Translated from our German original by AI. The German text was researched, written, and edited by the Psychedelia Foundation team and remains the authoritative version.
Neurobiological research on psychedelics has traditionally focused strongly on the serotonergic system, in particular on the 5-HT2A receptor. A recent review instead examines the significance of the opioid system for altered states of consciousness and highlights salvinorin A as a particularly clear example of a non-serotonergic mechanism of action.
Salvinorin A is the main psychoactive constituent of Salvia divinorum and acts as a selective agonist at the κ-opioid receptor (KOR). Pharmacologically, this makes the substance fundamentally different from classic serotonergic psychedelics such as LSD or psilocybin. For the review, the authors evaluated findings from preclinical and clinical work, among them in-vitro experiments, studies in genetically modified animal models, optogenetic investigations and neuroimaging studies in humans.
According to the findings reviewed, KOR activation by salvinorin A is associated with pronounced β-arrestin-biased signaling. The authors link the neurobiological processes this triggers to, among other things, a rapid desensitization of the receptors, temporary changes in neuronal function, an impairment of thalamocortical networks, reduced mesolimbic dopamine activity and a fragmentation of large-scale brain networks. These mechanisms could contribute to the intense and often dissociative changes in consciousness under salvinorin A.
The review also considers possible interactions between serotonergic psychedelics and the opioid system. Classic psychedelics may act indirectly on opioid receptors through processes downstream of the 5-HT2A system. The authors discuss possible contributions to pain and mood regulation in particular. These indirect mechanisms are to be distinguished from the direct KOR activation by salvinorin A.
Although salvinorin A is a potent KOR agonist, the animal models the authors draw on point to a comparatively low potential for abuse. Possible explanations given include its frequently aversive effect, the suppression of dopaminergic activity and the absence of positive reinforcement in the relevant experiments. The findings do not, however, allow any blanket statement that a potential for abuse or dependence in humans is ruled out.
In the authors’ view, looking at the opioid system broadens the previously strongly serotonin-centered model of psychedelics. Salvinorin A could serve as a model substance for research into non-serotonergic mechanisms of altered states of consciousness. The authors also see possible starting points for the development of new, selectively acting KOR ligands and for research into therapeutic applications in depression, addiction and chronic pain. Whether clinically usable therapies can in fact be developed from this remains to be shown by further work.
