Acute effects of lysergic acid diethylamide on circulating steroid levels in healthy subjects

Lysergic acid diethylamide (LSD) is a prototypic serotonergic hallucinogen that acts primarily at serotonin 5-HT1 and 5-HT2 receptors and has a pharmacology that also includes dopaminergic and adrenergic receptor interactions. Earlier research showed that many psychoactive drugs activate the hypothalamic–pituitary–adrenal (HPA) axis and raise glucocorticoid levels, but data on LSD's effects on circulating steroid hormones in humans have been limited and fragmentary. Animal studies and early human urine studies suggested HPA activation after LSD, and a prior human report by the group found an increase in plasma cortisol at 180 min, but comprehensive time courses and a broader steroid panel had not been examined over the full duration of LSD's effects. Strajhar and colleagues set out to characterise the acute effects of a single oral dose of LSD on a wide panel of plasma steroids over 24 h in healthy volunteers and to compare steroid time-courses with LSD plasma concentrations and psychotropic effects. The study aimed to determine which steroid classes (glucocorticoids, mineralocorticoids, androgens, progestogens) are altered by LSD, the timing of those changes relative to subjective effects and LSD exposure, and whether any concentration–effect hysteresis or acute tolerance is evident.

The study used a double-blind, placebo-controlled, cross-over design with two experimental sessions per subject in balanced order and washouts of at least 7 days. Sixteen healthy adults (eight men, eight women; mean age 28.6 ± 6.2 years) participated. Exclusion criteria included pregnancy, personal or first-degree family history of psychotic or major affective disorder, regular medication use, significant medical illness, recent or frequent illicit drug use, and positive urine drug screens. Subjects refrained from caffeine and limited alcohol before sessions; light smokers were allowed to maintain usual habits but were not to smoke during sessions. Each session began at 08:00 with baseline measures; a single oral dose of LSD 200 μg or placebo was administered at 09:00. Subjects remained resting in a calm laboratory environment; standardised lunch and dinner were provided. Blood for steroid assays was sampled 1 h before and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10 and 24 h after dosing via an indwelling catheter. Plasma was stored at −20 °C. Plasma LSD concentrations were measured by LC-MS/MS; 15 steroids (including cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, aldosterone, 11-deoxycorticosterone, 11-deoxycortisol, DHEA, DHEAS, androstenedione, testosterone, 5α-dihydrotestosterone, androsterone, progesterone, 17α-hydroxyprogesterone) were quantified by UPLC-MS/MS after solid-phase extraction. Method performance reported coefficients of variation <15%, accuracy 85–115% and recoveries 80–120%. Statistical comparisons between LSD and placebo used repeated-measures ANOVA on Cmax and AUC values; time courses were analysed with two-way ANOVAs (drug × time) and Tukey's post-hoc tests. AUCs were calculated from 0.5 h to 10 h (AUC10) by the trapezoidal method. Sex was included as a between-subject factor to test sex differences. The relationship between LSD exposure and steroid or subjective responses was explored with hysteresis plots and Spearman rank correlations between mean LSD concentrations and mean responses across the 12 time points; 17 correlations were tested and a Bonferroni-corrected significance threshold of P < 0.003 was applied. Analyses were performed in STATISTICA v12.

LSD (200 μg) produced significant increases in circulating glucocorticoids compared with placebo. Specifically, plasma cortisol, cortisone, corticosterone and 11-dehydrocorticosterone were elevated after LSD; sums (cortisol + cortisone and corticosterone + 11-dehydrocorticosterone) and the ratios cortisol/cortisone and corticosterone/11-dehydrocorticosterone were also increased, consistent with increased glucocorticoid production. No LSD effect was found on the cortisol precursor 11-deoxycortisol or on the mineralocorticoids aldosterone and 11-deoxycorticosterone. Among androgens, LSD significantly increased dehydroepiandrosterone (DHEA; both Cmax and AUC10) and increased the AUC10 but not Cmax of androstenedione. No changes were observed in DHEAS, testosterone, 5α-dihydrotestosterone or androsterone. Progestogens (progesterone and 17α-hydroxyprogesterone) were unaffected. There were no significant drug × sex interaction effects for the steroid responses; as expected, baseline testosterone was higher in men than women but the response to LSD did not differ by sex. Pharmacokinetic and temporal relationships were reported: mean LSD Cmax occurred at 1.7 ± 1.0 h and mean peak psychotropic effects (measured by VAS) at 2.4 ± 0.8 h. Corticosterone peaked earlier (1.9 ± 0.5 h) and returned to baseline earlier than cortisol, which peaked at 2.5 ± 0.8 h. Significant elevations were observed for corticosterone from 1–3 h and for cortisol from 1.5–6 h post-dose. Counterclockwise hysteresis was observed for the overall subjective 'any drug effect' and cortisol, consistent with an initial delay due to absorption/distribution; beyond ~2.5 h the psychotropic and cortisol changes paralleled plasma LSD decline, indicating a close concentration–effect relationship up to 24 h. Average plasma LSD levels correlated strongly with average subjective 'any drug effects' (Rs = 0.94, P < 0.001) and with average cortisol over time (Rs = 0.97, P < 0.001). Average subjective 'any drug effect' was also closely related to cortisol (Rs = 0.97, P < 0.001) and corticosterone (Rs = 0.90, P < 0.001). 'Good drug effects' and 'stimulation' correlated with LSD and with cortisol and corticosterone, whereas 'bad drug effects' and 'fear' did not correlate with glucocorticoid changes. By contrast, the authors note that in their prior MDMA dataset the concentration–effect plots showed clockwise hysteresis and evidence of acute tolerance, a pattern not seen with LSD in the present study.

Strajhar and colleagues interpret the findings as evidence that a single 200 μg oral dose of LSD acutely stimulates the HPA axis in healthy humans, producing increases in both inactive (cortisone, 11-dehydrocorticosterone) and active (cortisol, corticosterone) glucocorticoids. The temporal covariation between plasma LSD levels, glucocorticoid concentrations and psychotropic effects suggests a close exposure–response relationship for LSD. Importantly, no clockwise hysteresis was observed for LSD's subjective or glucocorticoid effects, indicating a lack of acute pharmacological tolerance within the 24 h observation window; this contrasts with the authors' earlier data on MDMA, which showed acute tolerance. The authors discuss mechanistic implications in the context of serotonergic stimulation: both LSD and other serotonergic hallucinogens (for example psilocybin) increase cortisol and prolactin, supporting a role for serotonin receptors in HPA axis activation. Comparisons with other stimulants suggest that serotonin and norepinephrine systems are more strongly linked to cortisol responses than dopamine alone; methylphenidate (predominantly dopaminergic) produced little cortisol change in prior work. The relatively larger relative increase in corticosterone versus cortisol is highlighted because corticosterone has greater brain penetration owing to differential transport at the blood–brain barrier, implying the possibility of more pronounced central effects mediated by corticosterone. The increase in DHEA is noted and the authors briefly consider its relevance given DHEA's neuroactive and putative anxiolytic/antidepressant properties. They acknowledge limitations, including evaluation of a single high dose, the healthy and drug-naive sample (which may limit generalisability to chronic or polydrug users), and the absence of measurements of upstream mediators such as corticotrophin-releasing factor or ACTH. The authors conclude that LSD induces acute glucocorticoid release via serotonergic mechanisms, that corticosterone in particular tracked subjective effects closely, and that LSD's glucocorticoid response showed no acute tolerance compared to MDMA.