Salvinorin-A is a terpene found in the leaves of the plant Salvia divinorum. When administered to humans, salvinorin-A induces an intense but short-lasting modified state of awareness, sharing features with those induced by the classical serotonin-2A receptor agonist psychedelics. However, unlike substances such as psilocybin or mescaline, salvinorin-A shows agonist activity at the kappa-opioid receptor rather than at the serotonin-2A receptor. Here, we assessed the involvement of kappa-opioid receptor and serotonin-2A agonism in the subjective, cardiovascular, and neuroendocrine effects of salvinorin-A in humans.
We conducted a placebo-controlled, randomized, double-blind study with 2 groups of 12 healthy volunteers with experience with psychedelic drugs. There were 4 experimental sessions. In group 1, participants received the following treatment combinations: placebo+placebo, placebo+salvinorin-A, naltrexone+placebo, and naltrexone+salvinorin-A. Naltrexone, a nonspecific opioid receptor antagonist, was administered at a dose of 50mg orally. In group 2, participants received the treatment combinations: placebo+placebo, placebo+salvinorin-A, ketanserin+placebo, and ketanserin+salvinorin-A. Ketanserin, a selective serotonin-2A antagonist, was administered at a dose of 40mg orally.
Inhalation of 1mg of vaporized salvinorin-A led to maximum plasma concentrations at 1 and 2 minutes after dosing. When administered alone, salvinorin-A severely reduced external sensory perception and induced intense visual and auditory modifications, increased systolic blood pressure, and cortisol and prolactin release. These effects were effectively blocked by naltrexone, but not by ketanserin.
Results support kappa opioid receptor agonism as the mechanism of action underlying the subjective and physiological effects of salvinorin-A in humans and rule out the involvement of a serotonin-2A-mediated mechanism.

BACKGROUND: Salvinorin-A is a terpene with agonist properties at the kappa-opioid receptor, the binding site of endogenous dynorphins. Salvinorin-A is found in Salvia divinorum, a psychoactive plant traditionally used by the Mazatec people of Oaxaca, Mexico, for medicinal and spiritual purposes. Previous studies with the plant and salvinorin-A have reported psychedelic-like changes in perception, but also unusual changes in body awareness and detachment from external reality. Here we comprehensively studied the profiles of subjective effects of increasing doses of salvinorin-A in healthy volunteers, with a special emphasis on interoception.
METHODS: A placebo and three increasing doses of vaporized salvinorin-A (0.25, 0.50, and 1mg) were administered to eight healthy volunteers with previous experience in the use of psychedelics. Drug effects were assessed using a battery of questionnaires that included, among others, the Hallucinogen Rating Scale, the Altered States of Consciousness, and a new instrument that evaluates different aspects of body awareness: the Multidimensional Assessment for Interoceptive Awareness.
RESULTS: Salvinorin-A led to a disconnection from external reality, induced elaborate visions and auditory phenomena, and modified interoception. The lower doses increased somatic sensations, but the highest dose led to a sense of a complete loss of contact with the body.
CONCLUSIONS: Salvinorin-A induced intense psychotropic effects characterized by a dose-dependent gating of external audio-visual information and an inverted-U dose-response effect on body awareness. These results suggest a prominent role for the kappa opioid receptor in the regulation of sensory perception, interoception, and the sense of body ownership in humans.

It has been shown that electrical stimulation of the mesencephalic tectum (MT) provokes defensive responses in both humans and rodents. During an emotional aversive state, some convergent studies have also demonstrated the existence of a complex interaction between endogenous opioid peptide- and γ-aminobutyric acid (GABA)-containing connections during fear-induced responses. It has been proposed that opioid neurons exert an influence on GABAergic interneurons, which, in turn, exert inhibitory tonic control on the mesencephalic excitatory pathways. Thus, opioid peptides can disinhibit neurons that are tonically inhibited by GABA, therefore, modulating the expression of defensive behavioural reactions. In the present work, we used both electric stimulation and microinjections of the GABAA receptor antagonist bicuculline in the inferior colliculus (IC) of Wistar rats in combination with microinjections of µ- and κ-opioid receptor selective agonists into the dorsal columns of periaqueductal grey matter (dPAG) to evaluate the effects on panic-like behaviours elicited by IC electrical and chemical stimulation. The present results showed that neurochemical lesions of the dPAG caused a significant impairment in the organisation of defensive responses by IC neurons, reducing the duration [t(14)=3.0; p<0.01] of defensive immobility and the duration [t(14)=2.8; p<0.05] and frequency [t(14)=2.5; p<0.05] of escape. Paradoxically, treating the dPAG with the µ-opioid receptor agonist met-enkephalin caused a significant reduction of panic-like behaviours induced by both electrical and chemical stimulation of the IC, increasing the escape behaviour threshold [F(2,23)=13.5; p<0.001] and decreasing the frequency [F(3,36)=11.7; p<0.001] and duration [F(3,36)=11.6; p<0.001] of escape and the duration of defensive immobility [F(3,36)=16.1; p<0.05]. In contrast, treating the dPAG with the κ-opioid receptor agonist salvinorin-A increased the frequency [F(3,36)=12.4; p<0.01] and duration [F(3,34)=16.1; p<0.01] of defensive immobility induced by GABAA receptor blockade in the IC. The present results suggest the existence of a complex neuronal network in the MT in which endogenous opioid peptides and GABAergic pathways interact in the control of fear-related behavioural responses.