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.