Time course of pharmacokinetic and hormonal effects of inhaled high-dose salvinorin A in humans

Salvia divinorum has been used historically in Mazatec shamanic practice and, more recently, has become a recreational psychoactive substance. Its principal psychoactive constituent, salvinorin A, is a kappa opioid receptor agonist that produces hallucinogenic effects distinct from classic serotonergic hallucinogens because it is not active at 5-HT2A receptors. Previous human pharmacokinetic data are limited and potentially incomplete: an earlier inhalation study measured plasma levels at only three post-inhalation time points that occurred well after the very rapid subjective peak observed in laboratory work, and differences in vaporisation techniques may have produced underestimates of typical plasma exposure from smoked or vapourised doses. Johnson and colleagues set out to characterise more precisely the time course of salvinorin A plasma levels after inhalation using a relatively efficient vapour-delivery method, and to relate those plasma levels to concurrent subjective and monitor-rated drug effects. The investigators also measured prolactin and cortisol, hormones known to respond to kappa agonists, and assayed residual drug remaining in the glass pipe to assess delivery efficiency. Frequent early blood sampling was used so that peak drug levels and their temporal relation to subjective effects could be examined directly.

This report analysed data from six healthy adults who had participated in a prior laboratory study of inhaled salvinorin A; the same participants completed a final, single high-dose inhalation session that included blood sampling. The mean age was 25 years (range 21–35). Participants reported prior S. divinorum use (mean 11 occasions) and prior classic hallucinogen use (mean 32 occasions). Two other individuals from the earlier cohort did not participate in the blood-draw session for safety or personal reasons. Each participant inhaled a single high dose of vapourised salvinorin A chosen as their highest tolerated dose from prior ascending-dose sessions: four participants received 21.0 mcg/kg and two received 18.0 mcg/kg. Subjective drug strength and a set of monitor-rated effects (including distance from usual daily reality, unresponsiveness, psychological distress, paranoia, anxiety/fear, motor activity, joy/peace, and physical distress), together with physiology (systolic and diastolic blood pressure and heart rate), were assessed every 2 minutes for 60 minutes after inhalation. Blood was collected at 13 time points up to 90 minutes post-inhalation; plasma was obtained by cold centrifugation. Salvinorin A was quantified by solid-phase extraction followed by LC‑MS/MS in triplicate, using a +5 mass analogue as internal standard. Prolactin and cortisol were assayed by ELISA in triplicate and averaged. Residual salvinorin A in the glass pipe was measured by three dichloromethane washes, drying, reconstitution and LC‑MS/MS analysis (triplicate samples). For statistical analysis, Pearson correlations were computed within each participant between hormone assays and subjective/monitor ratings using the seven time points common to blood draws and ratings (baseline, 2, 4, 10, 20, 30, and 60 minutes). Correlations between salvinorin A and hormones used the same seven time points, while correlations among hormones used all 13 time points. Group-level peak-value correlations (using each participant’s maximal value across the time course) were also examined to allow for delayed hormonal responses. Repeated-measures regression (SAS PROC MIXED with an AR(1) covariance structure) modelled the relationship between salvinorin A plasma level and participant and monitor ratings from baseline to 60 minutes; significance was set at p < .05. The percent of the prepared dose remaining as residue in the glass pipe was calculated from residual mass and the prepared absolute dose. The extracted text notes insufficient sample volumes for two hormone time points for one participant (missing 1 and 10 minute prolactin/cortisol results).

Plasma assays for salvinorin A were successfully obtained at all planned time points; triplicate assay coefficients of variation (CVs) for plasma samples and standards were < 10%. Mean salvinorin A levels peaked at 2 minutes post-inhalation and then declined rapidly, with more gradual reductions thereafter until levels approached baseline by 90 minutes. Individual peak times varied, occurring as early as 1 minute and as late as 4 minutes in some participants. Statistical analyses showed that salvinorin A plasma levels were significantly, positively associated with participant-rated drug strength and with certain monitor-rated drug effects across the time course. In contrast, salvinorin A level did not significantly predict a set of other monitor ratings (anxiety/fear, motor activity, joy/peace, physical distress) nor physiological measures (systolic and diastolic blood pressure, heart rate). These results were unchanged after controlling for lifetime use of classic hallucinogens and lifetime use of S. divinorum. Prolactin showed a reliable increase following salvinorin A administration, with mean peak levels occurring at about 15 minutes post-inhalation; some individuals exhibited a plateau of elevated prolactin from roughly 10 to 30 minutes. Cortisol showed a superficially similar mean time course but large individual variability, and some participants exhibited little evidence of a cortisol response. Within individual participants there were no significant correlations between cortisol or prolactin levels and drug effect ratings; the only notable individual correlations with physiology were one positive correlation between pulse and cortisol, and one negative correlation between systolic blood pressure and prolactin. Salvinorin A levels were not significantly correlated with either cortisol or prolactin within any individual. Prolactin and cortisol were positively correlated within participants across the full set of time points (Pearson r range .36–.92), with this correlation reaching significance in four of six participants. At the group level, correlations between peak values detected no significant relation between salvinorin A and prolactin (p = .82), salvinorin A and cortisol (p = .15), or prolactin and cortisol (p = .68). Residual salvinorin A recovered from the glass pipe averaged 57.1 mcg (SD = 24.3 mcg), representing a mean of 4.21% (SD = 2.25%) of the prepared absolute dose; CVs for triplicate residual assays were < 4%.

Johnson and colleagues emphasise three main findings: the vapour-delivery method was comparatively efficient; salvinorin A blood levels rose and fell rapidly with mean peak at about 2 minutes; and hormonal responses—prolactin reliably and cortisol variably—followed a delayed and more prolonged time course compared with the drug’s plasma profile. The investigators note that mean peak plasma levels in this study were substantially higher than reported in a prior human inhalation study despite lower absolute administered masses, which they attribute to greater delivery efficiency of the glass-pipe vapourisation method; factors such as temperature and airflow topography are suggested as possible contributors to that efficiency. In terms of pharmacodynamics, the study demonstrated a strong temporal correspondence between concurrent plasma salvinorin A levels and participant- and monitor-rated subjective drug effects, supporting the view that subjective intensity is closely tied to contemporaneous systemic exposure. Hormonal measures behaved differently: prolactin increased reliably but with a lag relative to plasma drug levels, and cortisol responses were inconsistent across participants. The authors interpret these hormonal patterns as evidence that endocrine responses to kappa agonism may be temporally dissociated from immediate subjective effects. The study team also highlights the practical relevance of the findings: because smoking and vapourisation both use inhalational routes, the pharmacokinetic data and the evidence for efficient delivery have implications for understanding recreational S. divinorum use and, to a limited extent, for potential therapeutic applications delivered via inhalation. The discussion presents individual variability in peak timing and hormonal responses as notable observations. The extracted text does not provide an extended list of limitations beyond reporting some missing hormone samples and inter-individual variability, so no additional author-acknowledged caveats are introduced here.

The investigators conclude that an efficient vapourisation method produced substantially higher salvinorin A plasma levels than previously reported, and that subjective drug intensity closely tracked concurrent plasma concentrations. Prolactin generally increased after administration but on a delayed and more prolonged time course than the drug itself, while cortisol increases were inconsistent across participants. These findings improve understanding of the pharmacokinetics and short-term hormonal effects of inhaled salvinorin A and are relevant to recreational use of S. divinorum and to considerations of inhalational delivery in any future therapeutic contexts.