Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action

This review (2019) examines the analgesic, anti-inflammatory, and psychoactive properties of the hallucinogenic plant Salvia Divinorum and its bioactive (analog) constituents.

Abstract

“Salvia divinorum is a herbal plant native to the southwest region of Mexico. Traditional preparations of this plant have been used in illness treatments that converge with inflammatory conditions and pain. Currently, S. divinorum extracts have become popular in several countries as a recreational drug due to its hallucinogenic effects. Its main active component is a diterpene named salvinorin A (SA), a potent naturally occurring hallucinogen with a great affinity to the κ opioid receptors and with allosteric modulation of cannabinoid type 1 receptors. Recent biochemical research has revealed the mechanism of action of the anti-inflammatory and analgesic effect of SA at the cellular and molecular level. Nevertheless, because of their short-lasting and hallucinogenic effect, the research has focused on discovering a new analogue of SA that is able to induce analgesia and reduce inflammation with a long-lasting effect but without the hallucinatory component. In this review, we explore the role of S. divinorum, SA and its analogues. We focus mainly on their analgesic and anti-inflammatory roles but also mention their psychoactive properties.”

Authors: Ulises Coffeen & Francisco Pellicer

Summary

Introduction

Salvia divinorum is an herbal plant native to the southwest region of Mexico that is used for healing multiple conditions such as insect bites, eczema, candidiasis, cystitis, and menstrual cramps, and even depression or alcohol addiction.

Salvinorin A (SA) is the main active compound of S. divinorum, and it has been reported to be the most powerful naturally occurring hallucinogen.

Pharmacological screening of SA showed that it activates only the opiate receptors and not the serotonin receptors. SA also activates the cannabinoid system through the modulation of the CB1 receptors.

Psychoactivity

Daz described how the intake of crushed leaves of S. divinorum produced short-lasting light-headedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and increased visual and auditory imagery, with no actual hallucinations. However, current research indicates that leaf extracts of S. divinorum with increased SA concentrations produce hallucinations.

Animal research reveals that even in less evolved species, SA exhibits rewarding effects. However, in two different strains of rats, SA could not establish a self-administration behavior and could only slightly modify extracellular levels of dopamine in Nacc.

Studies in humans, non-human primates, and rodents have shown that SA causes hallucinations and dissociative effects. In rats, SA increases absolute power in the anterior cortex and decreases absolute power in the posterior cortex.

Hooker et al showed that SA activates brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output in rodents and baboons. SA is mainly concentrated in the cerebellum and visual cortex.

Inflammation

Mazatec culture uses S. divinorum to treat GI disorders like abdominal swelling, diarrhea, and intestinal spasms, illnesses that course with chronic inflammation. Several studies have shown that SA inhibits motility in the GI tract under inflammatory conditions by activating KOR, CB1, and interestingly by activating cannabinoid type 2 receptors.

In vitro studies have shown that SA reduces iNOS expression and TNF production in macrophages, and restores IL-10 production, which limits the inflammatory response. SA also prevents epithelial barrier dysfunction.

KOR and CB1 receptors are localized and overexpressed in the enteric nervous system and immune cells after peripheral inflammation, for example, in clinical disorders like IBD.

New target of SA action has been identified, i.e., inhibition of leukotriene (LT) biosynthesis. SA reduces LT production in isolated macrophages and in zymosan-induced peritonitis and carrageenan-induced pleurisy.

Analgesia

Pain is one of the most common causes of medical and dental consultations. S. divinorum, their metabolites, and semi-synthetic analogs have shown potential as an analgesic agent.

Peripheral administration of salvinorin A and B to mice induces antinociceptive effect in thermal (tail-flick) and chemo-nociceptive (acetic acid abdominal constriction) assays in a dose-dependent manner. Pretreatment with nor-BNI (KOR antagonist) reverses the analgesic effect.

Salvinorin A (SA) has an analgesic effect in mice and in experimental models, but its role in the central processing of pain has not been totally studied.

SA could be an alternative to traditional treatments for chronic pain, but has the limitation of a low potency and a short half-life. However, SA can reduce mechanical allodynia induced by formalin.

The development of neuropathic pain is associated with cortical nuclei belonging to the neuropathic pain matrix. The insular cortex (IC) shows a moderate expression of KOR, but SA can induce a powerful antinociceptive effect in a model of neuropathic pain in rats.

Analogues

SA has different issues, including the administration route, short binding duration, high metabolic rate, and substrate for P-glycoprotein efflux transporter. The development of new derivates of SA that are capable of producing analgesic and anti-inflammatory effects but with a long-lasting duration is a current challenge.

Herkinorin, a opioid selective agonist, was tested in a model of acute and inflammatory pain in rats, and was able to reduce the nociceptive behavior even after repeated administrations, suggesting minimal tolerance.

2-O-Cinnamoylsalvinorin B (PR-38), which has been synthesized from SA in a simple two-stage process, is a strong regulator of intestinal motility and pain signaling via MOR but not KOR or CB1.

Tetrahydropyran salvinorin B (-THP SalB) has similar binding affinity and efficacy at the KOR compared to SA and has analgesic effects in the tail-withdrawal and formalin assays.

Side effects

Salvia divinorum, SA, and its analogues are used in the treatment of chronic diseases that occur with inflammation and pain. However, there are only a few studies related to the possible cytotoxicity after the prolonged use of these substances.

SA has low toxicity in rats and mice, showing no effects on cardiac conduction, temperature, galvanic skin response, pulse pressure, or histological changes. Moreover, SA is cytotoxic in different cell lines, but extensive in vivo and clinical studies are needed to clearly evaluate their toxicological effects.

Final remarks

Today, opiates are being abused and new molecules are not being developed as analgesics. Salvinorin A, a powerful KOR agonist and an allosteric modulator of CB1 receptors, can be used as an alternative therapy for inflammatory and neuropathic pain.

Study details

Compounds studied
Salvia Divinorum

Topics studied
Immunity Pain Safety

Study characteristics
Literature Review

PDF of Salvia divinorum: from recreational hallucinogenic use to analgesic and anti-inflammatory action