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Chronic pain is common, costly, and for many, remains inadequately treated by existing pharmacologic and non-pharmacologic approaches. In parallel with growing dissatisfaction with conventional therapies, classic serotonergic psychedelics, such as psilocybin, lysergic acid diethylamide (LSD), ayahuasca, N,N-dimethyltryptamine (DMT), and mescaline, administered alone or within psychedelic-assisted therapy models, have re-emerged as potential therapeutic tools for a range of health conditions, including chronic pain. In this review, we examine putative mechanisms of action relevant to pain, including effects on neuroplasticity, inflammation, large-scale brain network dynamics, and higher-order psychological processes, such as pain acceptance and cognitive flexibility. We also briefly overview findings from relevant preclinical models for pain. We then summarize recent observational studies and early-phase clinical trials that highlight preliminary signals of benefit across multiple pain conditions, including fibromyalgia, migraine, cluster headache, and other chronic pain syndromes. In addition, we critically evaluate safety considerations, contraindications, drug–drug interactions, and key regulatory challenges that will shape both research and clinical implementation of psychedelics for chronic pain. Finally, we offer pragmatic guidance for clinicians to work more skillfully with patients choosing to use these substances on their own. Although the existing literature suggests mechanistic plausibility and promising preliminary outcomes, the field is limited by small sample sizes, functional unblinding, and a lack of large, well-controlled randomized trials. We conclude by outlining critical methodological priorities and future research directions needed to rigorously evaluate the potential role of psychedelic compounds in the treatment of chronic pain.

Background CBD is widely studied for its stress-reduction and cognitive-enhancing properties, but its effects on hippocampal molecular organisation under physiological settings are unknown. Acute and long-term intraperitoneal CBD treatment at different doses was tested on hippocampus gene expression, circulating corticosterone, and behavioural performance in C57BL/6J mice. Results Short-term administration did not induce detectable transcriptional changes. In contrast, long-term treatment with 10 mg/kg CBD, but not lower or higher doses, resulted in significant hippocampal transcriptional remodelling. Overrepresentation analysis showed coordinated control of mitochondrial oxidative phosphorylation genes, particularly numerous respiratory chain complex I components, and purine and nucleotide metabolic pathways. Shared mitochondrial respiratory genes, not classical disease-associated effectors, enriched KEGG categories for neurodegeneration and retrograde endocannabinoid signalling. The endocrine profile showed a temporary increase in circulating corticosterone after short-term exposure, but long-term dosing decreased it. Behavioural effects were modest and limited across paradigms. Conclusions These results show that long-term administration of an intermediate CBD dose alters subsets of genes related to coordinated bioenergetic and nucleotide-related transcriptional adaptation in the hippocampus, which modulates endocrine stress markers but does not disrupt behaviour. The data suggest that chronic CBD exposure may cause metabolic recalibration in stress-sensitive brain circuits rather than acute neuromolecular reprogramming.