This review (2016) examines the psychoactive properties and therapeutic potential of Salvinorin A, a kappa-opioid receptor agonist that is the bioactive constituent of the indigenous plant Salvia divinorum. Next to highly potent psychoactive properties as a dissociative hallucinogen, preliminary scientific evidence also indicates it may have broad-range therapeutic applications for treating addiction, inflammation, pain, and depression.
Review: Until the mid-60s, only the Mazatecs, an indigenous group from Oaxaca, Mexico, used Salvia Divinorum (S. divinorum) due to its hallucinogen properties. Later it was found that the hallucinogen effects of this plant were caused by the presence of a neoclerodane diterpene Salvinorin A (salvinorin A), which is a highly selective agonist of kappa-opioid receptor (KOR) that cause more intense hallucinations than the common hallucinogens as lysergic acid, mushrooms, ecstasy and others. In fact, smoking of only 200-500 μg of S. divinorum leaves is enough to produce these effects thus making it the most potent natural occurring hallucinogen known. Due to its legal status in various countries, this compound has gained a worldwide popularity as a drug of abuse with an easy access through smartshops and internet. Furthermore, salvinorin A gathered an increased interest in the scientific community thanks to its unique structure and properties, and various studies demonstrated that salvinorin A has antinociceptive, antidepressant, in some circumstances pro-depressant and anti-addictive effects that have yielded potential new avenues for research underlying salvinorin A and its semi-synthetic analogs as therapeutic agents.
Salvia divinorum is a perennial shrub traditionally used by the Mazatec people of Oaxaca for ritual and medicinal purposes. Cruz and colleagues explain that the principal bioactive constituent of the plant is salvinorin A, a non‑nitrogenous neoclerodane diterpene that produces intense, short‑lived hallucinations and is a highly selective kappa‑opioid receptor (KOR) agonist. Clerodane diterpenes in general have attracted interest because of diverse biological activities, and salvinorin A stands out because its structure and receptor interactions differ from classical alkaloid opioids and serotonergic psychedelics. This paper reviews the pharmacology, pharmacokinetics, behavioural effects and potential therapeutic roles of salvinorin A, and highlights unresolved questions about its mechanism, metabolism, toxicity and long‑term effects. The authors aim to synthesise preclinical and observational evidence on antinociceptive, antidepressant, anti‑addiction, neuroprotective, anti‑inflammatory and gastrointestinal activities, and to discuss potential applications and safety concerns for human therapeutics.
Papers cited by this study that are also in Blossom
Johnson, M. W., Maclean, K. A., Reissig, C. J. et al. · Drug and Alcohol Dependence (2011)
Papers in Blossom that reference this study
Bagdasarian, F. A., Hansen, H. D., Chen, J. et al. · ACS Chemical Neuroscience (2024)
Chemical and receptor pharmacology: The review emphasises that salvinorin A is the major bioactive compound of S. divinorum and is a potent, highly selective KOR agonist. Unlike classical opioid ligands, it lacks a basic nitrogen atom, representing a structurally novel class of opioid ligands. The extracted text gives the molecular formula as C23H28O8 and a molar mass of about 432 g mol−1. In silico receptorome work cited in the review suggests other diterpenes in the plant are present at lower concentrations and are unlikely to account for the plant’s psychoactivity. Pharmacokinetics and metabolism: Pharmacokinetic findings reported include very rapid brain uptake in primate PET imaging, with the highest brain concentrations observed in cerebellum. Metabolism appears to include rapid ester hydrolysis of the 2‑acetoxy group to form salvinorin B and involvement of multiple CYP450 isoforms (CYP2D6, CYP2C18, CYP1A1 and CYP2E1) as well as glucuronosyltransferases. Salvinorin A was reported as a substrate for P‑glycoprotein in vitro, but its lipophilicity and permeability may reduce functional efflux from the CNS. Two half‑life estimates appear in the extracted text: 75 minutes (with reported clearance of 26 L/h/kg) and an earlier report of about 56 minutes in rhesus monkeys; the text does not clearly reconcile these values. The authors state that smoking produces pronounced effects and that the compound is absorbed through oral mucosa to a smaller degree; the extraction reports that “smoking only 200–500 mg” induces short‑lasting (up to 1 hour) intense hallucinations, but it is not clear from the extracted text whether that amount refers to plant material or to isolated compound. Effects on monoamines and behaviour: Multiple studies in rodents show that salvinorin A reduces dopamine levels in striatal regions (caudate putamen and nucleus accumbens), and alters serotonin and noradrenaline release in various synaptosomal preparations. Behaviourally, these neurochemical effects are associated with decreased locomotor activity, sedation and anhedonia in some paradigms. The compound also inhibited cocaine‑induced drug‑seeking in animal models, and attenuated cocaine‑induced behaviours, consistent with other KOR agonists' modulation of the mesolimbic dopamine system. Drug addiction and human use data: The authors review evidence that low doses in rodents (reported ranges 0.1–40 mg/kg) produced rewarding effects in place preference and self‑administration tests, whereas a high dose (160 mg/kg cited) produced aversive responses. The review also notes metabolic pathway overlap between salvinorin A and several abused drugs (for example, glucuronosyltransferase and various CYP enzymes), which could produce drug–drug interactions. A survey of 500 regular S. divinorum users is reported in which 0.6% self‑identified as feeling addicted or dependent; the review states there are no case reports demonstrating addiction to S. divinorum. Antinociceptive and analgesic effects: Preclinical analgesic effects were observed in tail‑flick, hot‑plate and abdominal constriction tests in mice, and in a mustard oil visceral pain model; these effects were dose‑dependent and short‑lived (around 20 minutes). The antinociception was not altered by mu or delta opioid antagonists, supporting a KOR‑mediated mechanism. The review contrasts the short duration of salvinorin A analgesia with longer‑acting mu opioid painkillers, and highlights the absence of reported dependence in animal studies as a potential advantage. Neurological and psychiatric effects: Animal behavioural studies and limited human case material are summarised. A single human case is cited in which a 26‑year‑old woman reported remission of chronic depression after minimal, regular oral use of S. divinorum; the review also cites forced‑swim test data in rats where a wide dose range (0.001–1000 mg/kg) produced antidepressant‑like effects reversible by a selective KOR antagonist. Conversely, higher doses (for example 2.0 mg/kg in one rat study) produced depressive‑like behaviour, reduced locomotion and impaired motivation, indicating dose‑dependent bidirectional effects. Anxiolytic effects were reported at low doses in rodents, whereas high doses produced cognitive deficits resembling ketamine‑like effects. The compound showed neuroprotective properties in cerebral ischaemia models, modulating aquaporin‑4 expression and reducing brain oedema and neuronal injury in hippocampus, cortex and striatum in preclinical work. Gastrointestinal and anti‑inflammatory actions: Preclinical work demonstrated inhibition of gastrointestinal motility in mice and suppression of myenteric cholinergic transmission in guinea‑pig ileum mediated by KOR activation, suggesting a pharmacological basis for traditional uses in diarrhoea. In two mouse colitis models, salvinorin A produced anti‑inflammatory effects mediated by KOR and cannabinoid receptor 1 (CB1), and reduced intestinal pain. The review also reports that salvinorin A inhibited leukotriene production in activated macrophages, implicating modulation of inflammatory lipid mediator biosynthesis. Toxicity and safety data: Short‑term toxicity studies in rats (2‑week exposure at various concentrations) reportedly showed no histological changes in spleen, brain, liver, kidney, blood and bone marrow. However, an in vitro study across six cell lines (N27, Caco‑2, HepG2, COS‑7 and HEK‑293 among them) found dose‑ and time‑dependent cytotoxicity, prompting the authors to call for more studies on chronic and continuous consumption. The review also notes that the intense hallucinations, dissociation, dysphoria and motor effects are major concerns for therapeutic use. Overall, the extracted text emphasises that human therapeutic trials are lacking and the long‑term safety profile remains unclear.
Cruz and colleagues interpret the collected literature as indicating that salvinorin A defines a novel, non‑nitrogenous class of selective KOR agonists with a broad preclinical pharmacological profile. They posit potential therapeutic applications across pain, addiction, neuroprotection, inflammatory disorders and gastrointestinal conditions, and note that semi‑synthetic analogues based on salvinorin A’s chemical scaffold are being developed to explore mixed opioid/cannabinoid activity and to refine pharmacokinetic and safety properties. The authors caution that several important uncertainties temper enthusiasm for clinical use. Key gaps include incomplete characterisation of mechanism(s) of action in humans, variable and partly inconsistent pharmacokinetic estimates reported in preclinical studies, possible drug–drug interactions owing to shared metabolic pathways with other drugs of abuse, and limited toxicity data—particularly for chronic exposure. They also highlight the compound’s intense psychotomimetic effects, arguing these would be undesirable in a therapeutic agent and present a safety concern for non‑controlled use. Implications discussed include the need for more preclinical work to elucidate receptor interactions and downstream signalling, development of analogues that retain therapeutic effects while minimising hallucinatory side‑effects, and properly controlled human studies to assess efficacy and safety. The authors stress that the recreational availability and low cost of S. divinorum have produced widespread non‑medical use, which complicates assessment of benefit–risk and underscores the importance of further research and regulatory consideration.
In their concluding remarks the authors restate that salvinorin A is the principal psychoactive component of S. divinorum and represents a unique class of selective KOR agonists with multiple preclinical therapeutic properties. They emphasise that, despite promising effects in animal models—antinociceptive, antidepressant, anti‑addiction, neuroprotective and anti‑inflammatory—there are no controlled studies demonstrating therapeutic benefit in humans. The review closes by calling for further research into pharmacology, long‑term safety and strategies to dissociate therapeutic actions from intense hallucinatory side‑effects, while acknowledging both the therapeutic potential of salvinorin A and the public‑health concerns arising from its recreational use.
Salvia is an important genus of the Lamiaceae (mint) family consisting of around 900 species. The name "Salvia" derives from a Latin word which means "to heal". S. divinorum (Fig.), also known as "magic mint", "diviner's sage", "Hierba Maria" and "Ska Maria Pastora", is a small perennial shrub herbal species, native to the Mexican state of Oaxaca. It is a psychoactive plant traditionally used by the Mazatecs for spiritual rituals, divination practices and various medicinal purposes. These include the use of small doses for the treatment of diarrhea, swollen belly, headaches and rheumatism. It is also used as an infusion or juice as a palliative agent. Additionally, Mazatecs use this plant for shamanic training and also for the training of medical apprenticeships. S. divinorum is consumed by chewing or drinking the juice obtained from the fresh leaves. Additionally, it may also be consumed through inhalation, volatilization or smoking dried leaves. It induces various effects, including visual and auditory effects, perceptual modification, dizziness, uncontrolled laughterand intense hallucinogens. The plant has undergone extensive phytochemical investigation and a number of compounds have been isolated (Table, Supplementary Information). Of these, the main constituent is salvinorin A (Fig.), a non-nitrogenous diterpene, along with its deacetylated form, salvinorin B. A range of other diterpenes has been isolated from S. divinorum such as salvinorin C-J, divinatorins A-F, salvidivins A-D and salvinicins A and B (Table, Supplementary Information). However, it has been shown that salvinorin A is not only the major component but is also the main compound responsible for the bioactive properties of S. divinorum. Clerodane diterpenes are a large group of specialized metabolitesthat, during recent years, have attracted lots of interest as a result of their noteworthy biological activities. These compounds are naturally occurring bicyclic diterpenoids that are found in several plant species of different families (Lamiaceae, Verbanaceae, Euphorbiaceae, Compositae and others) and in some organisms, such as fungi, bacteria and marine sponges. Their basic molecular structure is a transdecalin system with methyl groups attached to carbons 1, 2, 4a and 5, as well as a 3-methylpentyl chain also bound to C1 (Fig.). Modifications in this skeleton create different compounds and over than 1300 diterpenoids and nor-diterpenoids with the clerodane carbon skeleton have been isolated. One of them is Salvinorin A, which recently has attracted a lot of interest in the scientific community due to its active properties. Over the years, clerodane diterpenes aroused interest due to their structure/biological activities in different areas of application, including insect antifeedants, opioid receptor probes, nerve grow factor potentiators, and antitumor, antifungal, antibiotic, antipeptic ulcer, antiplasmodial, hypoglycemic, hypolipidemic and anti-thrombin inhibitory activities. An excellent review on the distribution, chemotaxonomic significance, chemical structures, and biological activities of clerodane diterpenes was published by Rongtao. 2. Salvinorin A, the major bioactive constituent of S. divinorum
The main properties of S. divinorum are attributed to salvinorin A, which is a potent and a highly selective kappa-opioid receptor (KOR) agonist. The other compounds present in the plant are at lower concentrations than salvinorin A, and it was shown by an in silico study in receptorome that their potential to be responsible for the psychoactive effects of the plant is not significant. Salvinorin A (Fig.) presents a unique form of interaction with residues that are not required by conventional KOR peptide and non-peptide agonists. The presence of a nitrogenous group was considered as a requirement for the interaction with the mu, kappa and delta opioid receptors, which led to the developing of new opioid receptor probes and new properties. However, salvinorin A is structurally and chemically different from the classical hallucinogens, being the first known diterpene with psychoactive properties and a non-nitrogenous hallucinogen. It has a molecular formula of C 23 H 28 O 8 (432 g mol À1 )and the IUPAC name is 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-1Hbenzo[f]isochromene-7-carboxylate. Analysis by EIMS of salvinorin A showed a mass spectrum with substantial fragments at m/z. It has been shown that smoking only 200e500 mg of salvinorin A induce short-lasting (up to 1 h) intense hallucinations. Also, the authors observed that it is absorbed through the oral mucosa and in a small percentage through the salivary flow but in both cases, it is enough to produce psychoactive effects. Furthermore, when it is smoked, its effects are much more pronounced and, on the contrary, when the contact with oral mucosa is minimized, it is mainly absorbed in the gastrointestinal tract and it is vastly inactivated. Salvinorin A has a fast elimination with a half-life of 75 min and a clearance of 26 L/h/Kg. Studies carried out in blood samples of Rhesus monkeys demonstrated that salvinorin B is the most representative metabolite of salvinorin A, resulting from the ester hydrolysis at the 2-acetoxy group by an esterase. This is probably why the hallucinogenic effect is short-lived.synthesized [ 11 C]-labeled salvinorin A and conducted a positron emission tomography study, in order to measure its pharmacokinetics and distribution in the brain and peripheral organs of female primates. The results demonstrated an extremely rapid brain uptake, and the compound was distributed throughout the brain with a highest concentration in cerebellum. The kinetics of the peripheral organs suggested at least two modes of metabolism and excretion: renal and biliary.demonstrated that salvinorin A is a substrate for glycoprotein P (P-gp) in vitro. However, it has high potency, lipophilicity and permeability, which probably compensate the effect of P-gp-mediated efflux on CNS. The authors also observed that the salvinorin A concentrations substantially decreased after exposure to CYP2D6, CYP2C18, CYP1A1 and CYP2E1 enzymes, which support the fact that salvinorin A is a substrate for CYP450 enzymes. Glucoronosyltransferases also diminished salvinorin A levels, which might be related to the presence of an ester group, a putative site for glucuronidation.showed that salvinorin A, at a dosedependent manner, could decrease the dopamine levels in the caudate putamen of mice, with similar effects to those of some synthetic kappa opioid receptor agonists including decreases in locomotor activity, sedation and anhedonia. Typically, KOR agonists produce a decrease in locomotor activity, but salvinorin A may induce it, suggesting the involvement of a different mechanism. Several studies have shown that salvinorin A is able to modify dopaminergic pathways through decreasing dopamine levels in the caudate putamen and dopamine neurotransmission levels in the dorsal striatum, mainly by regulation of dopamine release rather than its uptake. Indeed, in rats, salvinorin A has been shown to be able to inhibit cocaine-induced seeking behavior. Also, it inhibits the release of dopamine from synaptosomes isolated from mouse striatum and prefrontal cortex and the release of serotonin, while it stimulates the release of noradrenaline from synaptosomes of the hippocampus. However, in vivo studies performed in rats demonstrated that salvinorin A decreased the extracellular concentrations of dopamine in the nucleus accumbensand had no effect on the concentration of serotonin. Also, the authors observed that an impairment of the mesolimbic dopaminergic pathway is involved in salvinorin A-induced dysphoria and a decrease in serotonin bioavailability might be responsible for the sedative effects of the compound. Another study performed by, evaluated the toxicity of salvinorin A: rats were exposed to various concentrations of the drug for 2 weeks. At the end of the experiment, histological sections of spleen, brain, liver, kidney, blood and marrow bone showed no histological changes and toxicity for any of the doses of salvinorin A exhibited. However a study in vitro in six cell lines, N 27, Caco 2, Hep G2, COS 7 and Hek 293 cells, revealed that salvinorin A cytotoxicity is both dose and time-dependent, which highlighted the relevance of performing further studies focused on the chronic and continuous consumption of S. divinorum.
In general, drug addiction follows a cycle with three distinct stages: an initial binging stage where the consumers seek out ways to get the feeling of the drug; a second stage where the consumers undergo withdrawal symptoms; and then the anticipation stage which leads to further drug administration. The anti-addictive effect is one of the most relevant pharmacological effects of salvinorin A, already described in various behavioral studies, particularly those performed in rats. When rats were treated with low doses (0.1e40 mg/kg) of salvinorin A, the rewarding effects of the substance were demonstrated both in place preference and in self-administration tests. Otherwise, aversive effects were observed when rats were injected with a high dose of salvinorin A (160 mg/kg). Dopamine levels in nucleus accumbens have an important role in modulating the rewarding effects of drugs of abuse, food and sex, and its regulation in this cerebral region may be the pathway underlying the behavioral effect of salvinorin A. It decreases dopamine levels in nucleus accumbens in ratsand in caudate putamen in mice. Therefore, salvinorin A could be used for the treatment of drug consumers due to its ability to decrease dopamine levels and its dopaminergic activation, related to selfadministration of addictive drugs). An example is the cocaine seeking behavior, in which salvinorin A, as others traditional KOR agonists, attenuate cocaine-induced cocaine-seeking due to affecting the dopaminergic system. Another explanation for the potential use of salvinorin A in the treatment of drug addiction behavior is because salvinorin A shares many metabolic pathways with some drugs of abuse such as codeine and morphine (glucuronosyltransferase), oxycodone, MDMA, ketamine, THC (cytochrome p450 monooxygenase) and cocaine (carboxylesterase). This sharing could enhance drug-drug interactions which may has synergic or antagonic effects. Supporting these hypotheses is a survey with 500 S. divinorum regular users which reported that only a non-significant minor percentage (0,6%) of users were feeling addicted or dependent to plant consumptionand, till now, there are no case reports of addiction to S. divinorum.
Other important pharmacological effect of salvinorin A is the antinociceptive effect associated with selective short-lived stimulation of KOR (up to 20 min) in the central nervous system showed by dose-dependent mice tail-flick, hotplate and abdominal constriction tests, antagonist of m and d opioid receptor did not affected the salvinorin A antinociceptive response highlighting that salvinorin A is pure KOR agonist. In another study, a behavioral pain response to intracardiac injection of mustard oil were assessed in mice and showed that salvinorin A has antinociceptive properties (around 20 min) when injected intraperitoneally. The short analgesia effect of salvinorin A comparing to m opioid painkillers might be due to the short half-life time of salvinorin A showed to be around 56 min in a study conducted in Rhesus monkeys (M.. Although, opioid medication (OP) has been used for treatment pain with higher rate of success, but all medication has positive and negative effects. Some OP can cause dependence, breathing problems, overdose and even the need for higher stronger doses. Has described before, salvinorin A has antinociceptive effects and even more doesn't cause any dependence and has a safe physiological profile, opening new sights for the development of new opioid painkillers.
Previous studies and case reports have attributed antidepressant effects to salvinorin A. In a 26-year-old woman with chronical depression the antidepressant effect of S. divinorum was reported after smoking its leaves. Then, the patient orally consumed minimal doses of S. divinorum three times weekly by chewing the leaves and held them in the mouth for 15e30 min and, after 6 months, the symptoms had completely remised. In a study conducted by, the authors suggested that salvia use is most common among young adults aged 18e25 years as well as individuals who had engaged in risk-taking behaviors (selling illicit drugs, stealing) or illicit drug use (other hallucinogens/ecstasy) and observed that self-reported depression and anxiety were also associated with salvia use. The authors also observed that salvia use is part of a broader constellation of neurological, psychosocial and behavioral problems. The antidepressant effect of salvinorin A was also confirmed in behavioral experiments in forced swim test in rats. At doses ranging from 0.001 to 1000 mg/kg, salvinorin A induced an antidepressant effect which was reversed by nor-binaltorphimine, a selective KOR antagonist. However, in another study conducted in rats it was observed that a higher dose of salvinorin A (2.0 mg/kg) produced a depressive effect, a decrease in locomotor activity and an attenuation of motivational behavior. Thus, the authors concluded that salvinorin A might be used in the treatment of depression-like effects at low doses. Salvinorin A also presents an anxiolytic effect in rats at doses ranging from 0.001 to 1000 mg/kg, while at high doses (2 mg/kg) a cognitive insufficiency similar to ketamine (also a potent KOR agonist) was produced, which implies that KOR may be possible involved in some cognitive alterations in psychiatric disorders such as schizophrenia. Furthermore, salvinorin A demonstrated a neuroprotective effect via KOR and modulates aquaporin 4 expression in cerebral ischemia-induced brain injury, preventing brain edema formation and inhibiting neuronal damage in hippocampus, cortex and striatum. Other KOR agonists showed neuroprotection but the side effects such as respiratory depression were not desirable; however the short acting and rapid onset of salvinorin A exhibits no respiratory depression making it a suitable agent for treatment of stroke, cardiac arrest or asphyxia.
Capassoreported that salvinorin A inhibited gastrointestinal motility in mice accompanied by a gut inflammation. In another study carried out in guineapig ileum, it was showed that salvinorin A induced inhibition of myenteric cholinergic transmission via KOR activation, suggesting that S. divinorum, and salvinorin A, may constitute a pharmacological basis for the treatment of diarrhea. Mazatecs used this plant to treat diarrhea and they believed that could regulate eliminatory functions.
Salvinorin A displayed an anti-inflammatory effect in two mouse models of colitis, mediated by KOR and cannabinoid receptor 1 (CB1) and produced analgesic effects in mice with acute intestinal inflammation. As described, salvinorin A is a selective agonist of KOR with no affinity for cannabinoid receptors. Thus, therewith somehow cannabinoid system is activated, may be through formation of KOR-CB1 receptor heterodimers or by influencing its intracellular signaling cascades. With this finding, new substances are being developed based on salvinorin A structure with mixed opioid/cannabinoid agonist properties that modulate physiological activity of both endogenous systems and could be more effective comparing to selective agonists. Macrophages are important cells in the surveillance of immune system that, when activated, produce bioactive molecules, as the potent inflammatory lipid mediator leukotriene. Leukotriene is involved in several inflammatory and autoimmune diseases including asthma, allergic rhinitis and cardiovascular diseases. Salvinorin A inhibited leukotriene production in activated macrophages through an unknown mechanism, involving enzymes and/ or regulatory processes in leukotriene biosynthesis, suggesting a new mechanism for salvinorin A as anti-inflammatory agent and a possible natural-occurring substance for treatment of leukotrienerelated diseases.
Although S. divinorum has been used for centuries for spiritual and medicinal purposes, its use as a recreational drug is a recent phenomenon. Its potent hallucinogenic activity and ready availability in smartshops and internet resulted in an increasing popularity worldwide, especially amongst young people, as a drug of abuse. Although the relatively safe profile of S. divinorum, the exact mechanism of action, metabolism, toxicity and long-term effects remain largely unclear. Salvinorin A, the major bioactive compound of S. divinorum, represents a new class of non-nitrogenous KOR selective agonists, being the responsible for the psychoactive effects of the plant. In addition to its hallucinogenic activity, salvinorin A possesses antinociceptive, antidepressant and pro-depressant an anti-addiction effects and also acts in the gastrointestinal tract. Also, it showed beneficial effects in the treatment of a variety of mental disorders and some diseases including depression, anxiety, schizophrenia and Alzheimer's disease. Salvinorin A showed a broad spectrum for therapeutic uses, starting as a substance for the treatment of human's drug addiction through the decreasing of dopamine levels and dopaminergic activation, related to self-administration of addictive drugs and owing to share similar metabolic pathway of abuse drugs leading to drug-drug interactions. Following, as possible therapeutic agent for treatment of depression or some psychiatric disorders and further as a suitable agent to treat cardiac and respiratory problems. Nevertheless, its anti-inflammatory properties show it as a promising agent for some autoimmune/inflammatory and even more salvinorin A affect indirect the cannabinoid system. Salvinorin A could also be used to treat gastrointestinal problems and pain suppression. S. divinorum, and in the spotlight various semi-synthetic analogs of salvinorin A, demonstrated a great potential for human therapeutics because of the low toxicity profile, low dependence, safe physiological profile and therapeutic targets; also, the chemical structure salvinorin A and its putative effects have opened new perspectives and have led to the development of new compounds targeting KOR based on its chemical structure. Despite this, scientific community remains divided on whether this is, or not, a safe drug because of the extremely strong hallucinations that it produces turning it dangerous for human life following non-controlled consumption. Indeed, the putative toxicity promoted by long-term consumption of S. divinorum, and salvinorin A, was not fully determined, thus, further research is of utmost interest in order to clarify this issue. Despite all therapeutic effects, there are no studies regarding the therapeutic usage of salvinorin A on humans, its therapeutic potential of is unproven in humans and its intense hallucinatory effects (accompanied by dissociation, dysphoria and motor effects) are indeed a major concern and not desirable in a therapeutic agent. However, as kappa opioid system regulates the concentrations of important neurotransmitters which mediate motor activity, reward processes, mood, anxiety and others, its own activation highlights its putative role in the treatment of some neurologic disorders. Finally, both salvinorin A and S. divinorum became drugs of abuse thanks to their low cost, easy access and basic techniques to obtain salvinorin A from the whole plant. Nevertheless, the strong potential of this natural compound, and its semi-synthetic analogs, in human therapeutics should not be ruled out and new research lines based on S. divinorum and salvinorin A should be further explored.
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