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

This randomized, double‐blind, placebo‐controlled, cross‐over study (n=16) investigated the effects of LSD (200μg) on the plasma concentration-time profiles of steroid levels. LSD induced significant effects on plasma glucocorticoids, including cortisol and particularly corticosterone, which was also closely related to the subjective effects of LSD. The glucocorticoid response to LSD showed no acute pharmacological tolerance, in contrast to the glucocorticoid response to MDMA.

Abstract

“Introduction: Lysergic acid diethylamide (LSD) is a serotonin 5‐hydroxytryptamine‐2A (5‐HT_2A) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, although the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, although its influence on plasma steroid levels over time has not yet been characterised in humans.

Methods: The effects of LSD (200 μg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomised, double‐blind, placebo‐controlled, cross‐over study design. Plasma concentration–time profiles were determined for 15 steroids using liquid‐chromatography tandem mass‐spectrometry.

Results: LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone and 11‐dehydrocorticosterone compared to placebo. The mean maximum concentration of LSD was reached at 1.7 h. Mean peak psychedelic effects were reached at 2.4 h, with significant alterations in mental state from 0.5 h to > 10 h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5 h and 1.9 h, and significant elevations were observed 1.5–6 h and 1–3 h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens or mineralocorticoids compared to placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed.

Discussion: In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD‐induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance.”

Authors: P. Strajhar, Yasmin Schmid, E. Liakoni, Patrick. C. Dolder, K. M. Rentsch, D. V. Kratschmar, A. Odermatt & Matthias E. Liechti

Summary

Journal of

LSD is a prototypic serotonergic hallucinogen that interacts with serotonin 5-HT1 and 5-HT2 receptors, as well as dopamine D1,D2 and D3 receptors and adrenergic a1 receptors. It induces alterations in perception, empathogenic mood effects and moderate sympathomimetic stimulation.

LSD increases levels of 17-ketosteroid and 17-hydroxy-ketosteroid in urine, which is consistent with HPA axis activation, but effects on circulating corticosterone could not be shown. LSD also blunts the normal increase in 17-ketosteroid after ACTH administration.

Corticosteroids, androgens and progestogens may all contribute to or modulate psychotropic drug actions, including amphetamine and MDMA. Progesterone may also reduce cocaine self-administration in female rhesus monkeys.

Glucocorticoids play an important role in the stress response and the modulation of behaviour. 11-dehydrocorticosterone and corticosterone are the main glucocorticoids in rodents, but corticosterone has a higher brain/plasma concentration ratio than cortisol.

We evaluated the acute effects of LSD on a series of steroids over 24 h in healthy subjects and compared the results with the LSD exposure-psychotropic effect relationship.

Study design

A double-blind, placebo-controlled, cross-over design was used with two experimental test sessions in balanced order. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines in Good Clinical Practice.

Study procedures

The test sessions began at 08.00 h, and ended at 09.30 h. A single dose of LSD or placebo was administered orally at 09.00 h, and a 24 h blood sample collection was performed the next day. The subjects were resting in hospital beds during the test session and did not engage in any physical activity. The subjective and autonomic effects of LSD were also recorded in the present study and have been reported previously (3).

Steroid quantification

Plasma steroid hormone levels were determined as described previously with minor adaptations (6).

After mixing 700 ll of each plasma sample with 100 ll of protein precipitation solution, the samples were centrifuged for 10 min at 16 000 g at 4 °C and the steroids were eluted with 1 ml of methanol and evaporated to dryness. The steroids were separated and quantified by ultra-pressure LC-MS/MS using a reverse-phase column and MASSHUNTER software. The accuracy was between 85% and 115% tested at three concentrations for all analytes.

Statistical analysis

To determine the differences between LSD and placebo, maximum concentration (Cmax) values and areas under the concentration-time curve (AUCs) were compared for each steroid using repeated-measures ANOVA, with drug (LSD versus placebo) as the within-subject factor. Sex differences were determined by including sex (male versus female) as a between-subject factor in the ANOVA.

Results

LSD significantly increased the plasma concentrations of several steroid hormones compared to placebo, but had no effect on the concentrations of the androgens DHEA, testosterone, 5a-dihydrotestosterone or androsterone. Similarly, no sex differences in steroid levels were observed.

LSD was strongly correlated with circulating cortisol and corticosterone, and the relationship between LSD-induced subjective ‘any drug effects’ and circulating glucocorticoids was explored. Subjective drug effects increased together with plasma corticosterone levels but more rapidly than plasma cortisol levels after LSD administration. The average subjective ‘any drug effect’ was closely related to the levels of cortisol and corticosterone. The concentration – effect curves of MDMA for ‘any drug effects’, cortisol and corticosterone exhibited clockwise hysteresis, indicating acute pharmacological tolerance. The average subjective ‘any drug effects’ did not significantly correlate with the average plasma levels of MDMA over time.

Discussion

LSD increased glucocorticoid levels, and androgen levels, as well as the ratio of active to inactive androgens, in healthy humans. No acute tolerance to the effects of LSD was observed, in contrast to the acute tolerance observed with MDMA.

The LSD-induced increase in corticosterone was greater than the increase in cortisol, and this increase may reflect psychotropic alterations over time.

LSD stimulates the HPA axis in humans by activating serotonin 5-HT1 and 5-HT2 receptors, and also increases prolactin, ACTH, and cortisol. Psilocybin stimulates the HPA axis in humans by activating serotonin 5-HT2A/C receptors.

Many psychotropic drugs activate the HPA axis, including serotonin transporter inhibitors, cocaine, amphetamine, and methylphenidate, but only serotonin transporter inhibitors stimulate cortisol, and amphetamine stimulates cortisol more than dopamine, although methylphenidate does not stimulate cortisol as much as MDMA.

Stimulation of the HPA axis involves serotonin and norepinephrine systems. MDMA and LSD increase plasma concentrations of the glucocorticoids cortisol, corticosterone and 11-dehydrocorticosterone. A greater glucocorticoid response was observed after LSD administration than after MDMA administration. This indicates that the direct serotonergic stimulation of postsynaptic 5-HT1 and 5-HT2 receptors by LSD similarly or even more effectively stimulated the HPA axis compared to the release of both serotonin and norepinephrine by MDMA.

Both amphetamine and LSD are mediated by the same transmitter, likely norepinephrine. The subjective effects of LSD are faster than the cortisol response, but only the positive and stimulant subjective effects correlated with the steroid response over time.

Both cortisol and prolactin levels increase when the serotonin system is pharmacologically activated, but the prolactin response is greater after MDMA administration than after LSD administration.

MDMA-induced cortisol and corticosterone responses showed acute tolerance, whereas LSD-induced effects on the HPA axis were longer-lasting and did not show acute tolerance. This finding could be explained by the different pharmacological mechanisms of MDMA and LSD.

MDMA increased the mineralocorticoids 11-deoxycorticosterone and aldosterone, which promote sodium retention and increase extracellular fluid volume, thereby increasing blood pressure.

LSD increased DHEA, which is a precursor of many other steroids. DHEA has well-documented anxiolytic and antidepressant effects.

The present study has limitations, but used a high dose of LSD that produced pronounced psychotropic effects. Additionally, only psychiatrically and somatically healthy subjects with limited previous experience with hallucinogenic drugs were included.

LSD induced significant effects on plasma glucocorticoids, and the cortisol response was closely related to the subjective effects of LSD.

Acknowledgements

The authors thank Florian Enzler and M. Arends for their help with this study.