Journal of Pain Research, 2019, Volume 12, 1069-1076

DOI: 10.2147/JPR.S188619

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.

Keywords : Salvia divinorum, salvinorin A, pain, inflammation, psychoactivity

Introduction

Salvia divinorum (Lamiaceae) is a herbal plant native to the southwest region of Mexico. It was used for medical and religious purposes for centuries in the Mazatecan culture and has a hallucinatory component. Recently, S. divinorum extracts have been used in several countries as a recreational drug due to its hallucinogenic effects;1 its expanded use has been facilitated by its accessibility on the Internet.2 However, traditional preparations with smaller quantities have been used in illness treatments that converge with inflammatory conditions and pain, such as headaches, gastrointestinal (GI) problems, or rheumatism.3

Mazatecan people also use S. divinorum for healing multiples conditions, including insect bites, eczema, candidiasis, cystitis, and menstrual cramps, and even depression or alcohol addiction.4 These multiple therapeutic targets implicate a complex pharmacology and mechanism of action for this mystical plant.

In 1982, Ortega et al isolated a new neo-clerodane diterpene named salvinorin, which is the main active compound of S. divinorum.5 Two years later, Valdés et al isolated the components named divinorin A (a psychotropic terpenoid) and divinorin B, but later it was confirmed that both structures correspond to salvinorin A (SA) and B (SB), respectively, proposed by Ortega et al.6 Currently, phytochemical research has led to the isolation of several diterpenes, from SA to salvinorin F. As mention earlier, the main active diterpene of the plant is the SA, and it has been reported to be the most powerful naturally occurring
hallucinogen.7,8

Pharmacological screening of a battery of 50 receptors, transporters, and ion channels showed that SA shows significant activity only with the κ opioid receptors (KORs), and importantly, SA shows no action at the 5-HT2A serotonin receptor, which is the main molecular target for the classical hallucinogens such as psilocybin and lysergic acid diethylamide (LSD).9 Also, it has been described that the role of SA in the cannabinoid system, through the modulation of the cannabinoid type 1 (CB1) receptors, maybe due to the crossinteraction between KOR and CB1 receptors.10,11 Moreover, the peripheral action of SA includes inhibition of leukotrienes and cytokines related with inflammatory processes.12,13

In this article, we review the role of S. divinorum, SA, and its analogues, focusing mainly on their analgesic and antiinflammatory roles, as well as their psychoactive properties.

Psychoactivity

In a field research project performed between 1973 and 1983, Díaz described that the intake of an aqueous preparation of crushed leaves of S. divinorum produced short-lasting lightheadedness, dysphoria, tactile and proprioceptive sensations, a sense of depersonalization, amplified sound perception, and increased visual and auditory imagery, with no actual hallucinations.14 However, currently, the consumption of leaf extracts of S. divinorum with increased SA concentrations, which are sold on Internet sites, produces a potent hallucinatory effect. The reported hallucinogenic dosage of salvinorin A in humans is 250–500 μg, and its potency is slightly inferior to the well-known synthetic hallucinogen, LSD.15

Experimental consumption of SA in healthy volunteers indicated experiences related to disruptions in vestibular and interoceptive signals (eg, change in spatial orientation), and also recurring experiences like revisiting childhood memories, cartoon-like imagery, and contact with entities.16 Chronic consumption produces subjective symptoms of withdrawal, mainly anxiety, irritability, and malaise; also, this pattern of use results in failure to fulfill major role obligations leading to exacerbation of social and interpersonal problems, which are criteria used to diagnose substance use disorder.17

Animal research reveals that even in less evolved species, SA exhibits rewarding effects. In a model of conditioned place preference (CPP) in zebrafish, SA induced a “trancelike” effect which was blocked by pretreatment with the KOR antagonist Nor-binaltorphimine and with the CB1 antagonist rimonabant.18 In rats, SA action depends on the strain, dosage, and administration route. In Wistar rats, SA has shown rewarding effects in CPP model and induces an increase of extracellular dopamine in nucleus accumbens (Nacc);19 however, in two different strains (Male Lister Hooded and Sprague Dawley), SA could not establish a self-administration behavior and was only capable of slightly modifying extracellular levels of dopamine in Nacc.20 In this regard, in our laboratory, we found that intraperitoneal administration of S. divinorum ethyl acetate extract in Wistar rats does not modify dopamine levels in Nacc, suggesting that S. divinorum extract does not induce addictive behavior.21

As mentioned earlier, studies in humans, non-human primates, and rodents have shown that the hallucinogenic effects produced by SA are associated with the activation of the KOR but not 5-HT2A receptor.22,23 Also, the minutes-long hallucinogenic and dissociative effects of recreational S. divinorum in humans have been described in detail.24 Recently, our group analyzed these effects in rats, by recording the changes in electrocorticogram (ECoG) activity in the anterior and posterior regions of the brain (associated with motor activity and somatosensory perception, respectively) following
the administration of S. divinorum extract. We found that S. divinorum extract increased absolute power gradually in the anterior cortex, whereas it decreased absolute power in the posterior cortex at all frequency bands, from 10 minutes after the administration of S. divinorum,21 in a similar way to the decrease in spectral activity in the posterior region caused by inhalation of SA in humans.25

Hooker et al, through a small positron emission tomography (PET) system that measures brain metabolic changes using a radiotracer (18 FDG), revealed evidence that intraperitoneal administration of SA in rodents may activate brain circuits that mediate the effects of the drug on cognition, mood, fear and anxiety, and motor output, regions associated with the distribution of KOR, for example, the periaqueductal gray, bed nucleus of the stria terminalis, the cerebellar vermis, and the hypothalamus. Also, this effect was observed in the auditory, sensory, and frontal cortices.26 The same group showed that intravenous administration of SA in baboons crosses the blood–brain barrier reaching 3.3% of the injected dose within 40 seconds and clearing to half of the peak by 8 minutes, consistent with the distinctly rapid onset and recovery of hallucinations from smoked S. divinorum in humans. SA was mainly concentrated in the cerebellum and visual cortex, which may explain its behavioral and hallucinogenic effects when inhaled.27 Interestingly, Stiefel et al proposed that the consciousness-altering effects produce by SA are processed in part by the claustrum, a site with a high density of KOR.2

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