Safety pharmacology of acute LSD administration in healthy subjects

This pooled analysis (n=83) finds that LSD (25-200 µg) is physiologically and psychologically safe in healthy subjects when administrated in a controlled research setting.

Abstract

“Rationale Lysergic acid diethylamide (LSD) is used in psychiatric and psychological research and investigated as a potential treatment for medical and psychiatric disorders, including depression, anxiety, and cluster headache.

Objectives Safety data on clinical safety are available from small studies but not from larger samples. We report safety pharmacology data from a large pooled study sample on acute effects of LSD in healthy subjects.

Methods We conducted a pooled analysis of four double-blind, randomized, placebo-controlled, crossover studies that included a total of 83 healthy subjects and 131 single-dose administrations of LSD. LSD administrations were matched to dose groups according to measured LSD peak plasma concentrations to adjust for uncertainties in the correct LSD dose in some studies. Single doses were 25, 50, 100, and 200 µg of LSD base. We investigated subjective effects (self-rated any drug effect, good drug effect, bad drug effect, and anxiety), blood pressure, heart rate, body temperature, duration of the acute LSD response, acute (12 h) and subacute (24 h) adverse effects, reports of flashbacks, and liver and kidney function before and after the studies.

Results LSD dose-dependently increased subjective, physiologic, and adverse effects. The dose–response curves for the proportions of subjects with a certain amount of a subjective effect were steeper and reached a higher maximum for positive acute subjective effects compared with negative acute subjective effects. Maximal ratings of > 50% good drug effects were reached in 37%, 91%, 96%, and 91% of the LSD administrations at 25, 50, 100, and 200 µg. Maximal ratings of > 50% bad drug effects were reached in 0%, 9%, 27%, 31% at 25, 50, 100, and 200 µg, respectively. Mean ratings of Oceanic Boundlessness were 10%, 25%, 41%, and 44%, and mean ratings of Anxious Ego-Dissolution were 3.4%, 13%, 20%, and 22% at 25, 50, 100, and 200 µg, respectively. The physiologic effects of LSD were moderate. None of the subjects had systolic blood pressure > 180 mmHg at any time. Peak heart rate > 100 beats/min was observed in 0%, 6%, 20%, and 25% of the subjects at 25, 50, 100, and 200 µg, respectively. Maximal heart rates of 129 and 121 beats/min were observed in one subject at the 50 and 200 µg doses, respectively. Peak body temperature > 38° was observed in 0%, 11%, 7%, and 34% at 25, 50, 100, and 200 µg, respectively. Mean acute adverse effect scores on the List of Complaints were 5.6, 9.2, 12, and 13 at 25, 50, 100, and 200 µg, respectively. Kidney and liver function parameters were unaltered. Six subjects reported transient flashback phenomena.

Conclusions The single-dose administration of LSD is safe in regard to acute psychological and physical harm in healthy subjects in a controlled research setting.”

Authors: Friederike Holze, Toya V. Caluori, Patrick Vizeli & Matthias E. Liechti

Notes

Given the turbulent relationship society has had with psychedelic drugs, ensuring these drugs are safe is of the utmost concern for researchers as we progress through the psychedelic renaissance. In the 1960s, (false) reports of LSD causing people to leap from windows or leading to chromosome damage in unborn children convinced the public that psychedelic drugs were not only unsafe but also dangerous. As psychedelics re-enter the mainstream, ensuring that society at large is aware of the therapeutic benefits and the physiological safety of psychedelic drugs is imperative to harness the potential of psychedelics on a wide scale.

The present study seeks to add to the literature regarding the safety of psychedelic drugs. Generally, determining the efficacy and safety of a drug entails conducting randomized-controlled trials (RCTs) with large sample sizes. Although RCTs involving psychedelics are taking place across the globe, the number of participants in these trials tends to be small. Therefore, the authors of this study pooled the data from four RCTs investigating the effects of LSD in humans in order to better our knowledge regarding the safety of LSD.

The study found that:

• Out of 81 participants who received a total of 131 single doses of LSD, the subjective, physiological and adverse effects of LSD varied with dose concentration.
• While the subjective effects of LSD such as ego dissolution and feelings of boundlessness increased with higher doses of LSD, the physiological effects were minimal regardless of dose concentration.
• Overall, the effects LSD has on the cardiovascular system, the kidneys and the liver are negligible.

While this study does further inform us of the safety of LSD administered in a clinical setting, the authors did also report negative effects such as fear and anxiety. Further research is needed in order to better enhance our knowledge regarding the safety of psychedelic drugs overall. Moreover, making findings from such studies more publicly accessible will help to rewrite the narrative surrounding psychedelics.

Summary

LSD is used in psychiatric and psychological research and may be used for treatment.

Introduction

Lysergic acid diethylamide (LSD) is used recreationally and is currently under investigation as LSD-assisted psychotherapy for depression and anxiety, and as a treatment for cluster headache. Although recent Phase 2 trials showed only mild and transient adverse events, several psychological safety issues have previously been mentioned. Data on the safety pharmacology of single-dose administrations of LSD were collected from a series of clinical Phase 1 trials in healthy subjects. The studies used a dose range from low (25 g) to moderate (50 g) to moderate-high (100 g) to high (200 g) experiential doses.

Study design

This study was a pooled analysis of four double-blind, placebo-controlled, random-order, crossover studies in healthy subjects. It included 83 participants who were all psychiatrically screened and healthy. Four studies were conducted on healthy subjects with LSD. The studies included 16 healthy subjects who received 200 g LSD and placebo, 24 healthy subjects who received 100 g LSD and placebo, and 16 healthy subjects who received 25, 50, 100, and 200 g LSD and ketanserin.

Subjects and dose groups

83 healthy European/Caucasian subjects were recruited from the University of Basel campus and included in four studies. Sixteen participants received four single-dose administrations of LSD at different doses, and 67 participants received a single dose of LSD only.

The dose groups were adjusted based on the participants’ maximal concentrations of LSD in plasma. This was done because the doses in Study 4 were pharmaceutically exactly defined, whereas the doses in Studies 1 and 2 were not. Based on plasma LSD levels, four of the 16 participants in Study 1 were newly assigned to the 100 g group, three, 11, and two of the 24 participants were assigned to the 25, 50, and 200 g dose groups, respectively, and eight and two of the 27 participants were assigned to the 50 and 200 g dose groups.

We excluded 49 subjects because of psychiatric disorders, physical illness, a lifetime history of using illicit drugs more than 10 times, illicit drug use within the last 2 months, and illicit drug use during the study.

Study drug

Studies 1 and 2 used gelatin capsules containing 100 g of pharmaceutically pure LSD, and Studies 3 and 4 used an ethanolic LSD solution containing 25 or 100 g LSD with an exact content of 25.7 0.3 g and 98.7 1.6 g, respectively.

Study procedures

All studies included a screening visit, two to six test sessions, and an end-of-study visit. The test sessions were conducted in a calm standard hospital room equipped with a standard hospital bed for the participant.

The participants were assessed for emotional states before the LSD-induced experience, and baseline measurements were taken to ensure basic physical health. LSD or placebo was administered at approximately 9:00 AM, and the subjects were never alone during the next 12 – 16 h after drug administration.

Pharmacodynamic measures

Subjective effects were assessed using Visual Analog Scales before, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, and 24 h after LSD or placebo administration. Severe anxiety was defined as > 75% on the “anxiety” VAS. The 5D-ASC scale was administered 24 h (or 11.5 h in Study 3) after drug administration to retrospectively rate peak drug effects.

Blood pressure, heart rate, and body temperature were measured repeatedly at the same time points when the VASs were administered. Tachycardia, hyperthermia, and hyperpyrexia were defined as > 100 beats/min and > 38 °C, respectively.

Adverse effects were assessed using the List of Complaints, and participants were asked to report any adverse events from 24 h after drug administration until the next study visit.

Blood sampling and end‑of‑study visit

Blood chemistry and blood cell count tests were performed at the screening visit and the end-of-study visit, and the participants were asked to rate their experience as positive or negative, whether the controlled clinical setting influenced their experience, and whether they considered taking LSD again.

Statistical analyses

The statistical analyses were performed using Statistica 12 software (StatSoft, Tulsa, OK, USA). ANOVAs were used to evaluate the effects of LSD compared with placebo, and dose-response effects were also evaluated.

Positive subjective drug effects increased with increasing dose of LSD, and showed steeper dose – effect curves and higher maximal effects compared with negative subjective drug effects. The effect duration was dose dependent and 4.5 2.4 h, 7.2 2.5 h, 8.5 3.2 h, and 11 4.6 h for the 25, 50, 100, and 200 g LSD doses, respectively.

Acute effects of LSD on vital signs

LSD produced acute and transient increases in blood pressure, heart rate, and body temperature at doses > 25 g. Tachycardia was observed in 15% of all LSD administrations, and the highest body temperature was 38.8 °C.

Adverse effects of LSD

LSD produced significant acute and subacute adverse effects on the List of Complaints (LC) compared with placebo. Six subjects reported flashbacks 1 – 3 times after LSD administration, but no serious adverse reactions occurred.

Effects of LSD on kidney and liver function and changes in blood cell counts

Plasma creatinine levels, estimated glomerular filtration rate, alanine aminotransferase and -glutamyl transpeptidase levels remained unchanged, and red blood cell counts decreased and thrombocyte levels increased during the studies.

Subjects’ interest in using LSD again

Seventy-five percent of the subjects were LSD-naive at the time of the studies, and the other 25% had very limited experience with LSD. Eighty-three subjects reported that they would consider taking LSD again, and 66 reported that the controlled setting was important for their type of experience.

Discussion

The present analysis of four placebo-controlled studies of LSD found that LSD produced dose-dependent subjective good drug effects in most participants.

Subjective “bad drug effect” ratings were comparatively low, and positive subjective drug effects were reached at lower doses and to a higher extent than negative subjective drug effects. LSD produced moderate cardiostimulant effects in healthy subjects. This analysis is the largest and most comprehensive analysis of the acute safety of LSD in healthy subjects. The results are consistent with previous studies.

Acute LSD administration can induce a mostly positive experience without anxiety, and can also have long-term positive mood effects in healthy subjects. In the present analysis, anxiety was assessed using different measures, and the ratings of anxiety increased dose-dependently. Verbal support could reduce anxiety in all subjects, and benzodiazepines were not used. LSD induces predominantly positive experiences, reflected by nominally higher ratings of “good drug effect” and “openness” relative to “bad drug effect,” “anxiety,” and AED. However, the acute experience of psychedelics predicts therapeutic outcome in patients with depression.

Over 70% of participants reported positive subjective experiences, whereas only 8% reported negative experiences. This is similar to the findings of a study that investigated the safety of MDMA.

The importance of “set and setting” has previously been highlighted by many researchers using psychedelics. The environment where sessions occur needs to provide an individual feeling of security, and the participants’ personality and state of mind should be assessed immediately before LSD administration.

The subjective response to LSD was dose dependent, with longer effect durations with higher doses and a closer LSD-plasma concentration-effect relationship over time within subjects.

LSD produced mild hypertension and moderate hypertension in approximately 50% of all LSD administrations, and tachycardia in approximately 15% of all LSD administrations. Psilocybin produced comparable increases in systolic blood pressure to LSD, and MDMA produced greater increases in systolic blood pressure than LSD.

LSD dose-dependently increased body temperature, but did not increase above 38.8 °C. MDMA, on the other hand, increases body temperature by releasing both serotonin and norepinephrine, which may explain its greater sympathomimetic properties.

Participants reported a series of acute and subacute adverse effects after LSD administration. The nature of the reported subacute adverse effects indicates a state of “exhaustion” that might be comparable to feelings after intense brainwork or physical exertion.

LSD-induced flashbacks have previously been described, but the frequency and nature of flashbacks and risk factors are still unknown. None of the participants reported persisting changes in perception.

LSD did not influence liver enzyme levels on average 1 month after administration, but decreased red blood cell counts and increased thrombocytes were observed at the end-of-study visit.

In the present analysis, peak plasma concentrations of LSD were linked to subjective experiences within the same subject, and the dose – effect relationship reached a ceiling effect at 100 g.

The safety data presented in this paper can partially be applied to the use of LSD in patients. However, there have been no reports of serious adverse reactions to LSD or similar serotonergic psychedelics in modern clinical studies.

The present analysis has several limitations, including unstable formulations, reassignment of outcome data based on pharmacokinetics, and lack of accounting for individual differences in the bioavailability or metabolism of LSD. The present study included 83 participants who received LSD a total of 131 times. Although the findings were consistent with a smaller study with well-defined doses of LSD, the study was heterogeneous in terms of single- or multiple-dose administration of LSD, and a long-term follow-up is missing.

The present analysis has strengths. It assessed safety aspects for a range of LSD doses (25 – 200 g) and used full LSD-plasma concentration – time profiles from all participants, allowing comparisons with other studies that used different formulations.

Conclusion

Single doses of LSD were safe in a controlled clinical setting, but further study is needed to determine the risks and benefits of using LSD in a therapeutic setting.