Salvia DivinorumPlacebo

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

This double-blind, randomised 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.

Authors

  • Jordi Riba

Published

International Journal of Neuropsychopharmacology
individual Study

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.

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

Introduction

Salvia divinorum is a psychoactive plant traditionally used by the Mazatec people of Oaxaca for medicinal and spiritual purposes. Its principal active constituent, salvinorin-A, is a highly potent, non-nitrogenous neoclerodane diterpene with selective agonist activity at the kappa-opioid receptor (KOR). Previous reports have documented strong perception-modifying and somatic effects after use of S. divinorum or purified salvinorin-A, including tactile disturbances, altered body awareness and detachment from external reality, but these somatic alterations and their relation to interoception have not been directly examined in a controlled laboratory setting. Maqueda and colleagues designed the present study to comprehensively characterise subjective effects of increasing doses of inhaled, vaporised salvinorin-A in healthy volunteers, placing special emphasis on interoceptive changes (the internal representation of bodily state) and sense of body ownership. For safety, the investigators recruited a small sample of volunteers with extensive prior psychedelic experience and used a double-blind, randomized placebo-controlled design with ascending active doses.

Methods

Eight healthy volunteers (three males, five females; mean age 31 years) with extensive prior experience of psychedelic substances were recruited. Exclusion criteria included current or past psychiatric disorders, substance dependence, significant medical illness and pregnancy. Participants completed physical examinations, laboratory tests, ECGs and urinalysis; they were asked to abstain from medications and illicit drugs and were screened by urine tests and breath alcohol checks before each session. The study used a double-blind, within-subjects design over four experimental days. Each volunteer received three active vaporised doses of pure (>99%) salvinorin-A (0.25 mg, 0.50 mg, 1.0 mg) and one placebo in a randomized sequence. For safety the active doses were administered in ascending order for every participant (low before medium before high), while the position of the placebo among the four sessions was randomised. Salvinorin-A was prepared in acetone, evaporated from vials and heated in a round-bottom flask; participants performed a sustained 30-second inhalation while the flask base was heated and then reclined for the acute period. Subjective effects were assessed with a battery of validated instruments administered after each session: the Hallucinogen Rating Scale (HRS; six subscales), the Addiction Research Center Inventory (ARCI), the State-Trait Anxiety Inventory (STAI), the Altered States of Consciousness questionnaire (APZ) and both self-administered and experimenter-administered visual analogue scales (VAS). Interoceptive awareness was measured using a Spanish-translated Multidimensional Assessment for Interoceptive Awareness (MAIA) completed after each session. Participants were also invited to provide free written narratives describing any experienced effects. During the acute phase experimenter-administered VAS for intensity were obtained at baseline and at 1, 2, 5, 10, 15, 20, 30 and 45 minutes post-inhalation. Given the small sample size, the investigators used non-parametric statistics. Friedman tests for related samples evaluated dose effects (placebo, 0.25, 0.5, 1.0 mg) and significant outcomes were followed up with Wilcoxon signed-rank pairwise comparisons. The maximum experimenter-administered VAS score recorded in each session was used for between-dose comparisons. All tests used a significance threshold of p < 0.05.

Results

All eight participants completed the protocol. Acute effects were rapid and short-lived: experimenter-administered VAS scores peaked at 2 minutes post-inhalation and largely returned to baseline by about 20 minutes. Peak intensity values differed significantly across dosing conditions (χ2 = 23.26, df = 3, p < 0.001), with orderly dose–response relationships between placebo and the three active doses. On the Hallucinogen Rating Scale (HRS) a significant dose effect was observed across all six subscales: somaesthesia (χ2 = 18.04, p < 0.001), affect (χ2 = 19.65, p < 0.001), perception (χ2 = 22.67, p < 0.001), cognition (χ2 = 23.42, p < 0.001), volition (χ2 = 17.13, p = 0.001) and intensity (χ2 = 23.26, p < 0.001). Post hoc comparisons indicated orderly dose–response increases for each subscale. The ARCI showed a significant overall dose effect only on the LSD subscale (χ2 = 14.92, p = 0.002); pairwise tests revealed significant differences between placebo and each of the active doses on that subscale. The benzedrine group (BG) subscale showed statistically significant decreases at the medium and high doses versus placebo despite no overall dose effect. State anxiety as measured by the STAI demonstrated a modest dose effect (χ2 = 8.47, p = 0.037). Post hoc comparisons showed increases in STAI scores at the low and medium doses relative to placebo, but no difference between placebo and the high dose. APZ scores indicated strong dose-related alterations across its subscales: oceanic boundlessness (OSE; χ2 = 17.88, p < 0.001), dread of ego-dissolution (AIA; χ2 = 18.29, p < 0.001), and visionary restructuralization (VUS; χ2 = 21.17, p < 0.001). Medium and high doses differed from placebo on all APZ subscales, with the AIA subscale differentiating medium from high dose. Self-administered VAS items showed significant dose effects for most items, including measures of any effect, good effects, sudden onset, fear, altered time perception, altered body dimensionality, altered external reality, loss of contact with external reality and visual effects; the statistical tests reported χ2 values ranging from 11.14 to 22.95 (all p ≤ 0.011 except the non-significant "bad effects" item). Post hoc tests revealed increasing numbers of VAS items differing from placebo across doses (four items at low dose, eight at medium, ten at high). In cases of participant unresponsiveness during the acute phase an intensity score of 100 was assigned at that time point. On the MAIA, dose-related changes were apparent on attention regulation (AR; χ2 = 12.58, p = 0.006) and trusting (TR; χ2 = 14.61, p = 0.002). Attention regulation decreased in a dose-dependent manner, with medium and high doses lower than placebo. Trusting showed an inverted-U pattern: increases at low and medium doses and a decrease at the high dose. Emotional awareness (EA) showed a significant decrease at the high dose on pairwise testing despite no overall dose effect. Qualitative narratives and thematic analyses corroborated the quantitative measures. Commonly reported phenomena included a sudden rapid onset, sensations of being in two realities simultaneously, laughter, transformations into objects or geometric shapes, travel to other dimensions, dream-like quality and changes in dimensionality. Auditory experiences and perceived presences were frequent, sometimes including sensations that presences physically pulled or spoke to participants. Detailed interoceptive reports described being pulled, pressure or division of the body, temperature changes, tingling, sweating, vibrations, loss of contact with the body and out-of-body experiences. Two participants reported lateralised onset sensations.

Discussion

Maqueda and colleagues interpret their findings as replicating earlier reports that vaporised salvinorin-A produces very rapid-onset, short-duration psychotropic effects. The investigators note that all active doses produced psychoactive effects relative to placebo, with peak subjective intensity at about 2 minutes and near resolution by 20 minutes. The 0.25 mg dose was already reliably psychoactive in this sample and effects scaled with dose. The authors emphasise that while several perceptual and cognitive effects resembled those seen with classical 5-HT2A agonist psychedelics, salvinorin-A produced particularly intense somatic and dissociative effects. They describe a biphasic pattern for somatic/interoceptive measures: low and medium doses tended to heighten bodily sensations and increase MAIA trusting scores, whereas the high dose produced marked reductions in body awareness, depersonalization and loss of body ownership. Dissociative features were evident in increases on APZ subscales (OSE and AIA) and in participants' narratives describing loss of contact with external reality and unresponsiveness to visual and verbal cues. Concerning affective outcomes, the study found a paradoxical mix of reports of positive mood and relaxation alongside modest increases in state anxiety at low and medium doses. The authors suggest that ascending-dose administration, expectancy or ceiling effects could partly account for this pattern, and they compare their anxiety findings with previous, partly inconsistent reports. On neural mechanisms, the investigators propose that KOR distribution in neocortex, thalamus, ventral tegmental area, temporal and parietal cortices, and neighbouring structures such as the claustrum could plausibly underlie the observed visual, auditory, interoceptive and dissociative phenomena. They argue that KOR-mediated inhibition in thalamic nuclei might block relay of perceptual and somatic information to cortex, producing loss of contact with external reality, while KOR action in parietal areas could alter multisensory body representation. The authors call for neuroimaging work to directly test these hypotheses. Limitations acknowledged by the study team include the small sample size, the selection of highly experienced psychedelic users which limits generalisability, the fixed ascending order of active doses which could introduce order effects despite randomised placebo placement, and a sex imbalance that could interact with pharmacokinetics. These constraints temper inferences about dose–response generality and applicability to less experienced or more diverse populations. Overall, the investigators conclude that inhaled salvinorin-A produces a distinct subjective profile characterised by rapid, intense perceptual changes together with prominent somatic-dissociative effects, and they suggest the dynorphin–KOR system may play an underappreciated role in human sensory perception, interoception and sense of body ownership.

Conclusion

The inhalation of vaporised salvinorin-A produced rapid, short-lived, and very strong psychotropic effects in this small sample. Perceptual changes included prominent visual and, notably, frequent auditory phenomena. In contrast with classical serotonergic psychedelics, loss of contact with external reality and marked unresponsiveness to external cues were especially evident at medium and high doses. Interoceptive effects were dose-dependent and biphasic: low and medium doses increased bodily sensations and trust in one's body, while the 1.0 mg dose produced near-complete loss of body ownership and increased out-of-body experiences. The authors propose that the dynorphin–KOR system may have an important role in regulating sensory perception, interoception and body ownership in humans.

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INTRODUCTION

Salvia divinorum (Labiatae) is a rare perennial herb endemic to the Sierra Madre Oriental of Oaxaca, Mexico. The Mazatec people who inhabit this area have been using the leaves of the plant for centuries in the treatment of headaches, rheumatism, gastrointestinal diseases, and as a general medicinal tonic. The Mazatec also use S. divinorum leaves for spiritual purposes, divination, and as a catalyst for knowing the causes of illnesses and the adequate cures for their patients. During the last decade, interest in S. divinorum has increased in Europe and North America. Users of the plant in these areas have found new ways of administration that lead to stronger and more efficient effects, compared to the traditional intake routes used by the Mazatecs. These new administration routes include the sublingual route, and the smoking of dry leaves and fortified extracts. Retrospective studies in non-traditional users indicate that S. divinorum is mainly consumed by smoking leaf extracts. Use is occasional and experimental. Subjects reported consuming the drug an average of only two times. This low frequency of use has been attributed to intense somatic-dysphoric effects. Salvinorin-A, the main psychoactive constituent in S. divinorum, is a non-nitrogenous neoclerodane diterpene with an affinity for the kappa opioid receptor (KOR;. Despite its intense perception-modifying effects in humans, in vitro studies have shown that salvinorin-A does not bind to 5HT 2A receptors, the molecular target of classic psychedelics like lysergic acid diethylamide (LSD), mescaline, psilocybin, and dimethyltryptamine. The combination of intense perceptual and somatic effects is characteristic of salvinorin-A. Older nitrogenated KOR agonists such as enadoline are known to induce unpleasant reactions, and modifications in perception usually appear at high doses. The distinct effects of salvinorin-A are probably due to its high potency and selectivity at KOR. Previous reports of subjective effects include prominent somatic modifications. These range from tactile effects to a marked loss of control over the body. These modifications have been quantitatively demonstrated, for instance, as significant increases in scores on the Hallucinogen Rating Scale (HRS) somaesthesia subscale, which measures tactile, visceral, and interoceptive effects. These somatic and tactile effects may be related to altered interoception, but this has not been directly assessed. "Interoception" refers to the primary internal representation of the physiological condition of the body. This facet of awareness encompasses a series of processes that can range from somatic sensations to dissociation, and is related to the visceral state of the body and emotional experience. Altered interoceptive abilities have been implicated in addiction, anxiety, and depression, and their restoration is at the center of body-focused therapies. In the present study we wished to comprehensively assess the pattern of subjective effects of increasing doses of salvinorin-A, with a special emphasis on interoception. For safety reasons, we recruited a small number of participants who had extensive experience with psychedelics.

ETHICS

The study was conducted in accordance with the Declarations of Helsinki and its updates concerning experimentation on humans, and was approved by the hospital's ethics committee and the Spanish Ministry of Health. All participants gave their written informed consent prior to participation.

PARTICIPANTS

We contacted circles of individuals interested in the altered states of consciousness induced by psychoactive substances and explained to them the goals and methods of our study. We asked our contacts to pass the information to their acquaintances and we finally recruited a group of eight healthy volunteers (three males, five females). They all had a minimum experience with psychedelics of ten times and no history of adverse effects from their use. The volunteers were interviewed by the principal investigator (Dr Riba), who recorded their previous experience with perception-modifying drugs and explained the goals and methods of the present study. Exclusion criteria included a current or past history of psychiatric disorders, alcohol or other substance dependence, evidence of significant illness, and pregnancy. Participants underwent a complete physical examination that included a medical history, laboratory tests, ECG, and urinalysis. Participants received detailed information about the nature of salvinorin-A and the general psychological effects of psychedelics and their possible adverse effects as they are described in the psychiatric literature.

DRUG

Three doses of pure (>99%) salvinorin-A of 0.25, 0.50, and 1 milligrams were administered via inhalation after vaporization. Using previously described procedures, individual doses were prepared in vials that contained the salvinorin dose dissolved in 1 ml of acetone vehicle. Placebo vials contained the 1 ml acetone vehicle only. No other substance was added. Prior to administration, the content of the vial was placed in a round-bottom flask and the acetone allowed to evaporate. The residue was heated, vaporized, and administered to the participants as described below.

STUDY DESIGN AND EXPERIMENTAL PROCEDURE

The study was carried out in a double-blind fashion. Volunteers were informed that they would receive three doses of salvinorin-A (0.25, 0.5, and 1.0 mg) and placebo over four experimental days, with the sequence of drug conditions randomized. In order to control for expectancy, participants were told that administration would be made in a balanced fashion. For safety reasons, doses were actually administered in increasing order. The low dose of 0.25 mg always preceded the medium 0.50 mg dose and the medium dose always preceded the high 1 mg dose. The position of the placebo was randomly determined for each volunteer. Experimenters were aware of the ascending order of the active doses but did not know the position of the placebo in the sequence. Two weeks before the beginning of the experimental sessions, volunteers were instructed to abstain from all medications and illicit drugs, and remain drug-free throughout the study. Urinalysis for illicit drug use was conducted before each experimental session; volunteers tested negative for cannabis, opiates, benzodiazepines, cocaine, and amphetamine. Additionally, volunteers were instructed to abstain from alcohol 24 h before each experimental day, verified by breath analysis, and from tobacco and caffeinated drinks on the experimental day. Experimental days were 24 h apart. Upon arrival in the morning to the research unit, breath analysis for alcohol, urinalysis for illicit drug use, and a urine pregnancy test (for women only) were administered. Then salvinorin-A or placebo was administered by vaporization and inhalation. The administration method followed that previously developed and described in detail by Johnson and coworkers. The round-bottom flask was connected to a vacuum adapter, which was connected to a rubber tube to allow the inhalation of the vaporized salvinorin-A. The flask was kept from the participant's view using an aluminum foil screen. The volunteer was seated in a recliner bed while performing a sustained inhalation for 30 seconds while the base of the flask was heated with a butane flame for 30 seconds. After the 30-second period, they were instructed to exhale. Immediately thereafter, the bed was reclined until the volunteer was in a recumbent position. The room was kept dimly lit but the eyes of the participants were not covered. No music was used during the sessions. During the acute salvinorin-A effects, at regular intervals between 0 and 45 minutes, the investigator asked the participant to rate the intensity of subjective effects. After 60 minutes, the participant left the room and answered the battery of subjective effects questionnaires and instruments (see below). If they had experienced any noticeable effects, they were also asked to write in their own words a report of their experience. Four hours after drug administration, they were discharged and allowed to leave the research unit.

MEASUREMENTS

The psychological effects elicited by salvinorin-A were measured using a battery of subjective effects questionnaires and visual analog scales (VAS) administered in each experimental session. The Hallucinogen Rating Scale (HRS) was designed to measure the effects of dimethyltryptamine. It has previously shown sensitivity to inhaled salvinorin-Aand to smoked Salvia divinorum. The HRS measures psychedelicinduced subjective effects on six subscales: somaesthesia, reflecting somatic effects; affect, showing sensitivity to emotional and affective responses; cognition, describing modifications in thought processes or content; perception, measuring visual, auditory, gustatory, and olfactory experiences; volition, indicating the volunteer's capacity to willfully interact with his/ her "self" and/or the environment; and intensity, which reflects the strength of the overall experience. The range of scores for all scales is 0-4. In the present study, a Spanish version of the questionnaire was administered. The Addiction Research Center Inventory (ARCI;) consists of five scales or groups: the morphine-benzedrine group (MBG), measuring euphoria; the pentobarbital-chlorpromazine-alcohol group (PCAG), measuring sedation; the lysergic acid diethylamide scale (LSD), measuring somatic-dysphoric effects; the benzedrine group (BG), measuring subjectively experienced intellectual efficiency; and amphetamine (A), which is sensitive to stimulants. The range of scores is 0-16 for MBG, -4 to 11 for PCAG, -4 to 10 for LSD, -4 to 9 for BG, and 0-11 for A. A validated Spanish version was administered. The State-Trait Anxiety Inventory (STAI;consists of 20 self-rated-items on a four-point scale with the responses of not at all, somewhat, moderately, and very much. A validated Spanish version was administered. The Altered States of Consciousness questionnaire (Aussergewöhnliche Psychische Zustände, APZ;includes 72 true/false items distributed in three subscales: oceanic boundlessness (Ozeanische Selbst-entgrenzung, OSE), measuring changes in the sense of time, derealization, and depersonalization; dread of ego-dissolution (Angstvolle IchAuflösung, AIA), measuring thought disorder and decreased body and thought control associated with arousal and anxiety; and visionary restructuralization (Visionäre Umstrukturierung, VUS), referring to visual phenomena, such as illusions, hallucinations, and synesthesia, and to changes in the significance of objects. The range of scores is 0-13 for OSE, 0-22 for AIA, and 0-14 for VUS. A Spanish version of the questionnaire previously used in clinical studies involving psychedelic drugs was administered. Self-administered Visual Analogue Scales (VAS) were used to retrospectively rate peak effects during the session. They were 100 mm horizontal lines with which volunteers retrospectively indicated the intensity of the drug effects (from 0, no effects, to 100, extremely intense effects). There were ten labeled VAS lines. "Any effect" indicated any effect, either physical or psychological, that the volunteer attributed to the administered dosage. "Good effects" indicated any effect the volunteer assessed as good. "Bad effects" indicated any effect the volunteer assessed as bad. "Sudden start of the effects" Experimenter-administered VAS were used during the acute effects. The experimenter verbally asked the participant to rate the overall intensity of the experienced effects on a scale that went from 0 (no effect) to 100 (extremely intense effects). This "intensity" VAS was administered immediately before drug inhalation (baseline) and at 1, 2, 5, 10, 15, 20, 30, and 45 minutes after administration. This allowed assessment of the time course of effects. In cases of unresponsiveness by the participant, the maximum score (100) was assigned to that time point. The Multidimensional Assessment for Interoceptive Awareness (MAIA) is a 32-item, four-point Likert scale designed to measure interoceptive awareness. An exploratory factor analysis was conducted with 325 individuals trained and experienced in mind-body therapies such as yoga and Tai Chi. This analysis revealed eight subscales: noticing (NT), awareness of uncomfortable, comfortable, and neutral body sensations; not distracting (ND), tendency not to ignore or distract oneself from sensations of pain or discomfort; not worrying (NW), tendency not to worry or feel emotional distress with sensations of pain or discomfort; attention regulation (AR), ability to sustain and control attention to body sensations; emotional awareness (EA), awareness of the connection between body sensations and emotional states; self-regulation (SR), ability to regulate psychological distress by attention to body sensations; body listening (BL), active listening to the body for insight; and trusting (TR), experiencing one's body as safe and trustworthy. The MAIA showed acceptable internal consistency (Cronbach's alphas of 0.66 to 0.87), low intra-scale correlations (Person's coefficients of 0.16 to 0.6), and good construct validity. A later confirmatory factor analysis with 435 patients with chronic low back painconfirmed the essential factor structure of the MAIA with similar internal consistency (0.48 to 0.9) and intra-scale correlations (0.16 to 0.7). In the current study, the MAIA was translated into Spanish (Ds Riba and Maqueda). Participants completed the written assessment at the end of each test day based on their acute experience in the laboratory.

PERSONAL NARRATIVES

Participants were requested to write in their own words a description of the effects they had experienced, if any had been noticed. Table. Statistical analyses of subjective effects measures (HRS, ARCI, and STAI) after placebo, and 0.25, 0.5 and 1.0 mg salvinorin-A (n=8).

STATISTICAL ANALYSES

The statistical analysis was conducted using the SPSS software. Descriptive and inferential statistics were used on all instruments administered, except on the free narratives. Scores on each questionnaire subscale and VAS item were calculated for each participant and dosing condition. For the experimenter-administered VAS, the maximum score obtained in each session was used for comparisons between doses. Means and standard errors of the mean were used in the figures. However, given the small sample size, the obtained scores were analyzed by means of non-parametric statistics. First, we used Friedman tests for related samples with dose (placebo, 0.25 mg, 0.5 mg, and 1.0 mg) as a factor. When a significant effect was found, we performed pair-wise comparisons between doses using Wilcoxon signed-rank tests. In all tests performed, differences were considered statistically significant for p values lower than 0.05.

PARTICIPANTS

All participants were Spanish nationals who were interested in psychedelics for self-knowledge purposes. They had experience with synthetic and semi-synthetic mind-altering compounds, but also with natural psychedelics. The context of use had been among friends, and in the case of ayahuasca they had attended European adaptations of Brazilian ayahuasca ceremonies. Volunteers had a mean age of 31 years (21-38). They had extensive previous experience with psychedelic drugs, all having taken LSD and Psilocybe mushrooms. Four participants had smoked S. divinorum. Seven had experience with ketamine, five with 2C-B, five with smoked dimethyltryptamine, four with ayahuasca, and three with mescaline-containing San Pedro cacti. Five were not using cannabis at the time of the study and three were smoking one or two cannabis cigarettes per day.

HRS

Mean scores on all subscales of the HRS at the different doses administered are shown in Figure, and the results of the statistical analyses in Table. A significant effect of dose was observed in all subscales of the HRS (df = 3): somaesthesia (χ2 = 18.04, p < 0.001), affect (χ2 = 19.65, p < 0.001), perception (χ2 = 22.67, p < 0.001), cognition (χ2 = 23.42, p < 0.001), volition (χ2 = 17.13, p = 0.001), and intensity (χ2 = 23.26, p < 0.001). Post hoc comparisons revealed orderly dose-response relationships for all subscales.

ARCI

Mean scores on all subscales of the ARCI are shown in Figure, and the results of the statistical analyses in Table. A significant effect of dose was observed in the LSD subscale only (df = 3; χ2 = 14.92, p = 0.002). Post-hoc comparisons revealed significant differences between placebo and the low, medium, and high doses in the LSD subscale, but no differences between active doses. Despite the lack of an overall effect of dose, the post hoc comparisons showed statistically significant decreases for the BG subscale at the medium and high doses compared to placebo.

STAI

Mean scores on STAI are shown in Figure, and the results of the statistical analyses in Table. A significant effect of dose was observed in the STAI (df =3; χ2 = 8.47, p = 0.037). Post hoc comparisons revealed significant increases between placebo and the low and medium doses, but no differences between active doses or between placebo and the high dose.

APZ

Mean scores on all subscales of the APZ are shown in Figure, and the results of the statistical analyses in Table. A significant effect of dose was observed in all subscales of the APZ (df =3): OSE (χ2 = 17.88, p < 0.001), AIA (χ2 = 18.29, p < 0.001), and VUS (χ2 = 21.17, p < 0.001). Post hoc comparisons revealed orderly dose-response increases. Significant differences were seen between the medium and high doses and the placebo for all subscales. The medium and high doses were statistically different from the low dose and the AIA subscale differentiated between the medium and the high dose.

SELF-ADMINISTERED VAS

Mean scores on all self-administered VAS items are shown in Figure, and the results of the statistical analyses in Table. A significant effect of dose was observed in all but one of the VAS items (df =3): any effect (χ2 = 22.95, p < 0.001), good effects (χ2 = 19.86, p < 0.001), sudden start of effects (χ2 = 19.77, p < 0.001), fear (χ2 = 11.14, p = 0.011), altered time perception (χ2 = 19.77, p < 0.001), altered body dimensionality (χ2 = 12.13, p = 0.007), altered external reality (χ2 = 14.67, p = 0.002), lost contact with external reality (χ2 = 17.29, p = 0.001), and visual effects (χ2 = 21.00, p < 0.001). The item "bad effects" did not show any effects of dose. Post hoc comparisons revealed orderly dose-response relationships. Four VAS items were different from placebo at the low dose, eight at the medium dose, and ten at the high dose, including the "bad effects" item.

EXPERIMENTER-ADMINISTERED VAS

As shown in Figure, the onset of salvinorin-A effects was very rapid, reaching its maximum at 2 min post-administration and gradually decreasing to baseline levels after 20 minutes. The analysis of the peak values showed a significant effect of dose (χ2 = 23.26, df =3, p < 0.001). Post hoc comparisons showed significant effects relative to placebo and orderly dose-response relationships for the three active treatments (see Table).

MAIA

Scores on the MAIA subscales are shown in Figureand the results of the statistical analyses in Table. A significant effect of dose was observed in the attention regulation (AR, χ2 = 12.58, p = 0.006) and trusting (TR, χ2 = 14.61, p = 0.002) subscales of MAIA (df =3). Post hoc comparisons revealed that AR decreased in a dose-dependent manner, with the medium and high doses showing significantly lower AR than placebo. However, the TR displayed an inverted-U relationship (see Tableand Figure). The Wilcoxon test showed significant increases at the low and medium doses and a decrease after the high dose. Despite the lack of an overall effect of dose, the post hoc comparisons showed statistically significant decreases in the emotional awareness (EA) subscale at the high dose.

GENERAL EFFECTS

The most commonly reported themes are shown in Table, organized by dose. These included: (a) the sudden onset of effects; (b) Other less-frequent themes were also reported. These included the sensation of being in two realities at the same time (n = 5). For example: "I really wanted to be fully in that other reality, it was very familiar, like the reality of my childhood"; laughter (n = 3): "It was very fun to check how absurd the usual world was. I was dying of laughter with the perspective of the existence of other worlds containing life"; becoming an object (n = 3): "I changed from being a square, to a pentagon, to a pyramid"; travel to other dimensions (n = 3): "I have left my body and traveled to another world or dimension"; similarity of the experience with dreams (n = 2): "The experience is like dreaming, and then you have difficulties to remember it"; and changes in dimensionality (n = 2): "Consistent change of dimensionality, I pass from 3D to 2D." Another recurring theme was perceiving physical beings or presences (n = 4): "There were magical beings in that world"; "I felt the presence of other life forms in that other world." Sometimes participants perceived that the presences/beings were forces that pulled the body of the participant or talked to them, creating auditory hallucinations.

DETAILED INTEROCEPTIVE EFFECTS

All volunteers experienced profound interoceptive changes and described them extensively in their narratives. Excerpts of these reports are shown in Table. Participants experienced being pulled, pressured, or divided; changes in body temperature; tingling; sweating; relaxation; vibrations; loss of contact with the body; and out-of-body experiences. Volunteer reports also referred to the lateralization of effects (n = 2), starting from a specific side of reality: "I had the sensation that the effects of the substance were approaching me, like an air blast, from the left"; "I felt like another reality, just as real or even more authentic, was coming from the right."

DISCUSSION

The vaporization and inhalation of salvinorin-A proved an effective method of administration, replicating previous research. At the doses used, salvinorin-A showed a pattern of subjective effects with fast onset and short duration. At all doses, peak effects were reached at 2 minutes after the inhalation (second measurement time point), followed by a progressive decrement, to almost disappearing after 20 minutes. This pattern is analogous to those reported previously. The 0.25 mg of salvinorin-A chosen in the present study as the lowest dose was psychoactive (i.e. rated as significantly different from placebo on some measures) in all volunteers. The effects were dose-dependent, with the medium and higher doses leading to more, greater, and longer-lasting perceptual, affective, and somatic effects. The fact that salvinorin-A was psychoactive below doses of one milligram places it in the potency range of LSD. Salvinorin-A induced perceptual and cognitive effects that are typical of 5-HT 2A agonists such as LSD and other classical psychedelics, but with intense somatic effects and a strong dissociative component. Some of the somatic modifications showed a biphasic pattern. At low and medium doses, salvinorin-A increased ratings of bodily sensation. However, at the high dose body awareness was strongly decreased, leading to a depersonalization and loss of sense of body ownership. Assessment scores compare with those obtained by other laboratories. Scores on the HRS subscales confirm the psychedelic profile of salvinorin-A, being in concordance with previous studies both with smoked S. divinorum extracts and pure salvinorin-A. The intensity subscale of HRS shows the high intensity of effects perceived at medium and high doses, consistent with the results of. Our scores are similar also to studies using serotonergic hallucinogens like ayahuascaor psilocybin. The narratives of the volunteers included themes that are common to previous studies with salvinorin-A. For instance, the uniqueness of salvia compared to other psychedelics was reported in the present study by two volunteers: "The experience was surprising, how weird it is!," "This was a completely new experience for me." This is in concordance with the KOR agonism profile of the substance.

PERCEPTUAL EFFECTS

In the present study, significant dose-related effects were found in the instruments measuring alterations in visual and auditory perception. Auditory experiences were quite prominent and included hearing music and being verbally addressed by presences or beings. Visions were also reported frequently in the medium and high doses. These appeared as tunnel or windowlike visions, luminous walls and surfaces, metallic objects, geometric patterns, and other worlds of multiple colors: "I was in an immense forest full of fluorescent trees." As in previous studies, one participant referred to carnival imagery: "There were magical beings in that world, wearing garish dresses, similar to the clothes of a royal court jester."

SYNESTHESIA

A particular type of visual-proprioceptive synesthesia was experienced that has been previously reported from smoking S. divinorum. While visual-auditory synesthesia is common with serotonergic and non-serotonergic substances, visual-proprioceptive synesthesia is rarely described. This was experienced here by two volunteers in three experimental sessions (two in low dose and one in high dose). Objects perceived with eyes open or closed were felt as being associated with the body. For example, seeing external modifications in reality, like a wave, that affects or folds the volunteer's body: "The effects of the substance were approaching me, like an air blast, from the left. (…) they were distorting the objects in the room and also my body and sensations". One volunteer described the concept of a square present in the mind that was felt with the body: "A force was pressing the right side of my body (...), so my sensation was being a square. Visually I wasn't seeing any image, but that square was conceptually present in my mind".

EFFECTS ON AFFECT

Salvinorin-A led to paradoxical effects on emotion. Volunteers reported improved mood including relaxation and calm, as in previous studies. Participants described positive affect states such as "the experience has been very positive" and "I have enjoyed the experience very much". However, anxiety scores on the STAI were increased for the low and medium doses, but not for the high dose. This could be due to the ascending order in which active doses were administered, but could also reflect a ceiling effect. There are no direct references in the written reports to moments of anxiety or fear during the experience. One volunteer reported feelings of being isolated due to not being able to feel the presence of the experimenter in the room, and another volunteer expressed confusion of not being able to understand what was happening. Our results are similar to previous researchwhich reported a lack of negative affect and low anxiety ratings. In contrast, González and coworkers found above average anxiety levels, which could be related to expectancy, previous experience with psychedelics, or the uncontrolled environment of non-laboratory drug use.

INTEROCEPTIVE EFFECTS

Our results suggest biphasic effects of salvinorin-A upon certain aspects of interoception. Results from the MAIA show that salvinorin-A reduced participants' ability to sustain and control attention to their bodily sensations. Low and medium doses of salvinorin-A acutely led to increases in experiencing one's body as safe and trustworthy. Increased Trusting scores have been inversely correlated with experiencing chronic low back pain, perceived stress, depression, and trait anxiety; and have been directly correlated with having a mind-body practice and having strong body-listening skills. Thus, in our sample low and medium doses of salvinorin-A produced effects that could be viewed as adaptive, while high doses of salvinorin-A produced maladaptive effects (decreased body awareness).

DISSOCIATIVE EFFECTS

We observed a strong profile of dissociative effects and disconnection with reality. The body-related dysphoria subscale (LSD) of the ARCI showed lower scores compared to previous studiessuggesting dissociative effects and a perceived inability to interact with one's body and surroundings. Further, the high dose of salvinorin-A increased depersonalization and derealization (OSE subscale of APZ) and decreased body and thought control (AIA subscale of APZ). Paradoxically, the low and medium doses of salvinorin-A increased the MAIA trusting (TR) subscale, indicating an increased experience of one's body as safe and trustworthy. No other results in our study showed a similar inverted-U-shaped profile. It may be that at lower doses salvinorin-A increases bodily sensations, but that the dissociative effects of the high dose overwhelm the subtle trust-enhancing effects of the low and medium doses.

NEURAL SUBSTRATES OF SALVINORIN-A EFFECTS

In the encephalon, high levels of KOR are found in the neocortex, the thalamus and the ventral tegmental area (VTA). Despite lower amounts in the hippocampus, KOR activation effectively reduces the activity of excitatory afferents at this level. It also inhibits dopamine release from VTA afferents to the prefrontal cortex, and the activity of serotonergic and noradrenergic neurotransmission. The dynorphin-KOR system has been involved in stress responses, reward and addiction and various psychiatric disorders. KOR agonism in the temporal and parietal cortices could underlie the visual and auditory modifications (temporal cortex) and the altered experience of the body (parietal cortex). Posterior parietal areas in collaboration with subcortical structures and the premotor cortex play a role in the multisensorial experience of the body by codifying it into an axis of reference (e.g. hands, arms, or head). In one study in which the right angular was electrically stimulated, out-of-body experiences were elicited. In addition, the medial posterior parietal cortex is a key structure within the default mode network, which has been proposed to be associated with the intimate sense of self. The most likely structure mediating the loss of contact with external reality is the thalamus, which shows high KOR levels in humans. Studies in rodents have shown that the centromedian, paraventricular, and centrolateral nuclei of the thalamus are particularly rich in these receptors and cell bodies expressing them (Le. While the first two nuclei play an important role controlling arousal and the overall level of cortical activity, the paraventricular nucleus is associated with viscero-limbic functions. Lesions in the centrolateral nucleus lead to widespread reductions in activation of the reticular system, additional thalamic nuclei, and extensive limbic and cortical areas. A KOR-mediated inhibitory effect of salvinorin-A at this level could block the relay of perceptual and somatic information to the cortex and explain the loss of contact with external reality and with one's own body as reported by participants. Alternatively, the claustrum, a sheet of neurons neighboring the insula, also shows high KOR levels. Stiefel and coworkers have proposed that salvinorin-A could disrupt cerebral integration processes taking place at this level and lead to the effects of disconnection from reality induced by the drug. Future studies should use neuroimaging techniques to provide direct evidence of the brain areas targeted by salvinorin-A.

LIMITATIONS

The study included a relatively small number of subjects with extensive experience with psychedelics. Thus, our results may not be generalized to less experienced individuals. Additionally, as mentioned in the Methods section, the doses were administered in ascending order. Although the position of the placebo was varied randomly, this design may have influenced the results. In addition, the study had five female and three male participants. Due to the sex differences found in distribution and elimination of salvinorin-A,, the effects may have been more intense in the female than the male participants. However, the small sample size precludes the statistical analysis comparison between the two groups.

CONCLUSIONS

The inhalation of vaporized salvinorin-A led to very strong psychotropic effects of rapid onset and short duration. Perceptual modifications included the visual domain, and in contrast with 5HT 2A agonists, auditory hallucinations were very common. Also in contrast with the classical serotonergic psychedelics, loss of contact with external reality was prominent with the participants being unreactive to external visual and verbal cues, especially after the medium and high doses. While at the low and medium doses there was an increase in bodily sensations, at 1.0 mg there was an almost complete loss of body ownership and an increase in out-of-body experiences. These results suggest that the dynorphins -KOR system may play a previously underestimated role in the regulation of sensory perception, interoception, and the sense of body ownership in humans.

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