A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers, Johannes G. Ramaekers et al., 2020,

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

Johannes G. Ramaekers, Nadia Hutten, Natasha L. Mason, Patrick Dolder1, Eef L. Theunissen, Friederike Holze, Matthias E. Liechti, Amanda Feilding and Kim P.C. Kuypers

Journal of Psychopharmacology, 2020, 1–8.

doi : 10.1177/026988112094093



Background : Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has 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 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.



Lysergic acid diethylamide (LSD) is a psychedelic compound that was synthesized by the Swiss chemist Albert Hofmann in 1938. He was also the first to describe the psychoactive properties of the compound (Hofmann, 1979) such as psychosensory changes, illusionary changes of perceived objects, synesthesia, enhanced mental imagery, hyperamnesia, mysticism and ego dissolution (Grof, 1975; Katz et al., 1968; Liechti, 2017; Liechti et al., 2017; Passie et al., 2008; Schmidt et al., 2018). The altered state of consciousness under LSD is mainly mediated by activation of the 5-HT2A receptors (Kraehenmann et al., 2017; Nichols, 2016; Preller et al., 2017). From a physiological perspective, LSD is known to be non-toxic and medically safe when taken at dosages below 200 μg (Nichols and Grob, 2018), but traumatic mental experiences have been reported (Passie et al., 2008).

LSD may also possess therapeutic properties (Liechti, 2017; Vollenweider and Kometer, 2010) and has been implicated in the management of pain (Whelan and Johnson, 2018). Serotonergic agents, such as ergot alkaloids, have traditionally been used for the acute and preventive treatment of cluster headache and other primary headaches (Lambru and Matharu, 2011). LSD is yet another ergot alkaloid derivative, but most data supporting the use of LSD as analgesic are based on reports of self-medication.

Recent surveys (Andersson et al., 2017; Hutten et al., 2019; Schindler et al., 2015) among pain patients suggest that the use of psychedelics such as LSD can be effective for both prophylactic and acute treatment of cluster headache and migraines, even when used infrequently or at non-hallucinogenic doses.

Moreover, cluster headache patients who had used LSD to treat their condition reported cluster period termination and extension of the remission period (Sewell et al., 2006).

Controlled studies on the efficacy of LSD as an analgesic are virtually absent or dated. A comparative study between LSD (100 μg), meperidine, and dihydromorphinone was conducted in terminally ill patients (N=50) who complained of severe intolerable pain (Kast and Collins, 1964). LSD showed more protracted and more effective action than the other drugs. LSD strongly reduced subjective pain ratings and increased the number of pain-free periods during the day. Apart from the profound analgesic effects,
patients also experienced a psychedelic state, which to some was so disturbing that they refused a second administration of LSD. The same investigator later also reported that the same dose of LSD had significant analgesic action in an even larger case series of terminally ill (N=128) and reduced pain intensity for about 3 weeks (Kast, 1967). Likewise, administration of LSD-assisted psychotherapy to a case series of cancer patients (N=53) with pain, anxiety, and depression produced significant improvements in pain severity, pre-occupation with pain and physical suffering, anxiety, and depression (Grof et al., 1973; Pahnke et al., 1969). Another case series on treatment of phantom limb pain (N=9) with sub-hallucinogenic doses of LSD reported improvement in pain in five patients and decreased use of analgesics (Fanciullacci et al., 1977). Overall, these studies suggest a role for LSD in pain management but controlled research is warranted to provide further evidence.

From a medical point of view, controlled research on the efficacy of LSD in pain management should focus on non-hallucinogenic, low doses of LSD, which are more manageable and thus preferable over treatment with high doses of LSD that produce full-blown psychedelic effects. The present study was therefore designed to assess subjective pain perception in healthy volunteers who received three non-hallucinogenic “micro”-doses of LSD as part of a placebo-controlled trial. We measured their subjective
response to pain evoked by a Cold Pressor Test (CPT) as well as their objective pain tolerance. Based on the preliminary evidence described above, it was expected that LSD would reduce pain perception as compared with placebo treatment. In addition, ratings of dissociation and other psychiatric symptoms
as well as assessments of vital signs were included to monitor mental status as well as safety during treatments.