A unique natural selective kappa-opioid receptor agonist, salvinorin A, and its roles in human therapeutics

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.

Abstract

“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.”

Authors: André Cruz, Sara Domingos, Eugenia Gallardo & Ana Martinho

Summary

Only the Mazatecs used Salvia Divinorum, a hallucinogen.

1. Introduction

S. divinorum may be consumed by chewing, drinking or smoking the leaves. It induces various effects, including hallucinations and visual and auditory effects.

Clerodane diterpenes are naturally occurring bicyclic diterpenoids that are found in several plant species of different families and in some organisms, such as fungi, bacteria and marine sponges. They have been used in different fields of medicine for their biological activities.

2.1. Salvinorin A

Salvinorin A induces short-lasting intense hallucinations when smoked, and its effects are more pronounced when the contact with oral mucosa is minimized.

Salvinorin A has an extremely fast elimination with a half-life of 75 min and a clearance of 26 L/h/Kg, and its hallucinogenic effect is short-lived.

Salvinorin A is a substrate for glycoprotein P (P-gp) in vitro and CYP450 enzymes, but it has high potency, lipophilicity and permeability, which compensates the effect of P-gp-mediated efflux on CNS.

Salvinorin A is able to decrease dopamine levels in the caudate putamen and dopamine neurotransmission levels in the dorsal striatum, mainly by regulation of dopamine release rather than its uptake. It also inhibits the release of dopamine from synaptosomes isolated from mouse striatum and prefrontal cortex and the release of serotonin.

A study performed by Mowry et al. (2003) evaluated the toxicity of salvinorin A in rats. The study revealed that the toxicity is both dose and time-dependent.

2.2.1. Drug addiction

Drug addiction follows a cycle with three distinct stages: an initial binging stage, a withdrawal stage, and an anticipation stage.

Salvinorin A has an anti-addictive effect in rats, showing rewarding effects at low doses and aversive effects at high doses.

Salvinorin A, a traditional KOR agonist, decreases dopamine levels in the nucleus accumbens and caudate putamen in rats and mice, which may be the pathway underlying the behavioral effect of salvinorin A.

Salvinorin A may be used in the treatment of drug addiction behavior because it shares many metabolic pathways with drugs of abuse such as codeine and morphine, oxycodone, MDMA, ketamine, THC and cocaine.

2.2.2. Antinociceptive effects

Salvinorin A has an antinociceptive effect associated with selective short-lived stimulation of KOR in the central nervous system, highlighting that salvinorin A is a pure KOR agonist.

Although opioid medication has been used for treatment pain with higher rate of success, it has negative effects. Salvinorin A has antinociceptive effects and doesn’t cause any dependence.

2.2.3. Neurologic disorders

Previous studies and case reports have attributed antidepressant effects to salvinorin A. In a 26-year-old woman, the symptoms of depression were completely remised after 6 months.

In a study conducted by Perron et al. (2012), salvia use was most common among young adults aged 18 e25 years and was associated with risk-taking behaviors and illicit drug use.

Salvinorin A induces an antidepressant effect in rats at doses ranging from 0.001 to 1000 mg/kg, while at high doses (2 mg/kg) it produces a cognitive insufficiency similar to ketamine, which implies that KOR may be possible involved in some cognitive alterations in psychiatric disorders such as schizophrenia.

Salvinorin A, a KOR agonist, shows neuroprotective effects 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.

2.2.5. Anti-inflammatory agent

Salvinorin A, a selective agonist of KOR, produced analgesic effects in mice with acute intestinal inflammation, and may be used to develop new substances that modulate physiological activity of both endogenous systems.

Macrophages are important cells in the surveillance of immune system that produce bioactive molecules, including the potent inflammatory lipid mediator leukotriene. Salvinorin A inhibited leukotriene production in activated macrophages through an unknown mechanism.

3. Concluding remarks

S. divinorum has been used for centuries for spiritual and medicinal purposes, but has recently gained popularity as a recreational drug.

Salvinorin A, the major bioactive compound of S. divinorum, has psychoactive effects, antinociceptive, antidepressant and pro-depressant an anti-addiction effects, and also acts in the gastrointestinal tract.

Salvinorin A showed a broad spectrum for therapeutic uses, including the treatment of human’s drug addiction, depression, some psychiatric disorders, cardiac and respiratory problems, and even more.

S. divinorum and salvinorin A, semi-synthetic analogs of salvinorin A, demonstrated a great potential for human therapeutics due to their low toxicity profile, low dependence, safe physiological profile and therapeutic targets. However, the scientific community remains divided on whether this is a safe drug due to its intense hallucinatory effects.

Salvinorin A, a natural compound, was used as a drug of abuse because of its low cost, easy access and basic techniques to obtain it.