Salvinorin-A induces intense dissociative effects, blocking external sensory perception and modulating interoception and sense of body ownership in humans

This double-blind, randomized placebo-controlled, within-subjects study (n=8) investigated the effects of vaporized salvinorin-A (0.25, 0.50, & 1 mg) on interoception and the sense of body-ownership in healthy volunteers, who reported an increase of bodily sensations at moderate doses, and an almost complete loss of body ownership and out-of-body experiences at the highest. These effects were rapid and intense but short-lived and included perceptual modifications in the visual domain and commonly entailed auditory hallucinations that are not typical for serotonergic hallucinogens by contrast. This implicates that the Kappa opioid system plays a significant role in the regulation of sensory perception, interoception, and the sense of body ownership.

Abstract

“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 psychedeliclike 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 audiovisual 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.”

Authors: Ana Elda Maqueda, Marta Valle, Peter H. Addy, Rosa Maria Antonijoan, Montserrat Puntes, Jimena Coimbra, Maria Rosa Balleste, Maite Garrido, Mireia González, Judit Claramunt, Steven Barker, Matthew W. Johnson, Roland R. Griffiths & Jordi Riba

Summary

Salvinorin-A, a terpene found in Salvia divinorum, is a psychoactive plant with psychedelic-like effects on perception, body awareness and detachment from external reality.

Introduction

Salvia divinorum is a rare perennial herb endemic to the Sierra Madre Oriental of Oaxaca, Mexico. The Mazatec people use it for spiritual purposes, divination, and to know the causes of illnesses.

During the last decade, interest in S. divinorum has increased in Europe and North America. New administration routes have been found that lead to stronger and more efficient effects.

Salvinorin-A, the main psychoactive constituent in S. divinorum, binds to the kappa opioid receptor and induces intense perceptual and somatic effects. It does not bind to the 5HT 2A receptors, the molecular target of classic psychedelics.

Previous reports of subjective effects include prominent somatic modifications, which may be related to altered interoception. These modifications have been quantitatively demonstrated, for instance, as significant increases in scores on the Hallucinogen Rating Scale (HRS) somaesthesia subscale.

Participants

We recruited eight healthy volunteers who had a minimum experience with psychedelics of ten times and no history of adverse effects from their use. They underwent a complete physical examination, which included a medical history, laboratory tests, ECG, and urinalysis.

Drug

Three doses of pure (>99%) salvinorin-A were administered via inhalation after vaporization. Placebo vials contained the 1 ml acetone vehicle only.

Study Design and Experimental Procedure

The study was carried out in a double-blind fashion with volunteers receiving three doses of salvinorin-A (0.25, 0.5, and 1.0 mg) and placebo over four experimental days. The doses were administered in increasing order and volunteers were instructed to abstain from all medications and illicit drugs.

The volunteers were given breath analysis, urinalysis, and a urine pregnancy test, and then salvinorin-A or placebo was administered by vaporization and inhalation. The participants were seated in a recliner bed and the flask was kept from their view using an aluminum foil screen. The investigator asked the participant to rate the intensity of subjective effects and to write a report of their experience four hours after drug administration.

Measurements

The psychological effects of salvinorin-A were measured using a battery of subjective effects questionnaires and visual analog scales (VAS) administered in each experimental session. The HRS measures psychedelic-induced subjective effects on six subscales: somaesthesia, affect, cognition, perception, volition, and intensity.

The Addiction Research Center Inventory (ARCI) consists of five scales: morphine-benzedrine group (MBG), pentobarbital-chlorpromazine-alcohol group (PCAG), lysergic acid diethylamide group (LSD), benzedrine group (BG), and amphetamine group (A).

The Altered States of Consciousness questionnaire includes 72 true/false items and is divided into three subscales: oceanic boundlessness, dread of ego-dissolution, and visionary restructuralization.

Volunteers used Visual Analogue Scales to rate the intensity of the drug effects, which included physical and psychological effects. The scale had ten lines: “Any effect”, “Good effects”, “Bad effects”, “Sudden start of the effects”, “Fear”, “Changes in dimensionality”, “Changes in external reality”, and “Visions”.

Experimenter-administered VAS were used to assess the acute effects of the drug. The VAS was administered immediately before drug inhalation and at 1, 2, 5, 10, 15, 20, 30, and 45 minutes after administration.

The Multidimensional Assessment for Interoceptive Awareness (MAIA) is a 32-item, four-point Likert scale designed to measure interoceptive awareness. It has good construct validity and internal consistency, and was confirmed by a factor analysis with 435 patients with chronic low back pain.

Statistical Analyses

We used descriptive and inferential statistics on all instruments administered, except on the free narratives. Non-parametric statistics were used to analyze the obtained scores, and p values lower than 0.05 were considered statistically significant.

Participants

All participants were Spanish nationals who had taken LSD, Psilocybe mushrooms, ketamine, 2C-B, smoked dimethyltryptamine, ayahuasca, and mescaline-containing San Pedro cacti. They had experience with synthetic and semi-synthetic mind-altering compounds, but also with natural psychedelics.

Psychological Effects

The results show that all subscales of the HRS were significantly affected by dose, as were the perception, cognition, volition, and intensity subscales. There was no overall effect of dose, but there were statistically significant decreases in the BG subscale at the medium and high doses.

STAI

The mean scores on the STAI increased with increasing dose, but did not differ between active doses or between placebo and the high dose.

Significant effects of dose were observed in all subscales of the APZ, with the medium and high doses being statistically different from the low dose.

Self-Administered VAS

All but one of the self-administered VAS items showed a significant effect of dose, including any effect, good effects, sudden start of effects, fear, altered time perception, altered body dimensionality, altered external reality, lost contact with external reality, and visual effects.

Experimenter-Administered VAS

The onset of salvinorin-A effects was rapid, reaching its maximum at 2 min post-administration, and gradually decreasing to baseline levels after 20 minutes.

MAIA

The results show that the attention regulation (AR) and trusting (TR) subscales of the MAIA decreased in a dose-dependent manner, but the emotional awareness (EA) subscale showed an inverted-U relationship.

General Effects

Table 3 shows the most commonly reported themes, organized by dose, including sudden onset of effects, changes in bodily sensations, changes in perception of time, depersonalization, and derealization, and pleasurable effects.

Other less-frequent themes were reported, including the sensation of being in two realities at the same time, laughter, becoming an object, traveling to other dimensions, similarity of the experience with dreams, and perceiving physical beings or presences.

Detailed Interoceptive Effects

All volunteers experienced profound interoceptive changes, including being pulled, pressured, or divided, changes in body temperature, tingling, sweating, relaxation, vibrations, loss of contact with the body, and out-of-body experiences.

Discussion

Salvinorin-A showed fast onset and short duration subjective effects, with peak effects reached at 2 minutes after the inhalation, followed by a progressive decrement, to almost disappearing after 20 minutes.

Salvinorin-A was psychoactive in all volunteers at doses as low as 0.25 mg. It induced perceptual and cognitive effects that are typical of 5-HT 2A agonists such as LSD, but with intense somatic effects and a strong dissociative component.

Assessment scores compare with those obtained by other laboratories. The high intensity of effects perceived at medium and high doses is consistent with previous studies using serotonergic hallucinogens.

The narratives of the volunteers included themes that were common to previous studies with salvinorin-A, such as the uniqueness of salvia compared to other psychedelics.

Perceptual Effects

In the present study, significant dose-related effects were found in the instruments measuring alterations in visual and auditory perception. Participants reported experiencing tunnel or windowlike visions and being verbally addressed by presences or beings.

Synesthesia

Two volunteers experienced visual-proprioceptive synesthesia while smoking S. divinorum. They described seeing external modifications in reality that affected or folded their body, and experiencing the concept of a square present in the mind that was felt with the body.

Effects on Affect

Salvinorin-A led to paradoxical effects on emotion. Volunteers reported improved mood including relaxation and calm, but increased anxiety scores on the STAI, but there were no direct references in the written reports to moments of anxiety or fear during the experience.

Interoceptive Effects

Results suggest that salvinorin-A has adaptive and maladaptive effects upon certain aspects of interoception. Low and medium doses of salvinorin-A increase trust in one’s body, while high doses decrease trust in one’s body.

Dissociative Effects

We observed a strong profile of dissociative effects and disconnection with reality in high dose salvinorin-A users. However, low and medium doses of salvinorin-A increased the MAIA trusting subscale, indicating an increased experience of one’s body as safe and trustworthy.

Neural Substrates of Salvinorin-A Effects

In the encephalon, dynorphin-KOR is found in the neocortex, the thalamus and the ventral tegmental area (VTA), and inhibits excitatory afferents, dopamine release, serotonergic and noradrenergic neurotransmission, and various psychiatric disorders.

The temporal and parietal cortices are involved in the experience of the body and the sense of self. The posterior parietal cortex is a key structure within the default mode network.

The thalamus is the most likely structure mediating the loss of contact with external reality. A KOR-mediated inhibitory effect of salvinorin-A at this level could explain the loss of contact with external reality and with one’s own body.

The claustrum, a sheet of neurons neighboring the insula, also shows high KOR levels, which could be targeted by salvinorin-A.

Limitations

The study included a relatively small number of subjects with extensive experience with psychedelics, and the doses were administered in ascending order. The effects may have been more intense in the female participants.

Conclusions

The inhalation of vaporized salvinorin-A led to very strong psychotropic effects of rapid onset and short duration. The participants experienced loss of contact with external reality and an increase in out-of-body experiences.

Acknowledgments

This work was supported by the Spanish government and FEDER, and Marta Valle was supported by the Spanish Ministry of Health.