Chronic pain and psychedelics: a review and proposed mechanism of action

The extracted text presents a narrative, integrative review rather than a systematic review or meta-analysis. It surveys historical literature, clinical case reports and series, retrospective surveys and a small number of prospective non-randomised trials, and integrates preclinical and human neuroimaging studies that relate psychedelic pharmacology to pain mechanisms. The review also summarises safety literature and guidance for clinical administration. The extracted text does not report a formal search strategy, databases searched, inclusion/exclusion criteria, dates covered or methods for study selection or quality appraisal. Consequently, it is not possible from the extraction to determine whether the review used systematic methods or how comprehensively the clinical literature on psychedelics and chronic pain was identified. Where available, the authors draw on specific case series, surveys and experimental findings to illustrate clinical and mechanistic points, and they reference clinicaltrials.gov to describe the status of registered trials.

Historical and clinical literature: The review summarises longstanding cultural uses of psychedelic substances and traces modern scientific exploration from mid-20th century studies of LSD and psilocybin through a period of legal restriction to the recent revival of clinical research. Clinical evidence for analgesic effects is limited but includes early studies by Eric Kast in the 1960s showing LSD-induced analgesia in cancer pain that persisted for an average of 3 weeks after administration. Case series from the 1960s and 1970s reported benefits for phantom limb pain. More recent retrospective surveys and case reports suggest that LSD and psilocybin use is associated with reduced cluster headache severity and extended remission; psilocybin was reported to be roughly as effective as high-flow oxygen for aborting cluster headaches and superior to oral or intranasal triptans, though inferior to subcutaneous triptans. A small case series treated five cluster headache patients with the non-hallucinogenic LSD analogue BOL-148 (30 µg/kg orally, three doses over 10 days): four of five patients had pronounced, long-lasting reductions in headache severity and frequency, and the fifth had a 30% reduction lasting ~4 months. These clinical reports suggest analgesic potential but are heterogeneous in design and quality. Safety and tolerability: Classical psychedelics (LSD, psilocybin, mescaline) are described as having generally favourable physiological safety profiles and low rates of emergency medical treatment compared with substances such as methamphetamine, cannabis and alcohol. Lifetime psychedelic use is not associated in numerous studies with later development of mental health disorders, increased panic attacks or impaired cognition according to the extracted text. Key adverse concerns include acute psychological distress ('bad trips'), risk of self-harm or aggression in a minority of such episodes, and rare prolonged psychosis or persistent perceptual disturbance (HPPD). The review cites a survey of ~2000 individuals with prior psilocybin use in which 39% ranked their worst 'bad trip' among the top five most challenging experiences of their life and 11% reported the experience put themselves or others at risk. Prolonged psychosis after experimental LSD or mescaline administration was reported at a rate of 0.8 per 1000 in one survey; in studies combining LSD with psychotherapy, psychosis >48 hours occurred at 1.8 per 1000. Classical psychedelics lack evidence of physiological dependence or withdrawal. In contrast, several newer synthetic phenethylamines (eg, NBOMes, bromo-Dragonfly) have produced serious toxicity and fatalities. Guidance for clinical administration: The authors summarise safety recommendations emphasising careful patient selection, experienced administrators who can build rapport and support, and an aesthetically comfortable environment to reduce presession anxiety. They note the potential benefits of multiple administrators of varied background. Pharmacology and molecular effects: Classic serotonergic psychedelics primarily activate the 5-HT2A receptor. Phenethylamines tend to be selective for 5-HT2 subtypes, tryptamines bind non-selectively to many 5-HT receptors (and may act at σ1, trace amine receptors and SERT), while ergolines (eg, LSD) show affinity across 5-HT, dopaminergic and adrenergic receptors. Downstream effects include upregulation of immediate early genes (IEGs) such as c-fos, period-1, egr-1 and egr-2, and increases in BDNF and Arc expression in cortical regions in animal models. Nichols and colleagues demonstrated LSD-induced upregulation of multiple transcripts implicated in synaptic plasticity in prefrontal cortex. The hallucinogen R-(-)-DOI inhibited TNF-α-mediated inflammatory pathways in vitro and in vivo in some models, though it is unclear whether similar anti-inflammatory effects generalise across other 5-HT2A agonists. Pain-related neural mechanisms: The review highlights the role of descending serotonergic inhibitory pathways in spinal nociceptive modulation, mediated by several 5-HT receptor subtypes including 5-HT2A. Experimental evidence indicates that 5-HT2A receptor activation can produce persisting descending inhibition after nerve injury, whereas antagonism or genetic knockout can modulate hypersensitivity: ddC or vincristine-induced thermal allodynia and mechanical hypersensitivity in rodents were reversed by the selective 5-HT2A antagonist glemanserin and did not occur in 5-HT2A knockout mice. 5-HT2A receptors are expressed on dorsal root ganglion neurons and can depolarise these cells; spinal 5-HT2A receptors upregulate in models of inflammatory pain. Agonist-induced downregulation or internalisation of 5-HT2A receptors (reported for psychedelics) is proposed as a potential mechanism to counteract spinal sensitisation, though the authors note that direct evidence in dorsal horn neurons is lacking in the extracted text. Brain functional connectivity (FC): Functional MRI studies show that psychedelics disrupt the integrity of established brain networks and increase global integration, producing novel long-range functional connections. Chronic pain conditions are associated with altered FC, commonly involving reorganised connectivity between prefrontal cortex and insula that correlates with pain intensity and duration. The authors suggest that psychedelic-induced 'disintegration' and subsequent formation of alternative connectivity motifs could restore healthier network organisation in chronic pain. A case report described augmented benefit when psilocybin was combined with mirror visual feedback (MVF) therapy for phantom limb pain compared with MVF alone, hinting at possible synergy between psychedelics and rehabilitative or neuromodulatory therapies. Genetic and clinical correlates: The extracted text notes associations between specific 5-HT2A gene polymorphisms and conditions such as fibromyalgia, chronic widespread pain and pelvic pain, supporting a role for 5-HT2A signalling in pain perception. The authors compile converging lines of evidence—molecular, imaging and clinical case data—to argue for plausible mechanisms by which psychedelics could ameliorate certain chronic pain states.

The authors interpret the assembled evidence as suggestive but inconclusive: classic psychedelics have multiple pharmacologic and network-level effects that could plausibly translate into analgesia for some chronic pain conditions, yet clinical data are sparse and heterogeneous. They emphasise three mechanistic pathways as particularly relevant: 5-HT2A-mediated upregulation of genes linked to neuroplasticity, anti-inflammatory effects that could suppress proinflammatory signalling such as TNF-α in some models, and broad reorganisation of brain functional connectivity that may reverse maladaptive network changes present in chronic pain. Castellanos and colleagues position these hypotheses relative to prior research by noting that early clinical studies often lacked rigorous controls but nonetheless reported analgesic signals in cancer pain, phantom limb pain and cluster headache, while more recent imaging and molecular studies provide mechanistic plausibility. They also highlight that some non-hallucinogenic analogues (eg, BOL-148) produced clinical benefit in a small case series, which raises questions about the necessity of subjective psychedelic effects for therapeutic action. Key limitations acknowledged in the extracted text include the limited number and low methodological quality of many clinical reports, regulatory barriers created by Schedule I classification that constrain research, and the absence of clear mechanistic linkage between molecular actions and durable clinical analgesia. The authors note the lack of direct evidence for some proposed mechanisms—for example, whether psychedelics induce 5-HT2A internalisation in dorsal horn neurons is not reported in the available literature. For future work, the review calls for targeted, placebo-controlled trials across defined chronic pain subtypes, mechanistic studies to identify physiological mediators of analgesia, dose-finding research and trials that evaluate combinations of psychedelics with other therapeutic modalities (for example mirror therapy, physical therapy, nerve blocks or neuromodulation) to exploit potential synergistic effects. The authors also advocate for increased funding and the use of rigorous trial designs to close the explanatory gap about how psychedelic-induced analgesia might be produced and maintained.

Psychedelic compounds have a long history of human use and a recent renaissance in clinical research for psychiatric indications. The extracted text concludes that these agents have a generally favourable safety profile relative to opioids and that limited clinical reports over the past five decades indicate potential analgesic benefits in conditions such as cancer pain, phantom limb pain and cluster headache. While definitive mechanisms remain unclear, plausible pathways involve 5-HT2A receptor-mediated neuroplasticity, suppression of certain inflammatory pathways and disruption then reorganisation of pathological brain functional connectivity. Given the opioid epidemic and limitations of current non-opioid analgesics, the authors argue for further well-controlled research to determine whether psychedelics can be safely and effectively developed as analgesic treatments.