A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers

This is the first of a four-part study (n=24) exploring the effects of a microdose of LSD (5-20 µg) on a range of measures, including mood, cognition, empathy, creativity, and physiological parameters. This part of the study found that LSD increased the pain tolerance of participants.

Abstract

“Background: Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that have been implicated in the management of persistent pain. Clinical studies in the 1960s and 1970s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide.

Aim: The present clinical study is the first to revisit the potential of LSD as an analgesic and at dose levels which are not expected to produce profound mind-altering effects.

Methods: Twenty-four healthy volunteers received single doses of 5, 10 and 20 µg LSD as well as a placebo on separate occasions. A Cold Pressor Test was administered at 1.5 and 5 h after treatment administration to assess pain tolerance to experimentally evoked pain. Ratings of dissociation and psychiatric symptoms, as well as assessments of vital signs, were included to monitor mental status as well as safety during treatments.

Results: LSD 20 µg significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization.

Conclusion: The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations.”

Authors: Johannes G. Ramaekers, Nadia Hutten, Natasha L. Mason, Patrick Dolder, Eef L. Theunissen, Friederike Holze, Matthias E. Liechti, Amanda Feilding & Kim P. C. Kuypers

Notes

This study has also been covered in New Atlas, Futurism, Vice, Unilad and Inverse.

The same subjects were also studied by Hutten et al. (2020a), Holze et al. (2020), and Hutten et al. (2020b).

The study is supported in part by the Beckley Foundation.

Summary

Introduction

Lysergic acid diethylamide (LSD) is a psychedelic compound that was synthesized in 1938. It has been implicated in the management of pain and has been used for the acute and preventive treatment of cluster headache and other primary headaches.

The use of LSD as analgesic is based on reports of self-medication, and recent surveys suggest that LSD may be effective for treating cluster headache and migraines.

LSD, an ergot alkaloid derivative with psychedelic properties, has been implicated in the management of persistent pain, but clinical studies have evaporated after LSD was scheduled worldwide.

Controlled studies on the efficacy of LSD as an analgesic are virtually absent or dated. However, several case series have reported significant improvements in pain severity, pre-occupation with pain and physical suffering, anxiety, and depression, and decreased use of analgesics.

A study was conducted on healthy volunteers to assess the efficacy of LSD in pain management. The study used non-hallucinogenic, low doses of LSD and monitored mental status as well as safety during treatments.

Design and treatments

Twenty-four healthy participants received single oral doses of 5, 10, and 20 g LSD (hydrate) and placebo on four separate test days. A minimum washout of 5 days proceeded in between to avoid carry-over effects.

Participants

Participants were average age 22.7 years, had previous experience with psychedelics, and reported using alcohol, cannabis, ecstasy, amphetamines, cocaine, salvia, ketamine, and alprazolam.

The study was conducted in accordance with the Declaration of Helsinki and the Medical Research Involving Human Subjects Act. All participants were fully informed about all procedures, possible adverse reactions, and legal rights and responsibilities.

Procedures

Participants were recruited through advertisements at Maastricht University, via social media, and by word of mouth. They were examined by a study physician and given a resting ECG, blood and urine samples, and were given a body mass index between 18 and 28 kg/m2.

Participants were familiarized with tests and study procedures prior to their first treatment day, and were instructed to refrain from drug use and alcohol use on treatment days.

Participants underwent a CPT, BSI and CADSS assessments, and vital signs were recorded at baseline, every 30 min during the first 3 h after dosing, and at every hour thereafter. Blood samples were collected 1.5 and 6 h after drug administration.

The Cold Pressor Test

The cold water tank task (CPT) was used to induce a painful sensation. Participants had to hold their right hand in the water tank for 3 min until they could not take it anymore, and their subjective ratings of painfulness, unpleasantness and stress were assessed.

Clinician Administered Dissociative States Scale

The CADSS comprises 19 subjective items and is divided into three components: depersonalization, derealization, and amnesia. Component scores above 15 indicate severe symptoms, while scores below 5 indicate absent or mild symptoms.

Blood concentrations of LSD

Blood samples were centrifuged and plasma was frozen at -20°C until analysis for pharmacokinetic assessments. LSD plasma levels were analyzed by ultra-high-performance liquid chromatography tandem mass spectrometry.

Statistics

Analyses were conducted using the SPSS 25 program series to determine whether LSD doses differed from placebo in terms of effect on pain tolerance, painfulness, unpleasantness, and blood pressure.

Results

Mean pain tolerance, subjective ratings of painfulness, unpleasantness and stress during the CPT were significantly affected by Treatment and Time after treatment administration. LSD 20 g slightly increased symptoms of somatization and anxiety but not depression.

Treatment with LSD slightly increased symptoms of derealization, amnesia, depersonalization, and the total dissociation score, compared to placebo, and the symptoms of dissociation were associated with pain tolerance and a decrease in subjective pain perception.

LSD 10 g increased diastolic blood pressure, whereas LSD 20 g increased systolic and diastolic blood pressure. Canonical correlation analysis indicated that increments in blood pressure are associated with increased pain tolerance and a decrease in subjective pain perception.

Plasma samples were collected from 13-18 subjects after 5, 10, and 20 g doses of LSD. The mean concentrations were 150, 278 and 482 pg/mL, respectively.

Discussion

A controlled clinical study has been conducted on the therapeutic potential of LSD in pain management. The study found that LSD was effective at treating pain at doses that did not produce relevant mind-altering effects.

LSD 20 g significantly reduced pain perception as compared with placebo, increased pain tolerance by about 20%, and decreased subjective levels of experienced painfulness and unpleasantness. The effects were statistically robust and comparable to those observed after administration of opioids to healthy volunteers.

The analgesic effects of LSD 20 g were equally strong at 1.5 and 5 h after administration, and may outlast the 5 h time window that was applied in the current study.

LSD produced psychological and physical effects that were noticeable to the participants. However, the magnitude of these effects was small, and the level of cognitive interference produced by LSD 20 g is very mild.

LSD increased mean blood pressure but did not affect heart rate. The increase in blood pressure was mild and did not affect heart rate or temperature, suggesting that the increase in blood pressure after LSD is of limited clinical relevance.

LSD may influence pain perception in various ways, such as pharmacological changes in the processing of nociceptive information or psychological changes in coping with pain. Alternatively, LSD may be analgesic by promoting self-transcendence, in much the same way that meditation-induced self-transcendence is. LSD has partial agonist actions at 5-HT2A receptors and full antagonistic actions at 5-HT1A receptors in the dorsal raphe, a structure known to be involved in actions of descending pain inhibitory processes.

The analgesic effects of LSD may be due to hypertension-associated hypoalgesia, which is a mechanism by which the sympathetic nervous system activates the heart and increases blood pressure, which causes the brain to release serotonin, which reduces the perception of pain.

The present study provides compelling evidence that low doses of LSD can be effective in treating chronic pain, and suggests that LSD may be a novel pharmacological therapy that is devoid of problematic sequelae that are associated with current mainstay drugs, such as opioids.