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.