The translational potential of salvinorin A: systematic review and meta-analysis of preclinical studies

Salvinorin A, the main psychoactive compound in Salvia divinorum and a potent kappa opioid receptor agonist, has been tested in animal models of pain, stroke, addiction, and depression. It shows anti-nociceptive, anti-inflammatory, neuroprotective, and anti-addictive effects. However, findings on depression are inconsistent, with both antidepressant and depressogenic outcomes reported. Toxicity data indicate anxiogenic effects and motor and cognitive impairment, with minimal impact on vital parameters. Pharmacokinetic data show rapid onset, fast peak, and a half-life of about one hour. Sixteen structurally distinct analogues were identified with potentially improved safety and pharmacokinetic profiles.

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Abstract

Background: Salvinorin A, the main psychoactive compound of Salvia divinorum, is a potent and selective kappa opioid receptor agonist. While human clinical trials remain limited, animal studies suggest potential therapeutic applications in neurological and psychiatric disorders. This systematic review and meta-analysis aims to synthesize these preclinical findings, addressing three questions: (1) What is the therapeutic potential of salvinorin A in animal models of neurological and psychiatric disorders? (2) What are its toxic effects on behaviour, cognition, and physiological function? (3) What are its pharmacokinetic characteristics? Methods: A systematic search of Medline, Web of Science, and EMBASE for studies published up to June 28, 2024, identified 1718 publications, of which 82 were included in the qualitative synthesis and 10 in the meta-analysis. Results: Salvinorin A has been tested in animal models of pain, cerebrovascular insults, addiction, and depression. It exhibited anti-nociceptive, anti-inflammatory, neuroprotective, and anti-addictive effects. Findings on depression were inconsistent, with both antidepressant and depressogenic outcomes reported. Toxicity data indicate anxiogenic effects and motor and cognitive impairment, with minimal impact on vital parameters. Applied doses ranged from 0.1-10 mg/kg, with lower doses in stroke models. Pharmacokinetic data show rapid onset, fast peak, and a half-life of approximately one hour. Sixteen structurally distinct salvinorin A analogues were identified with potentially improved safety and pharmacokinetic profiles. Conclusion: Our findings support the therapeutic potential of salvinorin A for pain, addiction, and stroke, though its side effect profile may limit clinical application. The development of novel analogues could address these challenges.