Salvia is classed as an atypical dissociative because its active substance, salvinorin A, produces a dissociative state through the kappa-opioid receptor. Classic psychedelics work through the serotonin 5-HT2A receptor, and the familiar dissociatives ketamine and DXM through the NMDA receptor. Salvinorin A touches neither. Four lines of evidence support that picture.
The receptor screen of 2002
Bryan Roth's group at the NIMH Psychoactive Drug Screening Program tested salvinorin A against a large panel of brain targets. It bound potently and selectively to the kappa-opioid receptor, acted as an agonist at cloned kappa receptors in cell culture and at native receptors in guinea pig brain, and showed no significant activity at 50 other receptors, transporters and ion channels. It had no effect on the 5-HT2A receptor, which the authors describe as the principal target of classical hallucinogens (Roth et al., 2002).
The same paper noted a chemical oddity. Salvinorin A contains no nitrogen, which made it the first known naturally occurring non-nitrogenous drug selective for one opioid receptor subtype. Almost every other plant hallucinogen is an alkaloid with a nitrogen atom.
Kappa-opioid receptor, activated
Salvinorin A binds here potently and selectively, and has no significant activity at 50 other receptors, transporters and channels (Roth et al., 2002). The body's own ligands for this receptor are the dynorphins.
In people: loss of contact with the surroundings, body changes, short course of about 20 minutes.
Kappa-opioid receptor, naltrexone first
Naltrexone occupies opioid receptors. Taken before a dose of vaporised salvinorin A, it blocked the subjective effects, the rise in blood pressure and the hormone response (Maqueda et al., 2016).
Result: no salvia effect.
Serotonin 5-HT2A receptor, activated
The main target of the classic psychedelics such as psilocybin (as psilocin), LSD and mescaline. Salvinorin A has no action at this receptor (Roth et al., 2002).
In people: changes in perception and thought over several hours.
Serotonin 5-HT2A receptor, ketanserin first
Ketanserin blocks 5-HT2A. It blocked the effects of psilocybin in a dose-dependent way (Vollenweider et al., 1998) and left the effects of salvinorin A unchanged (Maqueda et al., 2016).
Result: psilocybin blocked, salvia not.
Blocking tests in people
The deciding test in people is whether blocking the receptor in a person blocks the experience. In a placebo-controlled study in Barcelona, 24 volunteers with psychedelic experience inhaled vaporised salvinorin A after a capsule of naltrexone, ketanserin or placebo. Naltrexone blocks opioid receptors; ketanserin blocks 5-HT2A (Maqueda et al., 2016).
Naltrexone stopped the subjective effects, the rise in systolic blood pressure and the release of cortisol and prolactin. Ketanserin changed none of them. The authors concluded that kappa-opioid agonism explains the effects and that a 5-HT2A mechanism could be ruled out.
For comparison, ketanserin does block psilocybin in people, in a dose-dependent way (Vollenweider et al., 1998). The same blocker splits the two drug classes cleanly.
| Test | Psilocybin | Salvinorin A |
|---|---|---|
| Main receptor | Serotonin 5-HT2A | Kappa-opioid |
| Blocked by ketanserin (5-HT2A blocker) | Yes | No |
| Blocked by naltrexone (opioid blocker) | Not tested in these studies | Yes |
| Contains nitrogen | Yes (tryptamine alkaloid) | No (diterpene) |
Sources: Vollenweider et al., 1998; Maqueda et al., 2016; Roth et al., 2002.
What the questionnaires picked up
On questionnaires designed for psilocybin and LSD, salvinorin A does register. At Johns Hopkins it raised scores on the Hallucinogen Rating Scale and on a scale for mystical-type experience (Johnson et al., 2011). The fuller analysis of eight volunteers found only partial overlap with classic hallucinogens and a set of effects of its own: dose-related dissociation, lower scores on a word recall and recognition test, and participants who said the state was qualitatively different from any other drug (MacLean et al., 2013).
Recreational users said much the same. In a Spanish questionnaire study of 32 users, the effects resembled high doses of classic psychedelics in some respects, but the "intense derealization and impairment" stood out as typical of salvia (González et al., 2006). In an online survey of 500 users run with Erowid, the most common answer to "what is it like" was that it was unique (38.4%) (Baggott et al., 2010).
Measurement is not settled. A Yale study with 10 people found psychotomimetic, dissociative and bodily effects, yet the patient-rated version of the Clinician-Administered Dissociative States Scale, the questionnaire often used for ketamine, showed no significant change (Ranganathan et al., 2012). Different instruments catch different parts of a two-minute state.
What a brain scan adds
In 2020 the first fMRI study of inhaled salvinorin A appeared, by a Johns Hopkins and Kentucky team that described the substance as an "atypical dissociative hallucinogen". Connectivity within brain networks tended to drop while connectivity between networks rose, and the strongest single effect was a weakening of the default mode network during the peak (Doss et al., 2020). The authors point out that this pattern looks strikingly like what other hallucinogens do, and call for direct comparisons. So the receptor is different while some of the large-scale brain effects overlap.
Where in the brain the kappa receptors do this is still a hypothesis. One proposal points to the claustrum, a thin sheet of neurons with a high density of kappa receptors that Francis Crick and Christof Koch suggested might coordinate conscious experience (Stiefel et al., 2014). The Barcelona group suggests that kappa receptors in parietal cortex could account for the altered sense of the body (Maqueda et al., 2015). Neither has been tested directly in people.
What this means for the experience
- Experience with psilocybin or LSD predicts little about salvia; the route through the brain is different.
- The dissociative character comes with the receptor. At higher strengths it is part of the expected effect, also in a calm session.
- The state arrives within seconds, so harm reduction rests on the room and a sober sitter. See why the body moves while awareness is elsewhere.
Read on: out-of-body experiences on salvia or salvia compared with ketamine, DXM and psilocybin.
