The Mexican Lamiacae Salvia Divinorum doesn’t have the same cachet as other psychedelic compounds that have seeped into western culture and medicine like Psilocybe mushrooms. However, this enigmatic member of the mint family has been an important part of ceremony and traditional healing for the Mazatec people of southern Mexico for centuries.
Ethnopharmacological studies of the plant date back to the 1930s, but it wasn’t until the 1980s and 1990s when the active ingredient was identified and its properties elucidated. From its complex pharmacology and yet to be determined mechanism of action (MoA), S. divinorum and its main active ingredient Salvinorin A (SalA) remain a bit of a mystery, unraveling clue by clue towards real promise for a variety of indications.
An obscured history
The recorded native range of S. divinorum is in Oaxaca, Mexico, a region bordered by the Pacific Ocean to the west and the Sierra Mazatec mountain range to the north. Growing in the understory of the forest, S. divinorum has been found in several locations between 500 and 1500 meters (1500 to 5000 feet) in altitude, mostly growing near water sources in partial or full shade. The plant primarily reproduces vegetatively (asexually), flowering sporadically when sufficient sun penetrates the forest canopy.
The Mazatec people have traditionally been the stewards of three main plants with psychoactive properties as part of their spiritual practices: psilocybe mushrooms, seeds from Ipomoea violecea L. (morning glory), and the leaves of S. divinorum. Mazatec use of the latter plant generally takes place during healing and divination ceremonies, as well as in the training of medical practitioners.
Demonstrating their conviction to the broad healing properties of the plant, the Mazatecs use S. divinorum to treat a variety of illnesses: gastrointestinal disorders (GI) such as diarrhea, palliative care for the chronically ill or old, headaches, rheumatism, and panzon de arrego (or swollen belly), an illness believed to be caused by black magic. The leaves are either chewed as a “quid” and either chewed or swallowed, allowing the SalA to be released from the leaves and absorbed transmucosally in the mouth, or crushed into a fine pulp and steeped in water.
Practitioners in training ingest increasingly larger doses of S. divinorum leaves, which they believe shows them the way to heaven, where the initiated learn from the tree of knowledge. These ceremonies are led by a ‘curandero’ and last approximately two to three hours, where the participants are guided through different states of consciousness. Ceremonies take place at night in remote locations to avoid disruption as absolute silence is considered essential for the ceremony.
The Spanish conquistadors chronicled many of the rituals as far back as the 16th century, but they relayed very little about S. divinorum itself. One reason could be that the Mazatecs had several names for the plant. In their native tongue, it is referred to as Ska Maria Pastora, Ska Maria, Ska Pastora, and in Spanish, Hojas de Maria Pastora, Hojas de la Pastora, Hoja de adivinacion, Herba Maria or La Maria.
Ethnographic reports of the use of this member of the mint family (Lamiacaea) in Mazatec shamanism was reported in the 1930s. But it took until 1962, when Albert Hoffman and Gordon Wasson documented and collected a flowering specimen of Ska Maria Pastora allowing the species botanical description as Salvia divinorum.
During their travels in 1962, Hoffman and Wasson recorded and attended many Mazatec ceremonies, some of which incorporated the use of the Salvia species which became known as Salvia divinorum Epling & Jevita. This expedition contributed much to the understanding of the cultural role and use of these species. Their work stimulated a flurry of research in ethnopharmacology, phytochemistry, neuropharmacology, and other disciplines. Additionally, living S. divinorum specimens which would prove vital to continued research were brought to UC Davis and propagated by psychiatrist and ecologist, Sterling Bunnell, also in 1962.
SalA intrigues western science
The scientific literature around S. divinorum is less extensive than other plants used by the Mexican indigenous peoples. The first mention in western academic literature was in 1939 by Jean Bassett Johnson from the University of California in Berkley. Then in 1945, Blas P. Reko reported a “magic plant” used by the Mazatecs called “hoja de adivinacion” (the leaf of prophecy).
In 1982, Ortega et al. isolated and identified the SalA as the main active compound of S.divinorum. Around a decade later, the diterpene was isolated and characterized, and its potent activity as a highly selective kappa-opioid receptor (KOR) agonist was described after another 10 years, in 2002. This initial discovery has led to a flurry of research on the chemistry and pharmacology of SalA and its analogs. Over 30 papers on SalA have been published since.
An unusual mechanism with unanswered questions
Research on the effects of SalA and its molecular target, the KOR, has been extensive since it represents the only known non-nitrogenous KOR selective agonist. This atypical KOR agonist has a complex pharmacological profile. Its unique MoA shows no interaction at the 5-HT2A serotonin receptor, which is the main molecular target for the classical hallucinogens such as psilocybin and DMT. Instead, it is hypothesized that SalA indirectly influences the cannabinoid system, and is a negative allosteric modulator (NAM) of the mu opioid receptor (MOR). Unlike the MOR agonists, which are among the most powerful and addictive analgesic medications in the world, KOR agonists tend to produce dysphoric effects, limiting their abuse potential.
SalA’s action, which may vary between males and females, is highly dependent on its dosage and whether administration is acute or chronic. Its hallucinogenic effects peak around 2 min and typically last for 20 min or less. Classical psychedelics are defined by their pharmacology, in that they are 5-HT2A agonists. So SalA raises a big question: How can KOR agonism cause effects associated with classical psychedelics?
Besides limited evidence that the CB1 receptor may be involved, it is possible that SalA can indirectly affect 5-HT2A receptors through signaling mechanisms that cut across different neuron subtypes. An additional hypothesis: there could there be more “functional selectivity” than we currently understand, which leaves investigators to ponder: Is SalA utilizing unique intracellular signaling pathways or even unidentified ones?
Clinical evidence: subjective effects of SalA
The scientific literature on SalA is predominantly limited to case studies and animal models. But the body of data on the compound in human subjects is growing. Despite being a non-serotonergic compound, one study found that ratings on end-of-day subjective effects measures indicated a moderate degree of overlap with classic serotonergic hallucinogens at high doses, including somatosensory, perceptual, cognitive, and mystical-type effects.
The most consistent finding across human studies of SalA and S. divinorum suggest that the majority of participants find the subjective effects of the drug to be unique compared to other pharmacological classes of drugs, including classic hallucinogens.
In a study carried out at Yale University, SalA produced very short-lasting psychoactive effects with some psychotomimetic features, most notably somaesthetic changes, dissociative effects, and perceptual alterations. Interestingly, cortisol effects were elevated, suggesting that SalA stimulates the hypothalamic-pituitary axis (HPA) activity in humans.
Is SalA addictive?
For the most part, addictive drugs share in common the capacity to increase dopamine in the nucleus accumbens (NAcc). SalA and synthetic KOR agonists decrease dopamine levels in the nucleus accumbens of rodents. In animal models, synthetic KOR agonists and SalA induce conditioned place aversion. Based on this research, aversion to SalA would indicate a negative association with administration, making addiction to SalA unlikely.
Potential clinical applications:
Treatment resistant depression
Reports of anecdotal use and case studies of 7 individuals from the early 2000s testified to positive mood-altering effects aiding recovery from treatment resistant depression (TRD). Most of these patients reported lasting benefits from their use of the herb with significantly reduced scores on quantitative measures of depression. Several reported benefits such as mood enhancement, increased feelings of relaxation, and increased self-awareness.
Further clinical support for the study of SalA as a potential treatment for depression comes from several accounts of the subjective effects of SalA in healthy volunteers. Controlled clinical studies in hallucinogen-experienced healthy volunteers reported positive mood effects, including a feeling of relaxation and calm.
Substance Use Disorder
While there is a large body of preclinical data supporting the potential of KOR agonists as anti-addictive therapies, there is little clinical data due to the undesirable side effects of the traditional KOR agonists, which includes dysphoria, sedation, and diuresis.
In one study, SalA has been shown to decrease the effects of cocaine in preclinical models. Research has demonstrated that the compound modulates cocaine-seeking behavior and attenuates behavioral sensitization by modulating dopamine levels within the reward pathways.
A recent study in rhesus monkeys demonstrated that SalA can decrease oxycodone self-administration in rhesus monkeys in a dose-dependent manner. The study hints at potential use for SalA, to be used in concert with oxycodone for the treatment of pain, while reducing the risk subsequent abuse.
In the last decade, biomedical research on SalA, as well as its metabolites and semi-synthetic analogs, shows potential for its use as an analgesic agent. While there are limited clinical reports on the use of SalA to relieve pain, potential stems from its mechanism of action as a potent KOR agonist and a negative allosteric modulator of CB1 receptors. Additionally, preclinical data showing vascular dilation as an effect of SalA supports clinical investigation in the treatment of inflammatory and neuropathic pain, as well as application in diverse areas such as acute, abortive therapy for migraines.
In summary: clues for a therapeutic candidate
SalA is a unique naturally occurring hallucinogen with centuries of ritualistic use, a fact that hints at a de-risked safety profile. Though little about its pharmacology and MoA are verified, ample research suggests potential benefit and further research as a therapeutic.
In the context of Revixia Life Sciences, SalA will target a variety of mental health indications. Pharmacologic intervention will be paired with a digital therapeutic developed by Introspect Digital Therapeutics, in effort to streamline preparation, integration, and continued patient engagement.