4.1. Lysergic Acid Diethylamide (LSD)
Lysergic acid diethylamide (LSD) is a non-exclusive 5-HT receptor agonist that has been investigated for its potential analgesic properties. It also interacts with certain dopaminergic and adrenergic receptors.66 Threshold dosages for psychedelic effects are as low as 20-30μg, although recreational dosages can range from 50-200μg.66 LSD has a prolonged action, with effects that can persist for six to nine hours after ingestion.66 Some of the putative analgesic mechanisms for LSD originate from both its general pharmacological action and its psychological effects: (1) anti-inflammatory action, for instance through inhibition of tumor necrosis factor (TNF) production37; (2) activation of inhibitory serotonergic descending pathways, inhibiting central sensitization67; and (3) modulation of emotional aspects of pain, potentially through alterations in consciousness, and/or the “psychedelic experience”.68
Studies from the 1960s had suggested some evidence that LSD could attenuate pain in various conditions, including chronic pain syndromes and terminal illness. An early double-blinded trial including patients with multiple chronic pain conditions compared the analgesic action of two opioids, dihydromorphine (2 mg) and meperidine (100 mg), with an open-label arm in which participants received 100μg of LSD.13 The study demonstrated that LSD had a more prolonged and effective analgesic potential, despite a slower onset of action. However, despite pain relief, patients were more likely to refuse the second administration of LSD, suggesting that its analgesic properties were accompanied by a lack of tolerability. This clinical trial was not only the first to explore the role of LSD for pain treatment, but through comments regarding “psychic work” and participants’ “distraction from pain”, it also hinted at early insights that pain is a multidimensional experience encompassing both biological and psychological components.
Recent studies, albeit limited, have reignited interest in the analgesic potential of LSD.69 In 2021, a randomized, placebo-controlled, crossover human laboratory study administered low doses of LSD (5, 10, and 20 μg) and showed an increase in pain tolerance and reduction in pain unpleasantness, using the Cold Pressor Test (CPT), a well-established laboratory model of pain.67 This study provided evidence that sub-hallucinogenic doses of LSD may produce analgesia in humans.
Preliminary evidence suggests that LSD may alleviate pain and improve the overall well-being of individuals suffering from chronic pain. Other areas of research interest include palliative care and cancer-related pain, headaches (including migraines and cluster headaches), and phantom limb pain.