Dose-related behavioral, subjective, endocrine, and psychophysiological effects of the κ opioid agonist Salvinorin A in humans

Abstract

Background: Salvia divinorum (Salvia) is an increasingly popular recreational drug amongst adolescents and young adults. Its primary active ingredient, Salvinorin A (SA)-a highly selective agonist at the κ opiate receptor-is believed to be one of the most potent naturally occurring hallucinogens. However, there is little experimental data on the effects of SA in humans.

Methods: In a 3-day, double-blind, randomized, crossover, counterbalanced study, the behavioral, subjective, cognitive, psychophysiological, and endocrine effects of 0 mg, 8 mg, and 12 mg of inhaled SA were characterized in 10 healthy individuals who had previously used Salvia.

Results: SA produced psychotomimetic effects and perceptual alterations, including dissociative and somaesthetic effects, increased plasma cortisol and prolactin, and reduced resting electroencephalogram spectral power. The SA administration was associated with a rapid increase of its levels in the blood. SA did not produce euphoria, cognitive deficits, or changes in vital signs. The effects were transient and not dose-related. SA administration was very well-tolerated without acute or delayed adverse effects.

Conclusions: SA produced a wide range of transient effects in healthy subjects. The perceptual altering effects and lack of euphoric effects would explain its intermittent use pattern. Such a profile would also suggest a low addictive potential similar to other hallucinogens and consistent with κ opiate receptor agonism. Further work is warranted to carefully characterize a full spectrum of its effects in humans, to elucidate the underlying mechanisms involved, and to explore the basis for individual variability in its effects.

Figure 1

Salvinorin A (SA) administration produced transient psychotomimetic effects measured as increases on PANSS positive subscale (Figure 1A) and the PSI (Figure 1B). Placebo Salvinorin A Low Dose (8 mg) Salvinorin A High Dose (12 mg) SA Doses are depicted as bars along the X axis. Change in PANSS (1A) and PSI scores (1B) are on the Y-axis. Error bars represent S.E.M. PANSS positive subscale scores range from 1–7 per item × 7 items. PSI scores range from 0–3 × 48 items.

Figure 2

Salvinorin A (SA) administration produced transient perceptual alterations measured as increases on the Hallucinogen Rating Scale (HRS) “Intensity” (Figure 2A) and “Somaesthesia” (Figure 2B) subscales. Placebo Salvinorin A Low Dose (8 mg) Salvinorin A High Dose (12 mg) SA Doses: Placebo, Low (8mg) and High (12mg) are depicted as bars along the X axis. Change in HRS scores is on the Y-axis. Error bars represent S.E.M. HRS scores range from 1–4.

Figure 3

Salvinorin A (SA) produced increases in plasma levels of SA and Salvinorin B (SB) measured in a subsample of subjects (n=7). Placebo Salvinorin A Low Dose (8 mg) Salvinorin A High Dose (12 mg) Neither SA nor SB levels were detectable prior to drug administration (baseline). Time is on the X axis as Baseline (Pre) and 15, 20 and 30 minutes after SA administration Plasma levels of SA and SB are on the Y-axis. Separate lines depict the low and high dose of SA. Error bars represent S.E.M.

Figure 4

Salvinorin A (SA) administration produced elevations in plasma Cortisol (Figure 4A) and Prolactin (Figure 4B). Time is on the X axis as Baseline (Pre) and 10, 15, 30 and 90 minutes after SA administration Plasma Cortisol (µg/dl) and Prolactin (ng/ml) levels are on the Y-axis. Separate lines depict the doses of SA. Error bars represent S.E.M.

Figure 5

Salvinorin A (SA) administration induced reductions in resting beta-band EEG power. Figure 5A depicts the grand-averaged resting EEG spectral power in the beta range (13–29 Hz) at midline electrode sites. Error bars represent S.E.M. Figure 5B depicts the topographic maps indicating grand-averaged beta power across the placebo and the two active SA doses.