Salvinorin A Does Not Affect Seizure Threshold in Mice.

The κ-opioid receptor has recently gained attention as a new molecular target in the treatment of many psychiatric and neurological disorders including epilepsy. Salvinorin A is a potent plant-derived hallucinogen that acts as a highly selective κ-opioid receptor agonist. It has unique structure and pharmacological properties, but its influence on seizure susceptibility has not been studied so far. Therefore, the aim of the present study was to investigate the effect of salvinorin A on seizure thresholds in three acute seizure tests in mice. We also examined its effect on muscular strength and motor coordination. The obtained results showed that salvinorin A (0.1-10 mg/kg, i.p.) did not significantly affect the thresholds for the first myoclonic twitch, generalized clonic seizure, or forelimb tonus in the intravenous pentylenetetrazole seizure threshold test in mice. Likewise, it failed to affect the thresholds for tonic hindlimb extension and psychomotor seizures in the maximal electroshock- and 6 Hz-induced seizure threshold tests, respectively. Moreover, no changes in motor coordination (assessed in the chimney test) or muscular strength (assessed in the grip-strength test) were observed. This is a preliminary report only, and further studies are warranted to better characterize the effects of salvinorin A on seizure and epilepsy.

Kappa Opioid Receptor Agonist Mesyl Sal B Attenuates Behavioral Sensitization to Cocaine with Fewer Aversive Side-Effects than Salvinorin A in Rodents.

The acute activation of kappa opioid receptors (KOPr) produces antinociceptive and anti-cocaine effects, however, their side-effects have limited further clinical development. Mesyl Sal B is a potent and selective KOPr analogue of Salvinorin A (Sal A), a psychoactive natural product isolated from the plant Salvia divinorum. We assessed the antinociceptive, anti-cocaine, and side-effects of Mesyl Sal B. The anti-cocaine effects are evaluated in cocaine-induced hyperactivity and behavioral sensitization to cocaine in male Sprague Dawley rats. Mesyl Sal B was assessed for anhedonia (conditioned taste aversion), aversion (conditioned place aversion), pro-depressive effects (forced swim test), anxiety (elevated plus maze) and learning and memory deficits (novel object recognition). In male B6.SJL mice, the antinociceptive effects were evaluated in warm-water (50 °C) tail withdrawal and intraplantar formaldehyde (2%) assays and the sedative effects measured with the rotarod performance task. Mesyl Sal B (0.3 mg/kg) attenuated cocaine-induced hyperactivity and behavioral sensitization to cocaine without modulating sucrose self-administration and without producing aversion, sedation, anxiety, or learning and memory impairment in rats. However, increased immobility was observed in the forced swim test indicating pro-depressive effects. Mesyl Sal B was not as potent as Sal A at reducing pain in the antinociceptive assays. In conclusion, Mesyl Sal B possesses anti-cocaine effects, is longer acting in vivo and has fewer side-effects when compared to Sal A, however, the antinociceptive effects are limited.

Salvia divinorum: An overview of the usage, misuse, and addiction processes.

Salvia divinorum, a sage plant with leaves that can produce a psychoactive high, has been used for hundreds of years for its psycho-mimetic effects in religious rituals in South America. Salvia has now become popular mainly with adolescents and young adults for the short-lived relatively pleasant experiences many consider a "legal high" and its ready availability through Internet purchases. The main (psycho)active compound in salvia is Salvinorin A, a potent κ-opioid agonist and although the short and long-term effects have not been examined in sufficient detail, it is widely believed to have low addictive potential and low toxicity. Recent findings, however, seem to suggest that Salvinorin A can precipitate psychiatric symptoms and negatively affect cognition. Its ready availability and increasingly widespread use requires clinicians to have knowledge and awareness of its effects.

The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.

The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas ß-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists.

Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans.

BACKGROUND: Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA)-a highly selective agonist at the κ opiate receptor-is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans. METHODS: In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological, and endocrine effects of 0 mg, 8 mg, and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia. RESULTS: SA produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin, and reduced resting electroencephalogram spectral power. The SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits, or changes in vital signs. The effects were transient and not dose-related. SA administration was very well-tolerated without acute or delayed adverse effects. CONCLUSIONS: SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with κ opiate receptor agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved, and to explore the basis for individual variability in its effects.

Acute and post-acute behavioral and psychological effects of salvinorin A in humans.

RATIONALE: Salvia divinorum has been used for centuries, and nontraditional use in modern societies is increasing. Inebriation and aftereffects of use are poorly documented in the scientific literature. OBJECTIVES: This double-blind, placebo-controlled, randomized study analyzed subjective experiences of salvinorin A (SA) inebriation and consequences of use after 8 weeks. METHODS: Thirty middle-aged, well-educated, hallucinogen-experienced participants smoked either 1,017 or 100 µg SA 2 weeks apart in counterbalanced order. Vital signs were recorded before and after inhalation. A researcher rated participants' behavior during sessions. Participants completed the Hallucinogen Rating Scale (HRS) assessing inebriation immediately after each session. Differences were analyzed between groups as functions of dose and time. After 8 weeks, participants were interviewed to determine reported consequences and aftereffects. RESULTS: Participants talked, laughed, and moved more often on an active dose. All six HRS clusters were significantly elevated on an active dose indicating hallucinogenic experiences. No significant adverse events were observed or reported by participants. CONCLUSIONS: The present results indicate similarities as well as differences between the subjective effects of S. divinorum and other hallucinogens. As a selective kappa opioid receptor agonist, SA may be useful for expanding understanding of the psychopharmacology and psychology of hallucinogenic states beyond serotonergic mechanisms.

Salvia divinorum use and phenomenology: results from an online survey.

Salvia divinorum is a hallucinogenic plant with ethnopharmacological and recreational uses. It differs from classic serotonergic hallucinogens such as LSD and psilocin in both phenomenology and potent agonist activity of the active component salvinorin A at κ-opioid receptors. Awareness of S. divinorum has grown recently, with both an increase in its public representation and concern over its potential harmful effects. This discussion is particularly relevant as S. divinorum is legal to use in many countries and regions and easily available through online retailers. Drawing upon previous investigations of S. divinorum and other hallucinogens, this study surveyed 154 recent users and questioned them on their use behaviours, consequences of use and other attitudinal measures. Although reporting an extensive substance use history, and considering the limitations of online surveys, there was little evidence of dysfunctional S. divinorum use, and few reports of troubling adverse consequences of use. Furthermore, there was no evidence that users exhibited increased schizotypy. Respondents reported that S. divinorum produced mixed hallucinogenic and dissociative effects, which lends support to assertions that it phenomenologically differs from other hallucinogens with primary serotonergic activity. The functions of use changed with greater experiences with the drug, and although many respondents reported use of S. divinorum as an alternative to illegal drugs it, was apparent that legal proscription would be unlikely to dissuade them from use. These results are discussed with reference to psychopharmacologically informed public health responses to substance use.

Receptorome screening: a powerful, facile approach to better understand and engineer drugs.

Receptorome screening is the process of characterizing one or more compounds for pharmacological activity (e.g., inhibition of radioligand binding, positive or negative efficacy) at a large panel of 'targets' (e.g., biologically relevant recombinant G protein-coupled receptors, ion channels and small-molecule transporters). Recently, receptorome profiles have led to mechanistic insights into the actions -both intentional and adverse- of several drugs. In the present review, I discuss in detail how receptorome screening increased our understanding of three drugs (salvinorin A, amisulpride and fenfluramine) and a class of medications (atypical antipsychotics). The cases presented suggest that receptorome screening of current medications, as well as investigational drugs and future compounds destined for use in humans, might enable us to predict salutary effects, as well as side effects, at the preclinical stage, which would have important economic and public health implications.