1. INTRODUCTION
The renewed interest in psychedelics has sparked growing attention to their potential therapeutic applications, prompting a new wave of modern clinical studies and trials. While traditionally associated with counterculture movements and recreational use, leading to their scheduling under the Controlled Substances Act at the start of the 1970s, recent research has shed light on the potential benefits of psychedelics in various mental health conditions, and more recently, both pain and substance use disorders (SUDs).
The continuing opioid epidemic, which claimed over 100,000 lives in the United States in 2021,1 is intertwined with the parallel crisis of chronic pain.2 The initial wave of the opioid epidemic stemmed from the excessive prescription of opioids for chronic pain-related conditions.3,4 Chronic pain not only serves as a precursor to possible opioid use disorder (OUD) but is also associated with poorer treatment outcomes for those with OUD, including sleep disturbances, diminished social functioning, and increased attrition rates from OUD treatment.5,6Despite the magnitude of this problem, there is a scarcity of controlled studies investigating pain management alternatives for those with OUD.7 The three medications currently approved for OUD all exert their therapeutic benefits primarily through the mu-opioid receptor (MOR) and, given their various adverse effects, ranging from gastrointestinal and immune (e.g., methadone and buprenorphine) to hepatic (e.g., extended-release intramuscular naltrexone), there exists a great need for medications that work outside of this system.8 Collectively, the challenges posed by opioid analgesic tolerance9 and the escalation of the opioid epidemic, due to the widespread availability of fentanyl derivatives, further emphasize the urgency to explore novel, non-opioid therapeutics for pain and OUD.
The serotonergic psychedelics, or the “classic” psychedelics, are a class of compounds that exert their psychedelic effects primarily at the serotonin 2A (5-HT2A) receptors.10 Common examples of serotonergic psychedelics include lysergic acid (LSD), psilocybin, ibogaine, noribogaine, ayahuasca, and N, N-dimethyltryptamine (DMT), which have been used in clinical trials investigating their utility independently for both pain and OUD since the 1960s.11-13 Psilocybin, one of the most studied serotonergic psychedelics in modern trials, has shown efficacy in the treatment of other SUDs, such as alcohol use disorder (AUD)14 and tobacco use disorder.15The potential efficacy of psilocybin for chronic pain in people receiving long-term opioid treatment (LTOT) is being tested in ongoing clinical trials.
This review will summarize the available data on the use of serotonergic psychedelics for the treatment of chronic pain and OUD. This review complements prior reviews on psychedelics 16-20 by presenting a synthesis of the mechanisms for how this class of compounds could be useful to treat OUD and chronic pain independently, as well as when these conditions co-occur. In addition, we propose mechanistic and methodological insights for future research needs, including trial design considerations in this area.
PSYCHEDELICS’ GENERAL MECHANISM OF ACTION
Serotonergic psychedelics are either full or partial agonists at the 5-HT2A receptor. Psychedelics can also be classified based on their chemical structure.21 The tryptamines, such as psilocybin, ayahuasca and DMT, contain an indole ring structure and are structurally similar to the neurotransmitter serotonin. The ergolines, such as LSD, contain the ergoline ring system and are derived from ergot fungi. Others, such as ibogaine and noribogaine, produce altered states of consciousness through serotonergic and other mechanisms.21
Preclinical studies using the head-twitch model in rodents, a behavior specifically mediated by 5-HT2A receptor agonism,22have shown that many psychedelics, such as LSD and psilocybin, reliably induce head-twitch responses,23,24 thus providing evidence that psychedelics have serotonergic activity. By this mechanism these compounds are known to induce profound alterations in perception, cognition, and emotion. Additionally, psychedelics appear to promote neuroplasticity25 and facilitate changes in neural connectivity, potentially underpinning their therapeutic effects. Elucidating the complex mechanisms underlying the efficacy of psychedelics can inform the optimization of psychedelic therapies for both OUD and chronic pain.