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

Analyses were performed with SPSS 25. Cold Pressor Test (CPT) parameters and vital signs were analysed using a univariate general linear model (GLM) that included Treatment (four levels: placebo and three LSD doses), Time after treatment (either 2 or 10 levels, as reported), the interaction Treatment × Time after treatment, and Participant as a random factor (N=24). Baseline-adjusted measures from the Brief Symptom Inventory (BSI) and the Clinician-Administered Dissociative States Scale (CADSS) were analysed with the same GLM structure but without a Time factor. The authors reported conducting mean-contrast tests comparing each LSD dose against placebo to determine dose-specific effects. Canonical correlation analyses were used to examine multivariate associations between a set of pain measures (pain tolerance, painfulness, unpleasantness) and sets of physiological or psychological measures (systolic and diastolic blood pressure; depersonalisation and derealisation). The threshold for statistical significance was set at p<0.05.

The authors report that a single 20 µg dose of LSD produced a measurable analgesic effect in healthy volunteers, whereas lower doses (5 and 10 µg) did not. LSD 20 µg increased pain tolerance (immersion time in the CPT) by about 20% and reduced subjective ratings of painfulness and unpleasantness. The changes in pain tolerance and subjective pain were described as medium to large in effect size and the authors state these effects were statistically robust; they note that the differences between LSD 20 µg and placebo would remain significant after a conservative Bonferroni correction (p<0.016). The analgesic effect was present at both 1.5 and 5 hours after administration with no significant Treatment × Time interaction, indicating a sustained effect across that interval. On safety and other subjective effects, LSD 20 µg produced small increases in several psychological symptoms as measured by the BSI and CADSS, including anxiety, somatisation, amnesia, depersonalisation, derealisation and overall dissociation. LSD 10 µg increased derealisation and the total dissociation score. However, average CADSS and BSI ratings were reported to range from not present to mild, and the authors emphasise that dissociation following 20 µg was substantially lower than levels reported after typical analgesic doses of compounds such as ketamine or single-dose cannabis in other studies. Physiologically, LSD increased mean systolic and diastolic blood pressure most prominently at 20 µg, but mean changes were less than 10 mmHg relative to placebo and values remained within the normal range; heart rate was not affected. The authors examined possible mechanisms. A canonical association between reduced pain perception and increased dissociation across treatments was observed but explained only about 6% of variance, suggesting a weak relationship and indicating that attentional reorientation or self-transcendence might contribute only modestly to analgesia at these low doses. Canonical correlations between blood pressure measures and pain measures explained about 14% of variance, consistent with prior work on hypertension-associated hypoalgesia and suggesting that modest blood pressure increases could partly account for the analgesic effects via baroreceptor-mediated descending inhibitory pathways. The authors also note possible pharmacological mechanisms involving serotonergic receptors (5-HT2A partial agonism and 5-HT1A antagonism in the dorsal raphe) and call for further research on how LSD interacts with 5-HT and other neurotransmitter systems involved in nociception. The authors conclude that the present study provides evidence for a moderate and protracted analgesic effect of LSD at a dose low enough to largely avoid a psychedelic experience. They state this is the first controlled clinical study in many years to revisit LSD’s analgesic potential and that 20 µg appears to be the minimal effective dose in healthy volunteers. They recommend extended dose-finding studies (for example exploring a low to medium range such as 20–50 µg) to determine the optimal balance between efficacy and mental interference, replication in patient populations with persistent pain and comorbid conditions, and investigation of tolerance with repeated dosing. The authors suggest low-dose LSD may merit further exploration as a novel pharmacological therapy for pain that could avoid some sequelae associated with current mainstay drugs.