
- Volume of distribution (Vd): 47.1 L/kg (extensive distribution)
- Clearance (Cl/F): 26 L/h/kg (rapid)
- Brain-to-plasma ratio: 0.050
- P-glycoprotein substrate (confirmed by P-gp ATPase assay)

**Human PK note:** No published formal human pharmacokinetic study with plasma concentration-time data exists. The rapid time course of effects (onset 2 min, offset 20 min when smoked) is consistent with rapid CNS penetration and rapid elimination [Ref 3].

### CYP Enzyme Involvement

Teksin et al. (2009 [Ref 15]) identified the following human CYP isoforms as metabolizing salvinorin A in vitro:
- **CYP2D6** (14.7% decrease in concentration after incubation)
- **CYP1A1** (significant substrate)
- **CYP2E1** (31.1% decrease — greatest effect)
- **CYP2C18** (significant substrate)
- **UGT2B7** (glucuronidation pathway)

**Clinical implication:** Drugs inhibiting CYP2D6 or CYP2E1 could potentially increase salvinorin A plasma levels and prolong effects. However, no clinical pharmacokinetic interaction studies have been conducted in humans. All interaction data are in vitro/preclinical only.

---

## Effects & Dose by Preparation

### Smoked/Vaporized (from controlled human studies)

**Doses studied:** 0.375–21 μg/kg inhaled (Johnson et al. 2011 [Ref 3])
**Onset:** ~2 minutes (first time point measured; peak coincides with onset)
**Duration:** ~15–20 minutes (definite effects absent by ~20 min [Ref 3])

**Effect profile (from Johnson 2011 [Ref 3], MacLean 2013 [Ref 11], Ranganathan 2012 [Ref 12], Addy 2012 [Ref 13]):**
- Dose-related increases on Hallucinogen Rating Scale and Mysticism Scale
- Internal and external hallucinations (highly dose-dependent)
- Spatial disorientation, loss of sense of physical location
- Vestibular and interoceptive signal disruption (feelings of pressure, being pulled/pushed)
- Proprioceptive distortions; body schema alterations
- Depersonalization and derealization
- Amnesia for portions of the experience (MacLean 2013 [Ref 11])
- Entity contact and encounters with "beings" or presences
- Revisiting of childhood memories and scenarios (recurring theme across sessions)
- Cartoon-like or animated visual imagery
- Temporal disorientation
- Post-acute: residual fatigue, mild cognitive fog lasting hours (Addy 2012 [Ref 13])
- Cardiovascular: Johnson 2011 found **no significant increase** in heart rate or blood pressure across doses up to 21 μg/kg

**Effect modifiers:** Pre-existing hallucinogen experience (participants were experienced users), comfortable setting, supportive supervision. Set and setting confirmed important by Hutton et al. (2016 [Ref 24]).

### Traditional Quid / Fresh Leaf Buccal Method

**Dose:** Typically 8–28 fresh leaves (numbers vary in ethnographic reports) held and chewed in the mouth for 15–30 minutes, with juice held sublingually
**Onset:** Approximately 15–30 minutes [Ref 37, Ref 4]
**Duration:** 30–90 minutes [Ref 37]
**Effects:** Based on Diaz (2013 [Ref 37]) field research 1973–1983:
- Light-headedness
- Dysphoria (common)
- Tactile and proprioceptive sensations
- Depersonalization
- Amplified sound perception
- Increased visual and auditory imagery but generally NOT full visual hallucinations at traditional doses

**FLAG for generation agent:** The distinction between quid effects and smoked effects is important but relies on uncontrolled traditional-use reports for the quid preparation. No RCT or controlled study has compared quid vs smoked in the same population.

### Water Infusion/Tea

- Used traditionally; leaves crushed and mixed with cold water
- Presumed less potent than quid due to lower buccal contact time and potential GI degradation
- No controlled study data exist for this preparation; traditional use data only [Ref 37]
- **FLAG:** No published dose-response or PK data for water infusion. Traditional-use accounts are the only evidence.

### Commercial Enhanced Extracts

- Products labeled 5×, 10×, 20×, 50× etc. are enriched leaf material
- Salvinorin A content: 13.0–53.2 mg/g (Chambers et al. 2023 [Ref 36])
- Labels do NOT reliably predict actual potency; considerable inter-product variability
- Typically smoked; same pharmacokinetics as smoked dried leaf but higher dose per gram of material
- **FLAG:** No published controlled human study using commercial enhanced extracts exists.

---

## Safety & Toxicity

### Toxicology Data

**Human LD50:** Not established. No human fatalities directly attributed to salvinorin A alone have been reported in the published literature (Brito-da-Costa et al. 2021 [Ref 2]; Calado et al. 2025 [Ref 8]).

**Animal LD50:** Not formally established in published literature. The systematic review by Zürrer et al. (2025 [Ref 7]) found no evidence of significant physiological toxicity in preclinical models at psychoactive doses.

**No reports of serious physiological adverse outcomes** have been documented in published literature (Grundmann et al. 2007 [Ref 25]; Brito-da-Costa et al. 2021 [Ref 2]).

### Cardiovascular Safety

Johnson et al. (2011 [Ref 3]) found no statistically significant increase in heart rate or blood pressure across doses from 0.375–21 μg/kg inhaled in human participants. This is in contrast to classical serotonergic psychedelics, which reliably increase heart rate.

### Psychological Risks

**Acute adverse reactions:**
- Intense fear, panic, and extreme disorientation are common, particularly with smoked high-dose preparations
- Dysphoria is more common than euphoria (especially with quid preparation — Diaz 2013 [Ref 37])
- Unpredictable and extreme intensity of experience may cause psychological distress

**Precipitated or prolonged psychosis:**
- El-Khoury & Sahakian (2015 [Ref 16]) reviewed the literature and presented two case reports linking *S. divinorum* use to persistent psychotic disorders in individuals with possible predispositions
- Dedomenici et al. (2022 [Ref 17]): case report of psychotic episode after unaware consumption, resistant to two pharmacological treatments, ultimately resolved with brexiprazole
- Zawilska & Wojcieszak (2013 [Ref 5]) note that potential psychiatric risks are "especially by teenagers, users of other substances of abuse, and individuals with underlying psychotic disturbances"
- **FLAG:** The causal relationship between *S. divinorum* and persisting psychosis is not established. All case reports involve individuals with potential pre-existing vulnerability. No prospective psychiatric data exist.

### Cognitive Effects

Braida et al. (2011 [Ref 28]) in rats (s.c.):
- Salvinorin A (160–640 μg/kg) impaired spatial long-term memory, episodic memory, and aversive memory
- Short-term memory was NOT impaired
- Effects blocked by selective KOR antagonist nor-BNI, confirming KOR mediation
- Disrupted attentional latent inhibition at 160 μg/kg

**Amnesia** for portions of the experience has been documented in human studies (MacLean et al. 2013 [Ref 11]).

### Tolerance, Dependence, and Withdrawal

**Tolerance:** Repeated use by recreational users commonly results in tachyphylaxis (rapid loss of effect with repeated dosing in a session) — observed in user survey data (Hutton et al. 2016 [Ref 24], Nyi et al. 2010). No formal published tolerance dose-escalation study exists for humans.

**Dependence:** No formal dependence syndrome has been described in published clinical literature. Mahendran et al. (2016 [Ref 21]) note that *S. divinorum* "is widely believed to have low addictive potential." The aversive phenomenology and KOR-mediated dopaminergic suppression (rather than enhancement) are thought to underlie this [Ref 9, Ref 34].

**Withdrawal:** No published withdrawal syndrome has been characterized. Nyi et al. (2010) internet survey: over 52% of users reported use reduction or cessation in the past 12 months, with the most common reason being "dislike of the high" (33%) or "loss of interest" (29%), suggesting low compulsive use.

**Abuse potential:** Ganado et al. (2026 [Ref 9]) and Butelman & Kreek (2015 [Ref 6]) both conclude that salvinorin A has **low abuse potential** due to aversive phenomenology, dopaminergic suppression, and absence of positive reinforcement in animal models.

### Herb–Drug Interactions

**Mechanistic/pharmacokinetic basis (Teksin 2009 [Ref 15]):**
- CYP2D6, CYP2E1, CYP1A1 inhibitors could potentially increase salvinorin A exposure
- P-glycoprotein substrates or inhibitors could alter CNS distribution
- These are **theoretical interactions based on in vitro metabolic data only**. No published clinical pharmacokinetic interaction studies exist for salvinorin A in humans.

**Pharmacodynamic concerns (mechanism-based, no clinical case reports):**
- **CNS depressants** (opioids, benzodiazepines, alcohol, cannabis): additive CNS depression, disorientation, respiratory concern theoretically possible
- **Lithium:** Seizure risk reported anecdotally with lithium + psychedelics combinations. No specific case reports with salvinorin A, but this concern is commonly cited in harm reduction literature [Ref 41 — note: no specific published interaction study found]
- **MAOIs/SSRIs:** Theoretical pharmacodynamic concern given the KOR–serotonin transporter interactions (see Morani 2011 behavioral data). No clinical case reports.
- **Anticholinergics:** No documented interaction
- **FLAG for generation agent:** No herb–drug interaction severity for *S. divinorum* is backed by a clinical case report or formal pharmacokinetic study. All interactions above are theoretical/mechanism-based. This must be clearly labeled as FLAG-level content.

### Contaminant and Adulterant Risks

Commercial products:
- Labeled potency claims are unreliable (Chambers 2023 [Ref 36])
- Plant material may contain pesticide residues (no published survey found)
- No reports of synthetic salvinorin adulteration in published literature
- **FLAG:** No published systematic contaminant/adulterant surveillance of commercial *S. divinorum* products was identified in this research.

### Vulnerable Populations

- **Pre-existing psychiatric conditions:** Strongest contraindication; psychosis risk in vulnerable individuals [Ref 16, Ref 17]
- **Adolescents:** Mahendran 2016 [Ref 21] and Zawilska 2013 [Ref 5] flag elevated risk in adolescents
- **Pregnant/breastfeeding individuals:** No published data exist; no data means no established safety; caution indicated
- **Personal or family history of psychosis or schizophrenia:** Specific caution flagged in multiple reviews
- **Hepatic impairment:** CYP enzyme involvement suggests possible altered metabolism in liver impairment; no published data

---

## Harm Reduction

**Published risk reduction themes (from Hutton et al. 2016 [Ref 24], Kruger et al. 2025 [Ref 41]):**

1. **Set and setting:** Hutton et al. (2016 [Ref 24]) found that set and setting emerged as a major independent theme in user experience; comfortable, familiar, and safe physical environment is considered especially important given the intensity of disorientation
2. **Presence of a sober sitter:** Strongly recommended given motor impairment and loss of reality testing at typical doses; falls and physical injury are risks during peak effects
3. **Dose titration:** Start with low doses when using smoked/vaporized preparations; the potency of commercial extracts is unreliable (Chambers 2023 [Ref 36])
4. **Not for inexperienced users:** Survey data indicate experienced drug users are more likely to approach with harm reduction mindset (Hutton 2016 [Ref 24])
5. **Sitting/lying down:** Due to pronounced vestibular effects and motor control impairment
6. **Short duration awareness:** Alerting users to the ~15–20 minute peak for smoked preparations helps prevent panic about the experience's intensity

**Drug testing:** Standard immunoassay panels (SAMHSA urine drug screens) do NOT detect salvinorin A. Specific LC-MS/MS testing is required (McDonough 2008 [Ref 27]). This has forensic implications.

**Cessation:** No published formal cessation or treatment pathways exist for *S. divinorum* use disorder (no formal use disorder criteria published). The majority of users self-discontinue without professional intervention (Nyi et al. 2010 — based on survey data, not reviewed in PubMed search).

---

## Legal Status

### United States — Federal

*Salvia divinorum* and salvinorin A are **not scheduled** under the Federal Controlled Substances Act (CSA) [Ref 20]. The DEA has listed *S. divinorum* as a "Drug and Chemical of Concern" but has not initiated formal scheduling proceedings. A 2002 Congressional bill to federally ban the substance failed to pass amid objections from scientists concerned about restricting research [Ref 20].

### United States — States

As of 2024–2026, approximately **27 states** have enacted bans or restrictions on *S. divinorum* [Ref 20, Ref 30]. State-level legal frameworks vary:
- **Outright bans** (controlled substance classification): Delaware, Florida, Illinois, Kansas, Kentucky, Louisiana, Mississippi, Missouri, Nebraska, North Dakota, Ohio, Oklahoma, Pennsylvania, South Dakota, Tennessee, Texas, Virginia, and others
- **Age restrictions only:** California (18+), Maine
- **No restriction:** Approximately 22 states including Alaska, Arizona, Idaho, Massachusetts, Montana, Nevada, New Hampshire, New Jersey, New Mexico, New York, Oregon, South Carolina, Utah, Washington, West Virginia, and District of Columbia
- **FLAG:** State-level status changes frequently. This list is based on 2024 sources and may be outdated. Generation agent should flag for editorial verification.

### Canada

*S. divinorum* is **controlled** as a Schedule IV substance under the *Controlled Drugs and Substances Act* (CDSA) [Ref 30]. This scheduling was enacted in 2017.

### United Kingdom

*S. divinorum* is **banned** under the **Psychoactive Substances Act 2016** (effective May 26, 2016), which prohibits the production, supply, and importation of any psychoactive substance not specifically exempted (tobacco, alcohol, medicines, caffeine) [Ref 30]. Salvinorin A is not specifically named — the act applies category-wide.

### Australia

*Salvia divinorum* and salvinorin A are classified as **Schedule 9 Prohibited Substances** under Australia's Therapeutic Goods Act — the most restrictive schedule, equivalent in intent to Schedule I (no accepted medical use) [Ref 30]. Live plants are also prohibited.

### Germany

Controlled under German narcotics law since approximately **2015** [Ref 30].

### European Union

There is no harmonized EU-level control. The following EU member states have domestic restrictions as of 2023–2024: Belgium, Denmark, Estonia, Finland, Iceland (EEA), Ireland, Italy, Romania, Slovakia, Spain, Sweden [Ref 29, Ref 30]. Not all EU member states restrict it.

### International Drug Conventions

*Salvia divinorum* and salvinorin A are **NOT listed** under any of the three UN drug control conventions:
- 1961 Single Convention on Narcotic Drugs
- 1971 Convention on Psychotropic Substances
- 1988 Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances

[Ref 29, Ref 30]. This absence from international scheduling is why the global legal landscape is highly fragmented.

### Other Jurisdictions with Restrictions

Brazil, Japan (controlled since 2007), South Korea, Norway, Poland, India, Vietnam, and others have domestic restrictions [Ref 30].

---

## Clinical Trials

Three completed clinical trials identified on ClinicalTrials.gov [Ref 31, Ref 32, Ref 33]:

1. **NCT03418714** — "Effects of Salvinorin A on Brain Function"
   - Sponsor: Johns Hopkins University
   - Phase: Phase 1
   - Status: COMPLETED
   - Conditions: Drug Effect
   - Related publications: Maqueda et al. 2016 [Ref 10]

2. **NCT01149824** — "Placebo Controlled Study of Sublingual Salvinorin A"
   - Sponsor: California Pacific Medical Center Research Institute
   - Phase: Not applicable
   - Status: COMPLETED
   - Related publications: Mendelson et al. 2011 [Ref 14]

3. **NCT00700596** — "Effects of Salvinorin A in Healthy Controls"
   - Sponsor: Yale University
   - Phase: Early Phase 1
   - Status: COMPLETED
   - Related publications: Ranganathan et al. 2012 [Ref 12]

No currently active or recruiting clinical trials for *Salvia divinorum* or salvinorin A were identified. Research interest has been largely preclinical in recent years, focused on analogues [Ref 39].

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief.

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## Gaps & Flags

### Data Absences

1. **No published human pharmacokinetic study** with plasma concentration–time curves for inhaled salvinorin A exists. All human PK inferences rely on rat data (Teksin 2009 [Ref 15]) and subjective-effects time courses (Johnson 2011 [Ref 3]).

2. **Quid preparation dose-response data absent.** The traditional quid preparation's onset (15–30 min) and duration (30–90 min) are based entirely on ethnographic/traditional-use accounts and field observations (Diaz 2013 [Ref 37]). No controlled study data exist. **FLAG for human review.**

3. **Water infusion preparation.** No published controlled data exist. Traditional-use accounts only. **FLAG for human review.**

4. **No published LD50 data** for salvinorin A in humans or formal preclinical LD50 determination.

5. **No cultivar-level alkaloid quantification** comparing concentration across different clonal lineages or growing conditions.

6. **No contaminant/adulterant surveillance** of commercial *S. divinorum* products identified in this literature search.

7. **No published data for pregnancy, pediatric use, or hepatic impairment** with salvinorin A or *S. divinorum*.

8. **First isolation papers** (Ortega 1982, Valdes 1984, Siebert 1994) are pre-digital or conference-era publications not indexed in PubMed. They are unverifiable by API. Cited as unverifiable via Casselman 2014 [Ref 4].

### Contradictions Between Sources

- Sublingual vs. buccal activity: the traditional quid involves buccal mucosal contact with fresh-leaf juice (including mechanical leaf-chewing stimulation of mucosal blood flow), while Mendelson 2011 [Ref 14] used a sublingual liquid formulation. The distinction may explain why the traditional quid reportedly produces effects while the controlled sublingual trial found none. This discrepancy is noted but not fully resolved in published literature.

### Safety-Critical Flags

1. **All herb–drug interaction severities for *S. divinorum*** are based on in vitro CYP data and theoretical pharmacodynamic mechanisms, not clinical case reports. Generation agent must label these as theoretical/mechanism-based.

2. **Psychosis risk** in the case reports involves individuals with possible pre-existing psychiatric vulnerability; causal relationship not established.

3. **State-level US legal status** is subject to frequent change; requires editorial verification against current state statutes before publication.

4. **Commercial extract potency labeling is unreliable** (Chambers 2023 [Ref 36]); generation agent should include explicit harm-reduction note about this.

### Sections Relying Primarily on Traditional-Use Evidence

- **Ethnobotany / traditional use**: relies on Diaz 2013 retrospective field research [Ref 37] and Casselman 2014 review [Ref 4]. **FLAG for human editorial review.**
- **Quid preparation effects and duration**: traditional-use accounts only. No controlled study data. **FLAG for human editorial review.**
- **Water infusion preparation**: traditional-use accounts only. **FLAG for human editorial review.**