Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers

This is the second publication of a four-part study. It was found that a microdose (20µg) of LSD increased neuroplasticity as measured by brain-derived neurotrophic factor (BDNF) levels at 6 hours (n=24). The results are, however, ambiguous and not present at all values/times.

Abstract

“Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. Given the increased interest in using low doses of psychedelics for psychiatric indications and the importance of neuroplasticity in the therapeutic response, this placebo-controlled within-subject study investigated the effect of single low doses of LSD (5, 10, and 20 μg) on circulating BDNF levels in healthy volunteers. Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterwards in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 h (5 μg) and 6 h (5 and 20 μg) compared to that for the placebo. The finding that LSD acutely increases BDNF levels warrants studies in patient populations.”

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

Notes

This study used the same participants as Ramaekers et al. (2020), Holze et al. (2020), and Hutten et al. (2020).

The study is supported in part by the Beckley Foundation.

Do also see these notes/critiques on Twitter by Matthew Baggott.

Summary

in healthy volunteers

Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. This placebo-controlled within-subject study investigated the effect of single low LSD doses on circulating BDNF levels in healthy volunteers.

Preclinical research has demonstrated that psychedelic substances, including DOI, LSD, DMT, and psilocybin, and alkaloids present in ayahuasca, affect neuroplasticity after acute, and chronic administration. In vitro studies with DOI, LSD, and DMT showed increased forming of new neurites, increased length of the arbors, and formation of synapses. Preclinical work with 5-MeO-DMT has also shown neuroplastic changes even after administration of low DMT doses, that are considered to be sub-hallucinogenic 1.

LSD base in low doses (0, 5, 10, and 20 mcg) affects BDNF plasma levels in healthy volunteers. These levels reflect mammalian brain-tissue BDNF levels, and this finding adds scientific evidence that LSD in low doses could have therapeutic potential in mood-related disorders.

Difficulties with the peripheral venous catheter during blood sample collection resulted in missing data for one participant. The statistical analyses were performed on complete cases (placebo-LSD dose) and revealed a statistically significant difference between AUC BDNF levels following 5 and 20 mcg LSD compared to placebo.

Figure 1 shows the total mean AUC (SEM) of BDNF and LSD plasma levels for complete # within- subject LSD dose-placebo cases. The results show that 5 mcg and 10 mcg LSD significantly reduced BDNF levels compared to placebo.

BDNF levels remained stable in the placebo conditions throughout the test frame, and reached their highest levels at four hours after administration of 5 mcg LSD.

This study provides preliminary evidence that low doses of LSD increase BDNF plasma levels in healthy volunteers up to 6 hours after administration, suggesting a window of opportunity for a therapeutic response.

Low LSD doses and BDNF 8 BDNF levels peaked at 4 hours for the 5 mcg dose, but significantly increased 2 hours later for the 20 mcg dose. This suggests that the peak had yet to come for the 20 mcg dose condition. Future studies will have to assess the effects of repeating dosing on neuroplasticity to understand whether this practice is beneficial. Previous studies investigating the repeated administration of ketamine and classical psychedelics have provided mixed results. Ketamine antagonizes NDMA receptors on presynaptic GABA neurons, resulting in an increased postsynaptic production of BDNF.

Ketamine and LSD might share a final common pathway when it comes to stimulation of BDNF, and future studies might focus on similarities between underlying biological pathways of the well-studied ketamine, and LSD, to understand the scope of effects LSD, might have.

Participants were twenty-four recreational psychedelic users who provided informed consent, passed medical screening including standard blood chemistry, hematology and urinalysis, and were scheduled with minimally five days in between. LSD and placebo were administered orally at 10:00 AM.

Participants were allocated to unique treatment orders, and blood samples were taken at -0.5h, +2h, +4h and +6h relative to drug administration. BDNF determination was assessed using an ELISA kit, and mean values were calculated and used in statistical analyses. LSD concentrations were determined using ultra-high performance liquid chromatography/ tandem mass spectrometry, and a different extraction procedure was used for samples with an LSD concentration below 5 pg/mL. This study adhered to the code of ethics on human experimentation.

In case of statistically significant effects at alpha= 0.05, effect sizes and their 95% confidence intervals (95% CI) are given; for Friedman tests, point-biserial correlations are calculated.

LSD increases blood plasma BDNF levels in healthy volunteers compared to placebo, and this may explain the beneficial effects experienced by people with psychiatric conditions.

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.