\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[ngerman,greek,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{From Taboo to Treatment: The Emergence of Psychedelics in the Management
of Pain and Opioid Use Disorder}



\author[1]{Jeremy  Weleff}%
\author[1]{Julio Nunes}%
\author[2]{Gabriel Costa}%
\author[1]{Mehmet Sofuoglu}%
\author[1]{R. Ross Maclean}%
\author[1]{Joao P. De Aquino}%
\affil[1]{Yale University}%
\affil[2]{Universidade de Ribeirao Preto}%


\vspace{-1em}



  
  \date{May 27, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
The rise of psychedelics in contemporary medicine has sparked interest
in their potential therapeutic applications. While traditionally
associated with countercultural movements and recreational use, recent
research has shed light on the potential benefits of psychedelics in
various mental health conditions. In this review, we explore the
emerging role of psychedelics in the management of chronic pain and
opioid use disorder (OUD), two critical areas in need of innovative
treatment options. Pain control remains a significant clinical
challenge, particularly for individuals with OUD and those who receive
long-term opioid therapy (LTOT) who develop marked tolerance to
opioid-induced analgesia. Despite the magnitude of this problem, there
is a scarcity of controlled studies investigating pain management
alternatives for these populations. Drawing from preclinical and human
evidence, we highlight the potential of psychedelics to act on shared
neurobiological substrates of chronic pain and opioid use disorder,
potentially reversing pain- and opioid-induced neuroadaptations, such as
central sensitization. We elaborate on the multifaceted dimensions of
the pain experience (sensory, affective, and cognitive) and their
intersections that overlap with opioid-related phenomena (opioid craving
and withdrawal), hypothesizing how these processes can be modulated by
psychedelics. After summarizing the available clinical research, we
propose mechanistic insights and methodological considerations for the
design of future translational studies and clinical trials, building on
a shared clinical and neurobiological understanding of chronic pain and
OUD. Our intention is to provide timely perspectives that accelerate the
development and exploration of novel therapeutics for chronic pain and
OUD amidst the escalating opioid crisis.%
\end{abstract}%



\sloppy


\textbf{From Taboo to Treatment: The Emergence of~Psychedelics~in the
Management of~Pain~and Opioid Use Disorder}

Jeremy Weleff, D.O.\textsuperscript{1*}

Julio C. Nunes, M.D. \textsuperscript{1*}

Gabriel P. A. Costa \textsuperscript{2}

Mehmet Sofuoglu, M.D., Ph.D. \textsuperscript{1,3}

R. Ross MacLean, Ph.D. \textsuperscript{1,3}

Joao P. De Aquino, M.D.\textsuperscript{1,3,4}

\textbf{* J.W. and J.C.N. contributed equally to this work.}

\begin{enumerate}
\tightlist
\item
  Yale University School of Medicine, Department of Psychiatry, 300
  George Street, New Haven, CT 06511, USA
\item
  Faculty of Medicine, University of Ribeir\selectlanguage{ngerman}ão Preto, Ribeirão Preto, SP,
  Brazil
\item
  VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT
  06516, USA
\item
  Clinical Neuroscience Research Unit, Connecticut Mental Health Center,
  34 Park Street, 3rd Floor, New Haven, CT, 06519
\end{enumerate}

\textbf{Running Title:} Psychedelics, Pain, Opioid Use Disorder

\textbf{CORRESPONDING AUTHORS}

Jeremy Weleff, D.O.

Yale School of Medicine, Department of Psychiatry

300 George St. New Haven, CT

Phone: 517-803-5675

Email: jeremy.weleff@yale.edu

Joao P. De Aquino, M.D.

Yale School of Medicine, Department of Psychiatry

950 Campbell Avenue, 151D, West Haven, CT 06516

Phone: 203-932-5711 Ext.2916

Email: joao.deaquino@yale.edu

\textbf{ABSTRACT WORD COUNT:} 249

\textbf{MANUSCRIPT WORD COUNT:} 7,998

\textbf{REFERENCES:} 148

\textbf{FIGURES:} 2

\textbf{TABLES:} 0

\textbf{KEYWORDS:} Nociception, Analgesia, Opioid Addiction,
Hallucinogen, Drug Development

\textbf{CONFLICTS OF INTEREST:} The authors disclose no conflicts of
interest. J.P.D. has been supported in clinical trials by Jazz
Pharmaceuticals, specifically through medication provisions.
Additionally, J.P.D. has been a compensated consultant for Boehriger
Inhelheim.

\textbf{FUNDING INFORMATION:} J.P.D. is supported by the grants
K23DA052682 and R21DA057240 from the National Institute on Drug Abuse
(NIDA).

\textbf{ABSTRACT}

The rise of psychedelics in contemporary medicine has sparked interest
in their potential therapeutic applications. While traditionally
associated with countercultural movements and recreational use, recent
research has shed light on the potential benefits of psychedelics in
various mental health conditions. In this review, we explore the
emerging role of psychedelics in the management of chronic pain and
opioid use disorder (OUD), two critical areas in need of innovative
treatment options. Pain control remains a significant clinical
challenge, particularly for individuals with OUD and those who receive
long-term opioid therapy (LTOT) who develop marked tolerance to
opioid-induced analgesia. Despite the magnitude of this problem, there
is a scarcity of controlled studies investigating pain management
alternatives for these populations. Drawing from preclinical and human
evidence, we highlight the potential of psychedelics to act on shared
neurobiological substrates of chronic pain and opioid use disorder,
potentially reversing pain- and opioid-induced neuroadaptations, such as
central sensitization. We elaborate on the multifaceted dimensions of
the pain experience (sensory, affective, and cognitive) and their
intersections that overlap with opioid-related phenomena (opioid craving
and withdrawal), hypothesizing how these processes can be modulated by
psychedelics. After summarizing the available clinical research, we
propose mechanistic insights and methodological considerations for the
design of future translational studies and clinical trials, building on
a shared clinical and neurobiological understanding of chronic pain and
OUD. Our intention is to provide timely perspectives that accelerate the
development and exploration of novel therapeutics for chronic pain and
OUD amidst the escalating opioid crisis.



\textbf{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,\textsuperscript{1} is intertwined with the
parallel crisis of chronic pain.\textsuperscript{2} The initial wave of
the opioid epidemic stemmed from the excessive prescription of opioids
for chronic pain-related conditions.\textsuperscript{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.\textsuperscript{5,6}Despite the magnitude of this problem,
there is a scarcity of controlled studies investigating pain management
alternatives for those with OUD.\textsuperscript{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.\textsuperscript{8} Collectively, the
challenges posed by opioid analgesic tolerance\textsuperscript{9} 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.\textsuperscript{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.\textsuperscript{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)\textsuperscript{14} and tobacco use
disorder.\textsuperscript{15}The 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 \textsuperscript{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.

\textbf{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.\textsuperscript{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.\textsuperscript{21}

Preclinical studies using the head-twitch model in rodents, a behavior
specifically mediated by 5-HT2A receptor
agonism,\textsuperscript{22}have shown that many psychedelics, such as
LSD and psilocybin, reliably induce head-twitch
responses,\textsuperscript{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
neuroplasticity\textsuperscript{25} 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.

\textbf{3. PSYCHEDELICS'ANALGESIC MECHANISMS}

Pain perception is a complex phenomenon involving somatosensory,
cognitive, and affective components.\textsuperscript{26} Serotonergic
signaling has been implicated in the peripheral and central mechanisms
of nociceptive transmission and modulation in both acute and chronic
pain states.\textsuperscript{27} Convergent preclinical and human
findings support and strengthen the involvement of the 5-HT2A receptor
in musculoskeletal pain perception, with relevance for clinical pain
conditions. In addition, human studies have provided evidence for the
involvement of 5-HT2A receptor in pain perception and processing.
Associations have been found between the T102C polymorphism of the
5-HT2A receptor gene and fibromyalgia, and other genetic variations in
5-HT2A polymorphisms have been associated with chronic widespread
pain.\textsuperscript{28,29} Psychedelics, through these serotonergic
and other properties, hold promise as novel analgesics by modulating
multiple dimensions of the pain experience.

\textbf{3.1 Modulation of bottom-up nociception}

The somatosensory dimension of pain encompasses its intensity, quality,
and spatial characteristics.\textsuperscript{30} Mechanistic studies
have demonstrated that 5-HT2A receptors are involved in the nociceptive
transmission through the spinal cord\textsuperscript{31} and that their
activation can inhibit the descending nociceptive transmission in states
of chronic and neuropathic pain.\textsuperscript{27,32,33} 5-HT2A
receptors are expressed in neurons in the dorsal root ganglia (DRG),
nodule-like structures found on the posterior root of each spinal nerve,
among other locations, which contain the cell bodies or afferent sensory
neurons carrying pain signals back to the central nervous system (CNS).
Therefore, the DRG are critical structures responsible for central pain
sensitization, a mechanism by which the CNS becomes sensitized to
nociceptive stimuli, promoting the maintenance of chronic pain states.
Some of the analgesic properties of psilocybin, for instance, are
believed to be mediated by downregulation of 5-HT2A receptor in the
DRG.\textsuperscript{34,35} This downregulation may counteract central
pain sensitization.

\textbf{3.2 Anti-inflammatory properties}

Besides neural transmission, inflammation is another key mechanism
involved in the pain experience. Chronic inflammation drives pain by
sensitizing peripheral nociceptors.\textsuperscript{36} This
inflammatory process involves various mediators that can initiate and
perpetuate chronic pain states.\textsuperscript{36} Serotonergic agonism
from psychedelics has the potential to inhibit inflammatory signaling
mediated by TNF-alpha, NF-kB, and inflammatory
cytokines.\textsuperscript{37,38} This is thought to occur through
activation of 5-HT2A receptors on immune cells. Hence, by suppressing
key inflammatory mediators, these anti-inflammatory properties of
psychedelics may also reduce inflammatory pain.

\textbf{3.3 Neuroplastic effects}

In addition to affecting the sensory and inflammatory aspects of pain,
psychedelics may also influence chronic pain through their ability to
promote neuroplasticity.\textsuperscript{25} Neuroplasticity is the
brain's ability to reorganize neural pathways and forge new
connections.\textsuperscript{39} Neuroimaging studies have revealed that
chronic pain conditions such as chronic low back pain, complex regional
pain syndrome, and osteoarthritis are all associated with altered
functional connectivity between spatially distinct brain
regions.\textsuperscript{40-43} For example, functional MRI (fMRI)
studies have demonstrated that chronic low back pain is associated with
a reorganization of functional connectivity between sensory, cognitive,
and limbic areas (e.g., \emph{nucleus accumbens} and the prefrontal
cortex {[}PFC{]}). It is also associated with a disruption of the
default mode network (DMN) --- a system of connected brain areas that
show increased activity when the individual is passively resting and
mind-wandering. These connectivity changes likely reflect maladaptive
plasticity and reorganization of functional brain circuits due to
persistent pain signaling.\textsuperscript{40,41} By stimulating neural
plasticity and regrowth of connections between brain
cells,\textsuperscript{44} psychedelics could potentially counteract
these observed connectivity alterations and remodel the disrupted
networks involved in pain. As a result, psychedelics could temporarily
disrupt these patterns of brain activity, providing a window for
rewiring neural connections and restoring more optimal network
functioning. This could potentially disentangle the clustering of
sensory, cognitive, and affective components of pain, enabling a
transformed understanding of the pain experience.

Relatedly, these compounds have been theorized to be linked with changes
in entropy and complexity in brain
dynamics,\textsuperscript{45,46}leading to changes that may be helpful
in breaking out of rigid cognitive and behavioral patterns. By
disrupting these patterns, psychedelics may facilitate the adoption of
more adaptive pain-related beliefs, thought processes, and actions.

\textbf{3.4 Impact on negatively valenced emotional states related to
the pain experience}

Both opioid use and chronic pain can disrupt pain modulatory systems,
altering not only nociception, the process of encoding noxious stimuli,
but also the affective component of pain, which can culminate in pain
catastrophizing. This maladaptive state of unrelenting pain is
characterized by magnification (heightening the threat value of
pain-related stimuli), helplessness (lack of control over pain), and
rumination (having a reduced ability to divert one's focus away from
pain-related emotions).

Beyond their impact on neural pathways, psychedelics could also
influence the affective and psychological experience of pain,
encompassing the feelings of unpleasantness, distress, suffering, and
reactions to the long-term implications of living with chronic
pain.\textsuperscript{47} The anterior cingulate cortex (ACC) is a
crucial area in processing the emotional and affective aspects of
pain.\textsuperscript{26,48} Psychedelics may modulate these affective
aspects by altering activities in the ACC. Studies using task-free fMRI
found that psilocybin reduces cerebral blood flow in the ACC, which was
associated with the intensity of subjective effects of
psilocybin.\textsuperscript{49} As a result, it is possible that
psychedelics might also have the potential to lessen these negative
emotions associated with pain. This is supported by evidence suggesting
that psilocybin may mitigate similar affective phenomena, such as
depressive rumination and obsessive thinking,\textsuperscript{50} which
can resemble the fear of movement seen in chronic pain. Given that
depressive and anxiety disorders often co-occur with chronic
pain,\textsuperscript{51} psychedelics may provide a more comprehensive
treatment strategy by targeting these affective aspects, which can often
be equally hard to discern and equally debilitating for these patients.

\textbf{3.6 Cognitive and psychosocial effects}

Pain also involves cognitive and behavioral processes such as attention,
memory, and evaluation.\textsuperscript{52} Psychological factors, such
as coping strategies, significantly influence the overall experience of
pain.\textsuperscript{53} In patients with chronic low back pain, fear
of movement, or \emph{kinesiophobia} , is associated with increased
activity in brain regions related to emotion and
fear.\textsuperscript{54} Higher levels of pain intensity can also lead
these patients to engage in more perseverative thinking, such as worry
and rumination, as they try to mentally problem-solve their
pain.\textsuperscript{55} In patients with chronic pain, these negative
metacognitive beliefs are associated with higher emotional distress and
lower mood.\textsuperscript{56} Psychedelics may have the potential to
facilitate changes in some of these harmful cognitive patterns by
loosening rigid mindsets like functional fixedness, and by allowing
greater problem-solving ability.\textsuperscript{57} Additionally,
psychedelics can induce a profound shift in consciousness, known as ego
dissolution, with increased emotional
sensitivity\textsuperscript{58}that could facilitate changes in
maladaptive cognitions and emotions related to pain. This may facilitate
the revaluation of maladaptive beliefs and attitudes towards pain,
potentially promoting confidence in one's ability to perform tasks
despite pain (i.e., self-efficacy). Additionally, it has been suggested
that psychedelics may impact automatic cognitive phenomena such as
attentional bias -- a process in which attention is preferentially
captured by pain and its cues. It is also worth noting that abnormal
attentional bias for pain and opioid cues have been respectively
identified among those with chronic pain and OUD\textsuperscript{59,60};
and attentional bias for both cues are potentially modifiable in
individuals with chronic pain and OUD receiving methadone or
buprenorphine.\textsuperscript{61}

In addition to altering pain-related cognitions, psychedelics have been
found to increase positive mood, feelings of social connectedness and
interpersonal closeness.\textsuperscript{62-64} A recent meta-analysis
revealed a significant inverse association between positive mood and
pain intensity in individuals with chronic
pain.\textsuperscript{65}Additionally, enhanced social functioning
associated with psychedelics could potentially improve interpersonal
interactions despite experiencing pain, and strengthen social support by
improving openness and communication. Together, these social and
relational changes have the potential to improve coping and readjust
maladaptive pain-related thoughts and behaviors.

In summary, psychedelics have the potential to improve pain management
through their multidimensional impact on sensory transmission,
inflammation, neuroplasticity, affect, anxiety, cognitive patterns, and
behaviors. Although these findings are promising, further research is
needed to comprehensively understand the various mechanisms by which
psychedelics may alleviate distinct forms of chronic pain. Elucidating
these mechanisms can further inform the development of interventions
that leverage these pharmacological and psychological effects to reduce
the suffering of patients with chronic pain (\textbf{Figure 1} ).

\textbf{4. CLINICAL APPLICATIONS OF PSYCHEDELICS FOR PAIN: CURRENT
KNOWLEDGE}

Early research beginning in the 1950s was focused on ways in which
psychedelics could be used as an adjunctive to facilitate engagement in
psychotherapeutic interventions. Regulatory restrictions on psychedelics
in the early 1970s halted research. For chronic pain treatment,
psychedelics have mainly been investigated in palliative care,
cancer-related pain, headaches, and phantom limb pain.

\textbf{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.\textsuperscript{66} Threshold dosages for psychedelic effects
are as low as 20-30\selectlanguage{greek}μ\selectlanguage{english}g, although recreational dosages can range from
50-200\selectlanguage{greek}μ\selectlanguage{english}g.\textsuperscript{66} LSD has a prolonged action, with effects
that can persist for six to nine hours after
ingestion.\textsuperscript{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)
production\textsuperscript{37}; (2) activation of inhibitory
serotonergic descending pathways, inhibiting central
sensitization\textsuperscript{67}; and (3) modulation of emotional
aspects of pain, potentially through alterations in consciousness,
and/or the ``psychedelic experience''.\textsuperscript{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 100\selectlanguage{greek}μ\selectlanguage{english}g of
LSD.\textsuperscript{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.\textsuperscript{69} In 2021, a randomized,
placebo-controlled, crossover human laboratory study administered low
doses of LSD (5, 10, and 20 \selectlanguage{greek}μ\selectlanguage{english}g) 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.\textsuperscript{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.

\emph{4.1.1 Palliative care and cancer-related pain}

Early reports of the use of LSD to mitigate cancer-related pain include
examinations of a single dose of LSD in patients with various forms of
metastatic cancers.\textsuperscript{13} Among the 128 participants
included in this study, a fraction had various forms of metastatic
cancer (i.e., breast, cervical, lung, larynx, and pancreatic cancer). A
single 100\selectlanguage{greek}μ\selectlanguage{english}g dosage of LSD, administered orally, improved pain for up to
two weeks, as measured by the numerical rating scale. No sensitivity
analyses were reported for the participants with cancer pain.

Suggested mechanisms included ``LSD produces an inability to maintain
selective attention ``, hinting at what is also called attentional bias.
This effect was proposed as a psychological mechanism to explain the
reduction of participants' concerns for pain, suffering, and death. They
noted that ``participants displayed a particular disregard for the
gravity of their situation and talked freely about their impending
death''. Later studies published throughout this early period mostly
replicated these early findings and emphasized the importance of
``distracting patients from their pain'' and reaching the ``psychedelic
experience'' to achieve the best results.\textsuperscript{70,71} Modern
trials of LSD in those with palliative cancer states have continued,
with a focus on mood, anxiety, and quality of life (QoL) outcomes. While
few details have been specifically reported on the measurement of pain
or the use pain as a primary outcomes measure, these studies provide the
foundation on which to further study the unique biological, analgesic,
and psychological effects, in the setting of cancer-related pain.

\emph{4.1.2 Headaches}

The research investigating the analgesic potential of LSD in headaches
has centered around both cluster-type headaches (CH) and migraine
headaches. Both conditions are generally chronic but episodic in nature,
making it important to distinguish between the specific use of
medications in their treatment, namely, the use of medications
for\emph{prophylaxis} or for acute \emph{abortive} treatment.
Interestingly, medications commonly used to abort these types of
headaches (many from the ergotamine and triptan families), partially
share LSD's (a lysergamide) mechanism of action as 5-HT receptor
modulators. The theoretical underpinnings of serotonin and possible role
of LSD and its analogs can play in the role of these types of headaches
have been considered since at least the 1960s. The use of
non-hallucinogenic LSD-analogs and other lysergamides have been studied
and used in the treatment of many of these headache
disorders.\textsuperscript{72} \textsuperscript{73} Despite mechanistic
plausibility, there have been no randomized clinical trials for LSD and
migraines. Other clinical studies investigating three single doses of an
LSD derivate (BOL-148, at a dose of 30 \selectlanguage{greek}μ\selectlanguage{english}g/kg/body weight) safely
improved CH cycles or significantly improved frequency/intensity of
episodes in four out of five patients.\textsuperscript{73} Other
qualitative studies with patients self-medicating with LSD reported
prophylactic and acute abortive benefits.\textsuperscript{74} Another
preliminary study suggests that micro-dosing, or using
sub-hallucinogenic dosages, of LSD may also be beneficial to prevent
headache episodes.\textsuperscript{75} In summary, the use of LSD for
headaches holds promise as a therapeutic option, but research in the
area is still in early stages.

Interviews with 53 patients living with CH who were using psilocybin or
LSD without medical supervision to treat the condition, have found that
seven of the eight participants who used LSD reported termination of
cluster periods, and four of those reported that the substance
significantly prolonged their periods of remission.
\textsuperscript{76}Online survey studies including 496 participants
from a specific CH support group suggested that a single dose of LSD
could prevent attacks, shorten, or even abort cluster episodes, or
induce remission.\textsuperscript{77} Several participants reported
using small, sub-hallucinogenic doses, suggesting that a psychedelic
experience may not be an essential component of therapeutic efficacy.

\emph{4.1.3 Phantom Limb Pain}

Phantom limb pain (PLB) is a painful experience interpreted by patients
after a limb amputation with few viable treatment
options.\textsuperscript{78} The causes of PLB are currently unclear,
but it is hypothesized to result from the disruption of ascending and
descending pain pathways that reorganize improperly, leading to an
ongoing misinterpreted pain perception. LSD has been previously
suggested as a possible treatment for PLB. Small case series
demonstrated that intravenous infusion or bolus injection of LSD (10
ng/mL at 0.5 ml/min) was ``curative'' in two patients, ``partially
helpful'' in three, and ``ineffective'' in two (although measurement and
definition of benefit were not systematically
described).\textsuperscript{79} An additional study found significant
benefits of LSD for PLB, with sustained self-reported pain reduction in
seven out of eight participants.\textsuperscript{80}

\textbf{4.2. Psilocybin}

4.2.1. \emph{Palliative care and cancer-related pain}

In a randomized, double-blind, cross-over trial of very low
(placebo-like) dose (1 or 3 mg/70 kg) vs. high dose (22 or 30 mg/70 kg)
psilocybin that the substance is indeed able to increase well-being and
life satisfaction among patients with
cancer.\textsuperscript{81}Unfortunately, this study did not include
pain as an outcome, but mechanistic plausibility remains. Furthermore,
psilocybin has been explored in the context of end-of-life care, where
it may alleviate psychological distress associated with dying, enhance
existential well-being and improve the quality of
life.\textsuperscript{81}

\emph{4.2.2. Headaches}

Psilocybin has also been suggested to produce significant reductions in
pain intensity and unpleasantness in patients with cluster
headaches.\textsuperscript{76} In survey studies, 22 of 26 patients
taking psilocybin for cluster headaches reported that the substance was
able to abort their crisis. Further, 18 participants reported an
extension of remission periods after a single dose of psylocibin. The
effectiveness of psilocybin for cluster headache in qualitative studies
has reported that psilocybin is ``perceived by participants to
shorten/abort a cluster period and bring chronic cluster headache into
remission more so than conventional medications''.\textsuperscript{77}

An exploratory double-blind, placebo-controlled, cross-over study
investigated psilocybin for migraines. Ten adults with migraine received
oral inactive placebo and psilocybin (0.143~mg/kg) in two test sessions
spaced two~weeks apart. Participants were closely tracked with headache
diaries. Over the two weeks after a single dose administration,
psilocybin was significantly more effective than placebo in reducing the
frequency of migraines.\textsuperscript{82} Overall, the research
considering psilocybin and pain seems to progress alongside LSD studies;
results are promising, yet in their early stages.

\emph{4.2.3. Chronic pain and LTOT}

One planned eight-week open-label non-randomized study with a six-month
follow of those with chronic pain on LTOT is ongoing. This study will
investigate the effect of psilocybin and psilocybin-assisted therapy in
one of two dosing sessions (25mg and 37.5mg) with the first occurring
during the period of opioid tapering.
{[}NCT05585229{]}.\textsuperscript{83}

\textbf{4.3. Ayahuasca}

Ayahuasca is a psychoactive substance, usually ingested as a beverage,
decocted from \emph{Banisteriopsis caapi} and \emph{Psychotria
viridis}plants. They are rich in DMT, a partial 5-HT serotonergic
receptor agonist and have direct monoamine-oxidase A (MAO-A) inhibiting
properties. Through both mechanisms, ayahuasca has psychedelic
effects.\textsuperscript{84} Ayahuasca has been historically and
culturally used by those in several countries in Central and South
America, however, it has recently been more widely used, particularly in
religious and spiritual contexts.\textsuperscript{85}

So far, no studies have investigated the role of ayahuasca in the
management of pain as a primary outcome. One recent study included the
Medical Outcomes Study 36-Item Short-Form (SF-36) as a secondary
measurement including a subcomponent rating of participant's bodily
pain.\textsuperscript{86} In this report, the authors conducted two
observational sub-studies: (1) one with first-time ayahuasca users (n =
40), and (2) adding a comparison group of long-term ayahuasca users (n =
23). Reported improvements in depression rates for first-time ayahuasca
users and lower depression scores among long-term ayahuasca users were
found. However, there were no significant changes in bodily pain for
first-time ayahuasca users. In a similar study with 23 first-time
ayahuasca users showed similar findings but with significant reductions
in the bodily pain component of the SF-36 for a subgroup of participants
(n = 8).\textsuperscript{87} Despite the mechanistic plausibility of
ayahuasca for pain treatment given its serotonergic and other relevant
mechanisms of action, the literature on the topic is underdeveloped and
the little available evidence is conflicting.

\textbf{4.4. Ibogaine and Noribogaine}

Ibogaine is an alkaloid substance obtained from the root bark of the
shrub \emph{Tabernanthe iboga,} endemic to Western African
regions.\textsuperscript{88} It has been historically used by indigenous
communities in West Africa for religious ceremonies, and also to treat
fatigue.\textsuperscript{88} Its ceremonial use is due to
its\emph{oneirophrenic} properties, which means it can invoke dream-like
states without loss of consciousness.\textsuperscript{88} While
preclinical studies of ibogaine and noribogaine have suggested that both
ibogaine and noribogaine dose-dependently increase the antinociceptive
properties of morphine, making it a potential opioid-sparing strategy in
pain management, no human laboratory clinical trials have investigated
the use of ibogaine for pain.

Convergent preclinical models have suggested that ibogaine could be used
as a modulator of morphine
antinociception.\textsuperscript{89,90}Co-administration of ibogaine in
various doses (1-40mg/kg) and morphine (4 mg/kg) increased
morphine-induced antinociception in a dose-dependent manner for rats in
a heat-pain paradigm. Further, the administration of 40mg/kg of
noribogaine, the primary metabolite of ibogaine, resulted in similar
effects. Ibogaine enhances the pain-relieving effects of morphine in
mice. After making all mice tolerant to morphine, researchers compared
two groups: one given morphine alone and the other with morphine and
varying doses of ibogaine or noribogaine. Both ibogaine and noribogaine
were found to increase morphine's antinociception effects. To our
knowledge, no studies have investigated whether patients receiving
morphine could have analgesic effects maximized by ibogaine, thus
reducing the total opioid requirement to alleviate pain.

\textbf{5. CLINICAL APPLICATIONS OF PSYCHEDELICS FOR OPIOID USE
DISORDER: CURRENT KNOWLEDGE}

Most research on classic psychedelics' therapeutic effects on OUD has
focused on opioid withdrawal. Other benefits like reduced opioid use
from pain relief are less studied. Although these psychedelics are seen
as having low abuse potential, their addiction risk in this group awaits
thorough evaluation.

\textbf{5.1. LSD}

There are two studies from the early phase of psychedelic research that
investigate the use of LSD in people with OUD. The first study,
conducted in 1965, was an open-label controlled trial that included 70
patients with OUD, who had recently been hospitalized for treatment of
opioid withdrawal.\textsuperscript{12} The study found that orally
administered LSD (at doses of 2ug/kg) was generally well tolerated with
no participants requiring medications to counteract adverse effects,
with only three participants reporting worsening of psychiatric
symptoms. The study did not collect data on traditional OUD outcomes,
pain, or functioning. The second study, conducted in 1973, was a
randomized controlled trial that included 74 participants with OUD at a
residential reentry program.\textsuperscript{11} Participants were
randomized to either a treatment (LSD 300ug-450ug) or control arm. The
treatment arm consisted of living in a halfway house from four to six
weeks and undergoing 24 hours of preparatory therapy over five weeks and
one week of integration therapy post-LSD. At 12 months, 9/36 (25\%) of
treatment arm participants remained abstinent, compared to 2/37 (5\%) of
the participants the control group. There were no statistically
significant group differences on changes in overall functioning. The
authors report that 12 of the 13 of participants who had a ``psychedelic
peak experience'' (using an unnamed questionnaire) appeared more likely
to have higher ``community adjustment scores'' at 12 months. The design
of this study makes it difficult to interpret the findings, as there was
no control for the impact of the residential treatment component in the
treatment arm. There are currently no registered studies planned
investigating LSD for OUD or for those on LTOT.

\textbf{5.2. Psilocybin}

Psilocybin has been minimally studied in those with OUD, even though it
is one of the most commonly investigated psychedelics in contemporary
trials for psychiatric disorders.\textsuperscript{91} Although there are
limited preclinical investigations of psilocybin in animal models of
opioid addiction, it has shown efficacy in the treatment of
AUD\textsuperscript{14} and tobacco use disorder\textsuperscript{15} in
modern trials. Other evidence has shown that in large samples of
naturalistic use, the classic serotonergic psychedelics as a group have
been shown to be associated with 27\% reduced risk of past-year opioid
dependence and 55\% reduced risk of daily illicit opioid
use.\textsuperscript{92,93} When this relationship is assessed
individually, there is some suggestion that lifetime psilocybin use may
be associated with a 30\% reduced odds of a past-year OUD
diagnosis.\textsuperscript{94}

There are several planned or ongoing registered studies examining the
safety and efficacy of psilocybin in those with either OUD or who
receive LTOT for chronic pain. One registered study plans an eight-week
double-blind, controlled intervention of hallucinogenic psilocybin
(30mg) versus a blinding dose of psilocybin (1mg), following an
inpatient buprenorphine-naloxone induction for OUD
{[}NCT06005662{]}.\textsuperscript{95} Primary outcomes include opioid
abstinence (timeline follow-back {[}TLFB{]}\textsuperscript{96} and
urine toxicology), treatment retention, and reduction in days using
opioids (self-report and urine toxicology). Secondary measures include
quality of life (World Health Organization Quality of Life-BREF
{[}WHOQOL-BREF{]}), depression (Beck Depression Inventory II
{[}BDII{]}), anxiety (State-Trait Anxiety Inventory {[}STAI{]}), and
abstinence from other non-opioid substance use (TLFB).

A Phase 1 study investigating the safety of psilocybin in persons with
OUD who were recently stabilized on buprenorphine-naloxone is also
currently underway {[}NCT04161066{]}.\textsuperscript{97} This study
aims to address two important questions; how psilocybin may impact the
effectiveness of medications for OUD (MOUD) and how concurrent MOUD may
affect psilocybin therapy. Assessments include safety and adverse events
as well as opioid craving (opioid craving scale {[}OCS{]}) and opioid
use (TLFB).

A planned randomized double-blind placebo-controlled study of those with
OUD engaged in methadone treatment who are concurrently using other
illicit opioids seeks to investigate primary outcomes of changes in
non-medical opioid use (by self-report and urine toxicology) as well as
quality of life (WHOQOL-BREF) {[}NCT05242029{]}.\textsuperscript{98}This
study has two planned dosing sessions (at 40mg) with further
randomization of the treatment group at the second dosing session to
investigate the impact of two doses. Importantly, secondary outcomes
include assessment of chronic pain, as well as measures of non-opioid
substance use, mood, and sleep, which may help to further our
understanding of psilocybin's utility as a treatment of co-occurring OUD
and chronic pain.

\textbf{5.3 Ayahuasca}

There is one observational study investigating the effects of ayahuasca
on substance misuse and psychological functioning in 12 participants
with no specific psychiatric or SUD.\textsuperscript{99} The
intervention was a four-day retreat including two ``ayahuasca
ceremonies'' (50-100mL of ayahuasca) and various addiction-related
psychosocial intervention groups. As a major limitation, the diagnosis
regarding opioid use (i.e., whether or not participants had OUD)
entering the study was not reported; however, it is noted that some
participants were receiving methadone treatment. The primary substance
use measure was the Four-Week Substance Use Scale (4WSUS). Scores
reportedly decreased for all substances except for cannabis; however,
data on primary opioid use was not clearly reported. There was no
observed difference in opioid use among participants when comparing the
proportion who had used opioids at the baseline and the six-month
follow-up. However, results showed statistically significant
improvements in multiple psychological measures, including mindfulness,
empowerment, hopefulness, quality of life-meaning, and quality of life
outlook across the whole group --- which is generally consistent with
prior research on ayahuasca.\textsuperscript{100} Other studies on
ayahuasca have also suggested its effects on decreasing substance use
and potentially mitigating other negative psychosocial effects of drug
use, which may deserve future attention.\textsuperscript{101} These
themes also appear in qualitative work in those using ayahuasca for
addiction-related issues in indigenous communities among whom SUD is
prevalent.\textsuperscript{102} At this time, however, there are no
currently registered ayahuasca trials for OUD or opioid dependence.

\textbf{5.4. Ibogaine and Noribogaine}

The studies investigating the use of ibogaine and noribogaine for OUD
and opioid withdrawal represents one of the larger collections of
clinical studies of a psychedelic for these conditions. There is a large
preclinical foundation exploring ibogaine and noribogaine in addiction
paradigms and for opioid withdrawal.\textsuperscript{103}

\emph{5.4.1. Ibogaine for OUD}

An open-label study of 27 treatment-seeking participants with OUD and/or
cocaine use disorder received a fixed-dose of either 500, 600, or 800 mg
ibogaine HCl in a 12-day inpatient setting showed statistically
significant reductions in various subscales of the Heroin Craving
Questionnaire (HCQN-29) by the time of discharge.\textsuperscript{104}An
open-label study of 14 participants with OUD who took ibogaine-HCl (10
mg/kg orally) showed temporary QTc prolongation on an electrocardiogram
(EKG)---a condition that may elevate the risk of irregular heart rhythm
and sudden death---and other side effects, including
ataxia.\textsuperscript{105} Both studies are limited by their small
size, lack of blinding, and short duration/limited follow-up.

Other case series exist of patients who received treatments in countries
where prescription ibogaine is legal. These studies reported reductions
in Addiction Severity Index-Lite (ASI-Lite), and Subjective Opioid
Withdrawal Scale (SOWS) up to one year post-treatment, with some
suggestion of decreased family/social status
problems.\textsuperscript{106} Notable are the serious safety concerns
raised within this study concerning a patient that died for which the
cause was attributed to cardiac arrythmias post-ibogaine use. Another
series of participants surveyed post-ibogaine treatment provide some
indication suggesting that despite return to use in a large proportion
of the sample one to two years after ibogaine exposure, there was some
indication of decreased opioid use, improvements in mood and anxiety
effects, and other improvements in psychosocial
measures.\textsuperscript{107} Other retrospective, observational and
case series provide additional data concerning dosing and the effect of
ibogaine on withdrawal and other addiction
outcomes.\textsuperscript{108,109}

There are two currently registered clinical trials investigating the use
of ibogaine for OUD. One is a Phase 2 RCT including patients with OUD
who receive methadone treatment who will be administered ascending doses
of ibogaine for opioid withdrawal
{[}NCT04003948{]}.\textsuperscript{110} The other is a Phase 1/2a dosing
study of healthy volunteers followed by a randomized, double-blind,
placebo-controlled study in patients seeking medically supervised opioid
withdrawal treatment {[}NCT05029401{]}.\textsuperscript{111}

\emph{5.4.2. Noribogaine for OUD}

Following an earlier Phase 1 study in healthy
volunteers,\textsuperscript{112} a double-blind placebo-controlled study
was conducted in 27 patients receiving methadone treatment who were
administered ascending doses (60, 120, and 240 mg) of noribogaine. The
study investigated its effect on opioid withdrawal, safety, and
pharmacokinetics.\textsuperscript{112} There no statistically
significant differences in opioid withdrawal symptoms (assessed using
the Subjective Opioid Withdrawal Scale {[}SOWS{]}, Objective Opioid
Withdrawal Scale {[}OOWS{]}, and Clinical Opioid Withdrawal Scale
{[}COWS{]}). Additionally, there was no difference in time to restart
opioid treatment. Conversely, noribogaine produced statistically
significant dose- and concentration-dependent increases of QTc interval
on the ECG, although no cardiac events were noted. To our knowledge,
there are no currently registered trials for OUD involving noribogaine
administration.

\textbf{DISCUSSION}

In this review, we have summarized mechanistic and clinical findings
regarding the potential of serotonergic psychedelics to treat both
chronic pain and OUD. As the opioid epidemic persists, it is imperative
that future research be directed toward this intersection, employing
rigorous methodologies to uncover the nuanced possible effects of
psychedelics on chronic pain and OUD. This concerted effort is pivotal
in advancing evidence-based treatments and ultimately alleviating the
burden of chronic pain, while minimizing reliance on traditional
opioid-based approaches, especially among persons with OUD. Overall,
convergent evidence studies provide early clinical and translational
support for the use of serotonergic psychedelics for chronic pain and
OUD, offering insights into their neurobiological effects, and
suggesting avenues for future mechanistic research and clinical trials.

The available literature regarding the role of psychedelics for pain
management is nascent but promising. Despite the nuanced needs of each
type of chronic pain, such as migraines or chronic low back pain, there
seems to be some common ground upon which psychedelics can exert their
analgesic effects. In short, psychedelics may have the potential to
alleviate pain not only through direct biological and pharmacological
mechanisms (e.g., anti-inflammatory properties and reduction of central
sensitization), but also through cognitive and psychological pathways
(e.g., through reducing attentional bias for pain and opioid cues;
counteracting fear avoidance; improving mood; and alleviating pain
catastrophizing).\textsuperscript{113}

However, there are also key differences between these clinical
populations that warrant considerations. Many chronic pain conditions
for which psychedelic treatment have been promising for, such as
migraines,\textsuperscript{114} typically do not involve high opioid use
rates. For other conditions, such as cancer-related pain and palliative
pain, high doses of opioids are the
norm.\textsuperscript{115}Ultimately, different pain conditions have
nuanced, variable factors that may impact their response to psychedelics
and each one of them will require tailored protocols and monitoring
procedures. While preliminary findings are promising for certain pain
syndromes, more research is still needed to establish safety, effective
dosing, and ideal administration settings across diverse chronic pain
populations with varying clinical and psychosocial backgrounds.

As future clinical directions, we hypothesize that psychedelics may play
a role in alleviating the burden of primarily through distinct
mechanisms, as a function of the type of chronic pain and severity of
opioid use at baseline. First, by alleviating episodes of acute pain,
the need for high-potency analgesics such as opioids may be spared,
thereby reducing the risks associated with opioids, including the
potential for the development of OUD. Second, by alleviating multiple
aspects of the pain experience and subjectively increasing well-being,
psychedelics may have the potential to be used as co-adjuvants of a
long-standing treatment for different forms of chronic pain, increasing
analgesic effectiveness and potentially serving as an opioid-sparing
strategy that reduces opioid-related adverse effects.

There is limited reporting across the psychedelic trials for OUD about
concurrent MOUD or other treatments participants were receiving.
Furthermore, the potential effects of psychedelics on different phases
of OUD --- ranging from current/active opioid use to acute withdrawal
and later stages or recovery/maintenance --- remain a critical area of
inquiry, necessitating longitudinal studies to examine the full spectrum
of therapeutic implications. Gaps exists about the possible effects of
psychedelics in the role of psychosocial changes and changes in other
recovery or harm reduction behaviors during the acute/longer term
recovery phase in OUD. In addition, there is little data concerning the
co-occurrence of chronic pain or changes in pain perception, despite the
high rates of chronic pain in OUD.\textsuperscript{116} The dearth of
comprehensive research underscores a significant gap in the literature,
leaving researchers with an incomplete understanding of the potential
risks and benefits at this juncture.

Despite burgeoning interest in the therapeutic potential of psychedelics
for both chronic pain and SUDs, studies that specifically address these
conditions in tandem are scarce. In \textbf{Figure 2} , we propose
various mechanisms of actions of psychedelics across the commonly
discussed neurocircuitry of both addiction and its overlap with chronic
pain. The biological, social, and psychological potential of these
substances to influence these various neurobiological substrates with
corresponding outcomes that can be assessed are described. The promising
analgesic effects of classic psychedelics, the growing evidence for
their utility in multiple SUDs and specifically in OUD, as well as their
impact on clinical phenomena that are relevant for both chronic pain and
addiction behaviors, suggest their potential as adjuncts or alternatives
to traditional opioid agonist for both chronic pain and OUD.

\textbf{Trial design considerations in psychedelic trials for those with
pain and/or OUD}

Here we lay out suggestions for future investigations and continued
optimization for safety and trial design for patients with chronic pain,
OUD, and/or those receiving LTOT. The goals of some of these suggestions
are to optimize pain and OUD measures for trials that assess outcomes
for either or both of these conditions. Specific recommendations
regarding psychedelic clinical investigations were addressed in recent
draft Food and Drug Administration (FDA) guidance documents and recent
guidelines.\textsuperscript{117} Kiluk and colleagues also reviewed
clinical trial design challenges and opportunities for emerging
treatments in OUD.\textsuperscript{118,119} Addressing the existing
methodological limitations is imperative for improved study design and a
better understanding of the various possible uses for psychedelic
medications for chronic pain and OUD, conditions with limited treatment
options.

\emph{6.1.1. Choice of pain- and opioid-related outcomes}

A careful selection of pain- and opioid-related outcomes is necessary to
provide clinically relevant evidence. As discussed in this review, the
pain experience is multifaceted, composed of sensory, affective, and
cognitive components. Therefore, a combination of mechanistic human
laboratory studies and clinical trials broadly examining various
components of the pain experience is warranted to understand the
analgesic effects of psychedelics. Early analgesic signals may be
identified using a combination of laboratory pain techniques, such as
quantitative sensory testing (QST),\textsuperscript{120} a
psychophysical tool to reliably assess analgesia and pain
modulation\textsuperscript{121}; along with psychological constructs
assessing cognitive-affective components of pain (i.e., pain attentional
bias, pain catastrophizing, self-efficacy, and fear
avoidance).\textsuperscript{6,122} Quantifiable outcomes will be key to
assessing pain-related functioning. These include measures of physical
functioning and activity (e.g., pedometer count). The specific choice of
pain-related outcomes can be tailored to the needs of each clinical
population.

Likewise, the experience of using opioids, whether medically or
non-medically, is also complex and multifaceted. Human laboratory
studies are well-suited to identify the potential therapeutic effects of
early stages of opioid withdrawal, various types of opioid craving
(e.g., pain-, stress-, and cue-induced craving), and acute changes in
hedonic states associated with chronic opioid exposure (e.g.,
hypohedonia and anhedonia).\textsuperscript{123,124} Longer-term
clinical trials should include real-world outcomes such as the success
of induction onto MOUD, treatment retention, adherence to MOUD, and the
MOUD doses required to suppress craving and withdrawal. Studies
specifically including persons with co-occurring OUD and chronic pain
are required since a third of people with OUD also have chronic pain and
this population has unique clinical needs and treatment trajectories. In
summary, a comprehensive assessment of pain- and opioid-related outcomes
is paramount to generate clinically pertinent evidence.

\emph{6.1.2 Concurrent opioid use or MOUDs}

The use of psychedelics as an add-on to, or concurrently with
medications that work at the MOR may have unintended effects. Being
prepared to prevent or mitigate possible withdrawal states should be
taken into consideration. The impact of possible withdrawal states on
the subjective psychedelic experience should also be considered and
timing of dosing of any concurrent MOR should be thoughtfully
considered. For many studies of ibogaine and noribogaine, MOUD is
commonly switched to shorter-acting medications such as
controlled-release oral morphine products or other short-acting MOR
agonists.\textsuperscript{125} There are also possibly important safety
concerns related to concurrent use of opioids and some psychedelics,
which are reviewed below.

\emph{6.1.3 Subjective effects of psychedelics}

There remains ongoing debate concerning the necessity for the
hallucinogenic effects of psychedelics, with arguments both for and
against their importance.\textsuperscript{126,127} There is a suggestion
that in both, at least, treatment-resistant depression and tobacco use
disorder, the subjective components and quality of the acute psychedelic
experience may be important for therapeutic
efficacy,\textsuperscript{128} while there remains some preliminary data
in OUD this may be the case. Conversely, for cluster and migraine
headaches, the acute subjective psychedelic effects may be independent
from their clinical effects.\textsuperscript{129} These studies were
dovetailed by recent healthy human laboratory data, putting into
question the therapeutic relevance of hallucinogenic effects for
analgesia.\textsuperscript{67} Measurement and investigation into the
importance of hallucinogenic and subjective effects remains crucial to
further our understanding of this phenomenon (and supposed ``biological
effects'' from the ``psychological effects'') and the viability of
sub-psychedelic dosing/microdosing paradigms and active control groups
that receive low or blinding doses of psychedelics in some studies,
which may have some effect on outcomes.

\emph{6.1.4 Psychedelic-assisted psychotherapy (PAP)}

The role of psychedelic-assisted psychotherapy (PAP) is another
important methodological concern in future trial design regarding
investigations for chronic pain and OUD. Despite concomitant
psychotherapy being a component of other modern trials of psilocybin for
other SUDs,\textsuperscript{14,130} protocols have included mostly
manualized cognitive behavioral therapy- or motivational enhancement
therapy-based interventions. The efficacy for evidence-based
psychosocial treatments for chronic pain\textsuperscript{131} and
substance use\textsuperscript{132} remain modest, with small to medium
effect sizes across trials. As such, adjunctive psychedelics may
increase the efficacy and/or engagement in evidence-based psychosocial
treatments. The importance of psychotherapy during these psychedelic
trials on efficacy remains to be seen as there are exist few repeated
evaluations or studies have not been powered to assess differences
between groups on psychotherapy. Draft FDA guidance on psychedelic
trials has also questioned the use of PAP as it raises concerns about
standardization and the introduction of other forms of bias. The many
types of PAP have been reviewed in detail, including discussions on
trial design during each phase of psychedelic
trial,\textsuperscript{133,134} as have theoretical considerations for
its use in other components of recovery and synergy with other treatment
paradigms such as twelve-step facilitation (TSF).\textsuperscript{135}

\emph{6.1.5 Treatment setting}

There is a large variation across the existing studies for psychedelics
for OUD studies in regard to treatment settings. For example, the early
LSD studies were mostly carried out in residential settings, the study
investigating ayahuasca was completed in a retreat setting, and many of
the trials with ibogaine or noribogaine were carried out in various
medical treatment centers. Pain studies have traditionally occurred in
two settings: (1) human laboratory investigations and (2) real-word,
ambulatory and emergency room studies. Treatment setting determination
may also be influenced by which phase of treatment is being targeted
(i.e., acute withdrawal) or by other safety concerns that may require
continuous medical monitoring. Treatment setting is overall an important
consideration for research design but also for real-world implementation
if such psychedelic treatments receive regulatory approval.

\emph{6.1.6 Blinding and expectancy bias}

The issue of blinding, blinding procedures, and blinding failures in
psychedelic trials has received considerable attention in the
literature.\textsuperscript{136} While expectancy bias remains an issue
for all clinical trials, expectancy bias has been well documented in the
pain literature and should be thoughtfully considered in future trial
designs around pain and psychedelics.\textsuperscript{137} Systematic
reviews of the RCTs of psychedelics have illustrated that many trials
have used various forms of placebo groups including placebo control
groups, inert placebo control, or active placebo control, or both, but
there is room to improve on quality and blinding assessment and blinding
failure in these trials.\textsuperscript{138} Blinding integrity tools
in the context of psychedelic micro-dosing studies have also been
recently developed, as well as recommendations to improve blinding
issues in psychedelic trials.\textsuperscript{139} The impact of
preparatory sessions on expectancy, as well as the set and setting and
other controllable factors in psychedelics sessions, should be also
thoughtfully considered as possible factors influencing
outcomes.\textsuperscript{140}

\textbf{Specific safety considerations in psychedelic trials for those
with pain and/or OUD}

\emph{6.2.1 Addictive and ``abuse potential''}

Concerns about the addictive potential (development of hallucinogen use
disorder {[}HUD{]}) or ``abuse potential'' of psychedelics have been
raised as a common argument against the investigation of psychedelics
for SUDs, since their historic scheduling as a Schedule I controlled
substances (i.e., high potential for abuse and no currently accepted
medical use). Still, the evidence to support the addictive potential of
psychedelics is scant. Current FDA guidance for psychedelic trials
outlines guidance for the assessment of this
risk.\textsuperscript{117}National Survey on Drug Use and Health (NSDUH)
data reports the rates of HUD criteria by DSM-IV criteria very low
amongst respondents that have used a hallucinogen (less than
\textless{}1\% for both meeting criteria for ``abuse'' and dependence).
Other data from the NSDUH concerning serotonergic psychedelics
specifically, commonly reports that past use of these compounds is
associated with lower rates of certain SUDs (specifically meeting OUD
criteria in some studies),\textsuperscript{94}as do other studies of
naturalistic psychedelic use reporting a decrease in the use of multiple
substances including opioids.\textsuperscript{93}In addition, some of
the recent trials investigating psilocybin for MDD that have included
longer term follow-up have noted no reported additional psilocybin use
up to 12 months after the trial amongst
participants.\textsuperscript{141} Overall, only more data in study
participants with co-occurring SUDs and/or chronic pain conditions and
further, more specific FDA guidance around psychedelic studies will
determine best practices for study design and risk assessment around the
serotonergic psychedelics. Detailed discussions and considerations
around assessing the abuse potential of psychedelics and their current
drug scheduling have been reviewed in detail here.\textsuperscript{142}

\emph{6.2.2 Other adverse effects}

Generally, the classic psychedelics have been deemed to be relatively
low risk for adverse events,\textsuperscript{143} although there are
special populations (such as older adults, and those with cardiac
disorders) that have generally not been included in studies and deserve
particular attention to possible cardiovascular adverse events including
increased heart rate, blood pressure, and myocardial
ischemia.\textsuperscript{144} As a general concern for psychedelic
trials, reports of suicidal ideation (SI), non-suicidal self-injurious
behavior (NSSBI), and hospitalizations for severe depression have been
reported in some recent trials of psilocybin for depression as have been
noted in earlier trials of psychedelics for
SUDs.\textsuperscript{145}These serious psychological adverse events
appear rare and may reflect baseline risk for participants with mood
disorders and/or SUDs, and it is uncertain what additional risks that
those with chronic pain may incur. In addition, risks of hallucinogen
persisting perception disorder (HPPD) a low concern but possible
concern.\textsuperscript{146} Guidance suggests additional measurement
of long term follow up for return to use or later overdose events which
would shed light on other possible risks for
psychedelics.\textsuperscript{119} Notably, rigorous reporting of
adverse events across psychedelic studies has varied and deserves
attention in future trial design.\textsuperscript{143}

Other serotonergic psychedelics have cardiovascular risks, including QTc
prolongation and possible valvular disease, warranting adequate
screening and monitoring of participants with OUD, whose QTc interval
may be prolonged at baseline, and who may have underlying cardiac
disorders as a consequence of intravenous drug
use.\textsuperscript{147,148} The concurrent use of methadone, which has
relevant cardiac effects, and a psychedelic like ibogaine (also with
well documented cardiac effects) may warrant additional safety
monitoring.

\textbf{Conclusion}

Psychedelic-assisted interventions for chronic pain and OUD present a
promising avenue for therapeutic innovation. Although preliminary
evidence suggests potential benefits, more rigorous research is needed
to establish the safety, efficacy, and optimal protocols for
psychedelic-assisted interventions in these conditions. Future studies
should focus on carefully selected, population-specific pain- and
opioid-related outcomes, elucidating mechanisms of action, refining
treatment protocols, and addressing safety concerns. This research is
essential to ensure the responsible and evidence-based integration of
psychedelics into research settings and potentially clinical practice.
In the context of rapid attitudinal and regulatory changes regarding
psychedelics, it remains to be seen whether their therapeutic potential
for chronic pain and OUD --- two of the most vexing problems of modern
healthcare --- can be fully realized.

\textbf{REFERENCES}

1. Spencer MR, Mini\selectlanguage{ngerman}ño AM, Warner M. Drug Overdose Deaths in the United
States, 2001-2021. \emph{NCHS Data Brief} . Dec 2022;(457):1-8.

2. Ciccarone D. The triple wave epidemic: Supply and demand drivers of
the US opioid overdose crisis. \emph{Int J Drug Policy} . Sep
2019;71:183-188. doi:10.1016/j.drugpo.2019.01.010

3. Kolodny A, Courtwright DT, Hwang CS, et al. The prescription opioid
and heroin crisis: a public health approach to an epidemic of
addiction.\emph{Annu Rev Public Health} . Mar 18 2015;36:559-74.
doi:10.1146/annurev-publhealth-031914-122957

4. Vital signs: overdoses of prescription opioid pain relievers and
other drugs among women--United States, 1999-2010. \emph{MMWR Morb
Mortal Wkly Rep} . Jul 5 2013;62(26):537-42.

5. Barry DT, Beitel M, Joshi D, Schottenfeld RS. Pain and
substance-related pain-reduction behaviors among opioid dependent
individuals seeking methadone maintenance treatment. \emph{Am J Addict}
. Mar-Apr 2009;18(2):117-21. doi:10.1080/10550490902772470

6. Mun CJ, Beitel M, Oberleitner L, et al. Pain catastrophizing and pain
acceptance are associated with pain severity and interference among
methadone-maintained patients. \emph{J Clin Psychol} . Dec
2019;75(12):2233-2247. doi:10.1002/jclp.22842

7. Oliveira D, Fontenele R, Weleff J, Sofuoglu M, De Aquino JP.
Developing non-opioid therapeutics to alleviate pain among persons with
opioid use disorder: a review of the human evidence. \emph{International
Review of Psychiatry} . 2023:1-20. doi:10.1080/09540261.2023.2229430

8. Fuehrlein BS, Ross DA. Opioid Use Disorder: A Desperate Need for
Novel Treatments. \emph{Biol Psychiatry} . Apr 1 2017;81(7):e43-e45.
doi:10.1016/j.biopsych.2017.01.014

9. De Aquino JP, Parida S, Avila-Quintero VJ, et al. Opioid-induced
analgesia among persons with opioid use disorder receiving methadone or
buprenorphine: A systematic review of experimental pain
studies.\emph{Drug Alcohol Depend} . Nov 1 2021;228:109097.
doi:10.1016/j.drugalcdep.2021.109097

10. Nichols DE. Psychedelics. \emph{Pharmacol Rev} . Apr
2016;68(2):264-355. doi:10.1124/pr.115.011478

11. Savage C, McCabe OL. Residential psychedelic (LSD) therapy for the
narcotic addict. A controlled study. \emph{Arch Gen Psychiatry} . Jun
1973;28(6):808-14. doi:10.1001/archpsyc.1973.01750360040005

12. Ludwig AM, Levine J. A CONTROLLED COMPARISON OF FIVE BRIEF TREATMENT
TECHNIQUES EMPLOYING LSD, HYPNOSIS, AND PSYCHOTHERAPY. \emph{Am J
Psychother} . Jul 1965;19:417-35.
doi:10.1176/appi.psychotherapy.1965.19.3.417

13. Kast EC, Collins VJ. STUDY OF LYSERGIC ACID DIETHYLAMIDE AS AN
ANALGESIC AGENT. \emph{Anesth Analg} . May-Jun 1964;43:285-91.

14. Bogenschutz MP, Ross S, Bhatt S, et al. Percentage of Heavy Drinking
Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the
Treatment of Adult Patients With Alcohol Use Disorder: A Randomized
Clinical Trial. \emph{JAMA Psychiatry} . Oct 1 2022;79(10):953-962.
doi:10.1001/jamapsychiatry.2022.2096

15. Johnson MW, Garcia-Romeu A, Griffiths RR. Long-term follow-up of
psilocybin-facilitated smoking cessation. \emph{Am J Drug Alcohol Abuse}
. Jan 2017;43(1):55-60. doi:10.3109/00952990.2016.1170135

16. Mosca A, Chiappini S, Miuli A, et al. Ibogaine/Noribogaine in the
Treatment of Substance Use Disorders: a Systematic Review of the Current
Literature. \emph{Curr Neuropharmacol} . Oct 17
2022;doi:10.2174/1570159x21666221017085612

17. van der Meer PB, Fuentes JJ, Kaptein AA, et al. Therapeutic effect
of psilocybin in addiction: A systematic review. \emph{Front Psychiatry}
. 2023;14:1134454. doi:10.3389/fpsyt.2023.1134454

18. Liester MB. A review of lysergic acid diethylamide (LSD) in the
treatment of addictions: historical perspectives and future
prospects.\emph{Curr Drug Abuse Rev} . 2014;7(3):146-56.
doi:10.2174/1874473708666150107120522

19. Bogenschutz MP, Johnson MW. Classic hallucinogens in the treatment
of addictions. \emph{Prog Neuropsychopharmacol Biol Psychiatry} . Jan 4
2016;64:250-8. doi:10.1016/j.pnpbp.2015.03.002

20. Rodrigues LS, Rossi GN, Rocha JM, et al. Effects of ayahuasca and
its alkaloids on substance use disorders: an updated (2016-2020)
systematic review of preclinical and human studies. \emph{Eur Arch
Psychiatry Clin Neurosci} . Jun 2022;272(4):541-556.
doi:10.1007/s00406-021-01267-7

21. Kelmendi B, Kaye AP, Pittenger C, Kwan AC. Psychedelics. \emph{Curr
Biol} . Jan 24 2022;32(2):R63-r67. doi:10.1016/j.cub.2021.12.009

22. Nakagawasai O, Arai Y, Satoh SE, et al. Monoamine oxidase and
head-twitch response in mice. Mechanisms of alpha-methylated substrate
derivatives. \emph{Neurotoxicology} . Jan 2004;25(1-2):223-32.
doi:10.1016/s0161-813x(03)00101-3

23. Silva MT, Calil HM. Screening hallucinogenic drugs: systematic study
of three behavioral tests. \emph{Psychopharmacologia} . May 28
1975;42(2):163-71. doi:10.1007/bf00429548

24. Yamamoto T, Ueki S. The role of central serotonergic mechanisms on
head-twitch and backward locomotion induced by hallucinogenic
drugs.\emph{Pharmacol Biochem Behav} . Jan 1981;14(1):89-95.
doi:10.1016/0091-3057(81)90108-8

25. de Vos CMH, Mason NL, Kuypers KPC. Psychedelics and Neuroplasticity:
A Systematic Review Unraveling the Biological Underpinnings of
Psychedelics. \emph{Front Psychiatry} . 2021;12:724606.
doi:10.3389/fpsyt.2021.724606

26. Price DD. Psychological and neural mechanisms of the affective
dimension of pain. \emph{Science} . Jun 9 2000;288(5472):1769-72.
doi:10.1126/science.288.5472.1769

27. Bardin L. The complex role of serotonin and 5-HT receptors in
chronic pain. \emph{Behav Pharmacol} . Sep 2011;22(5-6):390-404.
doi:10.1097/FBP.0b013e328349aae4

28. Bondy B, Spaeth M, Offenbaecher M, et al. The T102C polymorphism of
the 5-HT2A-receptor gene in fibromyalgia. \emph{Neurobiol Dis} . Oct
1999;6(5):433-9. doi:10.1006/nbdi.1999.0262

29. Nicholl BI, Holliday KL, Macfarlane GJ, et al. Association of HTR2A
polymorphisms with chronic widespread pain and the extent of
musculoskeletal pain: results from two population-based
cohorts.\emph{Arthritis Rheum} . Mar 2011;63(3):810-8.
doi:10.1002/art.30185

30. Talbot K, Madden VJ, Jones SL, Moseley GL. The sensory and affective
components of pain: are they differentially modifiable dimensions or
inseparable aspects of a unitary experience? A systematic
review.\emph{Br J Anaesth} . Aug 2019;123(2):e263-e272.
doi:10.1016/j.bja.2019.03.033

31. Okamoto K, Imbe H, Morikawa Y, et al. 5-HT2A receptor subtype in the
peripheral branch of sensory fibers is involved in the potentiation of
inflammatory pain in rats. \emph{Pain} . Sep 2002;99(1-2):133-43.
doi:10.1016/s0304-3959(02)00070-2

32. Patel R, Dickenson AH. Modality selective roles of pro-nociceptive
spinal 5-HT(2A) and 5-HT(3) receptors in normal and neuropathic
states.\emph{Neuropharmacology} . Dec 2018;143:29-37.
doi:10.1016/j.neuropharm.2018.09.028

33. Liu QQ, Yao XX, Gao SH, et al. Role of 5-HT receptors in neuropathic
pain: potential therapeutic implications. \emph{Pharmacol Res} . Sep
2020;159:104949. doi:10.1016/j.phrs.2020.104949

34. López-Giménez JF, González-Maeso J. Hallucinogens and Serotonin
5-HT(2A) Receptor-Mediated Signaling Pathways. \emph{Curr Top Behav
Neurosci} . 2018;36:45-73. doi:10.1007/7854\_2017\_478

35. Haleem DJ. Serotonin-1A receptor dependent modulation of pain and
reward for improving therapy of chronic pain. \emph{Pharmacol Res} . Aug
2018;134:212-219. doi:10.1016/j.phrs.2018.06.030

36. Seifert O, Baerwald C. Interaction of pain and chronic
inflammation.\emph{Z Rheumatol} . Apr 2021;80(3):205-213.
Wechselwirkungen von Schmerz und chronischer Entzündung.
doi:10.1007/s00393-020-00951-8

37. Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory
agents.\emph{Int Rev Psychiatry} . Aug 2018;30(4):363-375.
doi:10.1080/09540261.2018.1481827

38. Abbott FV, Hong Y, Blier P. Activation of 5-HT2A receptors
potentiates pain produced by inflammatory
mediators.\emph{Neuropharmacology} . Jan 1996;35(1):99-110.
doi:10.1016/0028-3908(95)00136-0

39. Puderbaugh M, Emmady PD. Neuroplasticity. \emph{StatPearls} .
StatPearls Publishing

Copyright © 2023, StatPearls Publishing LLC.; 2023.

40. Shen W, Tu Y, Gollub RL, et al. Visual network alterations in brain
functional connectivity in chronic low back pain: A resting state
functional connectivity and machine learning study. \emph{Neuroimage
Clin} . 2019;22:101775. doi:10.1016/j.nicl.2019.101775

41. Baliki MN, Mansour AR, Baria AT, Apkarian AV. Functional
reorganization of the default mode network across chronic pain
conditions. \emph{PLoS One} . 2014;9(9):e106133.
doi:10.1371/journal.pone.0106133

42. Baliki MN, Geha PY, Apkarian AV, Chialvo DR. Beyond feeling: chronic
pain hurts the brain, disrupting the default-mode network
dynamics.\emph{J Neurosci} . Feb 6 2008;28(6):1398-403.
doi:10.1523/jneurosci.4123-07.2008

43. Baliki MN, Petre B, Torbey S, et al. Corticostriatal functional
connectivity predicts transition to chronic back pain. \emph{Nat
Neurosci} . Jul 1 2012;15(8):1117-9. doi:10.1038/nn.3153

44. Ly C, Greb AC, Cameron LP, et al. Psychedelics Promote Structural
and Functional Neural Plasticity. \emph{Cell Rep} . Jun 12
2018;23(11):3170-3182. doi:10.1016/j.celrep.2018.05.022

45. Hipólito I, Mago J, Rosas FE, Carhart-Harris R. Pattern breaking: a
complex systems approach to psychedelic medicine. \emph{Neurosci
Conscious} . 2023;2023(1):niad017. doi:10.1093/nc/niad017

46. Carhart-Harris RL, Chandaria S, Erritzoe DE, et al. Canalization and
plasticity in psychopathology. \emph{Neuropharmacology} . Mar 15
2023;226:109398. doi:10.1016/j.neuropharm.2022.109398

47. Gracely RH, Harte SE. Emotional/Affective Aspects of Pain. In:
Binder MD, Hirokawa N, Windhorst U, eds. \emph{Encyclopedia of
Neuroscience} . Springer Berlin Heidelberg; 2009:1092-1095.

48. Kasanetz F, Acuña MA, Nevian T. Chapter 18 - Anterior cingulate
cortex, pain perception, and pathological neuronal plasticity during
chronic pain. In: Rajendram R, Patel VB, Preedy VR, Martin CR,
eds.\emph{The Neurobiology, Physiology, and Psychology of Pain} .
Academic Press; 2022:193-202.

49. Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates
of the psychedelic state as determined by fMRI studies with
psilocybin.\emph{Proc Natl Acad Sci U S A} . Feb 7 2012;109(6):2138-43.
doi:10.1073/pnas.1119598109

50. Barba T, Buehler S, Kettner H, et al. Effects of psilocybin versus
escitalopram on rumination and thought suppression in
depression.\emph{BJPsych Open} . Sep 6 2022;8(5):e163.
doi:10.1192/bjo.2022.565

51. Bair MJ, Robinson RL, Katon W, Kroenke K. Depression and pain
comorbidity: a literature review. \emph{Arch Intern Med} . Nov 10
2003;163(20):2433-45. doi:10.1001/archinte.163.20.2433

52. Dick BD, Rashiq S. Disruption of attention and working memory traces
in individuals with chronic pain. \emph{Anesth Analg} . May
2007;104(5):1223-9, tables of contents.
doi:10.1213/01.ane.0000263280.49786.f5

53. Linton SJ, Shaw WS. Impact of psychological factors in the
experience of pain. \emph{Phys Ther} . May 2011;91(5):700-11.
doi:10.2522/ptj.20100330

54. Meier ML, Stämpfli P, Vrana A, Humphreys BK, Seifritz E,
Hotz-Boendermaker S. Neural Correlates of Fear of Movement in Patients
with Chronic Low Back Pain vs. Pain-Free Individuals. \emph{Front Hum
Neurosci} . 2016;10:386. doi:10.3389/fnhum.2016.00386

55. Schütze R, Rees C, Smith A, Slater H, O'Sullivan P. Metacognition,
perseverative thinking, and pain catastrophizing: A moderated-mediation
analysis. \emph{Eur J Pain} . Jan 2020;24(1):223-233.
doi:10.1002/ejp.1479

56. Ziadni MS, Sturgeon JA, Darnall BD. The relationship between
negative metacognitive thoughts, pain catastrophizing and adjustment to
chronic pain. \emph{Eur J Pain} . Apr 2018;22(4):756-762.
doi:10.1002/ejp.1160

57. Sweat NW, Bates LW, Hendricks PS. The Associations of Naturalistic
Classic Psychedelic Use, Mystical Experience, and Creative Problem
Solving. \emph{J Psychoactive Drugs} . Nov-Dec 2016;48(5):344-350.
doi:10.1080/02791072.2016.1234090

58. Millière R, Carhart-Harris RL, Roseman L, Trautwein FM,
Berkovich-Ohana A. Psychedelics, Meditation, and
Self-Consciousness.\emph{Front Psychol} . 2018;9:1475.
doi:10.3389/fpsyg.2018.01475

59. MacLean RR, Sofuoglu M, Brede E, Robinson C, Waters AJ. Attentional
bias in opioid users: A systematic review and meta-analysis. \emph{Drug
Alcohol Depend} . Oct 1 2018;191:270-278.
doi:10.1016/j.drugalcdep.2018.07.012

60. Schoth DE, Nunes Vd Fau - Liossi C, Liossi C. Attentional bias
towards pain-related information in chronic pain; a meta-analysis of
visual-probe investigations. (1873-7811 (Electronic))

61. MacLean RR, Heapy AA, Waters AJ, et al. Integrating cognitive bias
modification for pain and opioid cues into medication for opioid use
disorder clinical care: Feasibility, acceptability, and preliminary
results. (1879-0046 (Electronic))

62. Griffiths RR, Johnson MW, Richards WA, et al. Psilocybin-occasioned
mystical-type experience in combination with meditation and other
spiritual practices produces enduring positive changes in psychological
functioning and in trait measures of prosocial attitudes and
behaviors.\emph{J Psychopharmacol} . Jan 2018;32(1):49-69.
doi:10.1177/0269881117731279

63. Forstmann M, Yudkin DA, Prosser AMB, Heller SM, Crockett MJ.
Transformative experience and social connectedness mediate the
mood-enhancing effects of psychedelic use in naturalistic
settings.\emph{Proc Natl Acad Sci U S A} . Feb 4 2020;117(5):2338-2346.
doi:10.1073/pnas.1918477117

64. Weiss B, Nygart V, Pommerencke LM, Carhart-Harris RL, Erritzoe D.
Examining Psychedelic-Induced Changes in Social Functioning and
Connectedness in a Naturalistic Online Sample Using the Five-Factor
Model of Personality. \emph{Front Psychol} . 2021;12:749788.
doi:10.3389/fpsyg.2021.749788

65. Ong AD, Thoemmes F, Ratner K, Ghezzi-Kopel K, Reid MC. Positive
affect and chronic pain: a preregistered systematic review and
meta-analysis. (1872-6623 (Electronic))

66. Whelan A, Johnson MI. Lysergic acid diethylamide and psilocybin for
the management of patients with persistent pain: a potential
role?\emph{Pain Manag} . May 2018;8(3):217-229.
doi:10.2217/pmt-2017-0068

67. Ramaekers JG, Hutten N, Mason NL, et al. A low dose of lysergic acid
diethylamide decreases pain perception in healthy volunteers. \emph{J
Psychopharmacol} . Apr 2021;35(4):398-405. doi:10.1177/0269881120940937

68. Reiche S, Hermle L, Gutwinski S, Jungaberle H, Gasser P, Maji\selectlanguage{polish}ć \selectlanguage{english}T.
Serotonergic hallucinogens in the treatment of anxiety and depression in
patients suffering from a life-threatening disease: A systematic
review.\emph{Prog Neuropsychopharmacol Biol Psychiatry} . Feb 2
2018;81:1-10. doi:10.1016/j.pnpbp.2017.09.012

69. Kooijman NI, Willegers T, Reuser A, et al. Are psychedelics the
answer to chronic pain: A review of current literature. \emph{Pain
Pract} . Apr 2023;23(4):447-458. doi:10.1111/papr.13203

70. Grof S, Goodman LE, Richards WA, Kurland AA. LSD-assisted
psychotherapy in patients with terminal cancer. \emph{Int
Pharmacopsychiatry} . 1973;8(3):129-44. doi:10.1159/000467984

71. Kurland AA. LSD in the supportive care of the terminally ill cancer
patient. \emph{J Psychoactive Drugs} . Oct-Dec 1985;17(4):279-90.
doi:10.1080/02791072.1985.10524332

72. Fuentes JJ, Fonseca F, Elices M, Farr\selectlanguage{ngerman}é M, Torrens M. Therapeutic Use
of LSD in Psychiatry: A Systematic Review of Randomized-Controlled
Clinical Trials. \emph{Front Psychiatry} . 2019;10:943.
doi:10.3389/fpsyt.2019.00943

73. Karst M, Halpern JH, Bernateck M, Passie T. The non-hallucinogen
2-bromo-lysergic acid diethylamide as preventative treatment for cluster
headache: an open, non-randomized case series. \emph{Cephalalgia} . Sep
2010;30(9):1140-4. doi:10.1177/0333102410363490

74. Andersson M, Persson M, Kjellgren A. Psychoactive substances as a
last resort-a qualitative study of self-treatment of migraine and
cluster headaches. \emph{Harm Reduct J} . Sep 5 2017;14(1):60.
doi:10.1186/s12954-017-0186-6

75. Fadiman J, Korb S. Might Microdosing Psychedelics Be Safe and
Beneficial? An Initial Exploration. \emph{J Psychoactive Drugs} .
Apr-Jun 2019;51(2):118-122. doi:10.1080/02791072.2019.1593561

76. Sewell RA, Halpern JH, Pope HG, Jr. Response of cluster headache to
psilocybin and LSD. \emph{Neurology} . Jun 27 2006;66(12):1920-2.
doi:10.1212/01.wnl.0000219761.05466.43

77. Schindler EA, Gottschalk CH, Weil MJ, Shapiro RE, Wright DA, Sewell
RA. Indoleamine Hallucinogens in Cluster Headache: Results of the
Clusterbusters Medication Use Survey. \emph{J Psychoactive Drugs} .
Nov-Dec 2015;47(5):372-81. doi:10.1080/02791072.2015.1107664

78. Subedi B, Grossberg GT. Phantom limb pain: mechanisms and treatment
approaches. \emph{Pain Res Treat} . 2011;2011:864605.
doi:10.1155/2011/864605

79. Fanciullacci M, Bene ED, Franchi G, Sicuteri F. Brief report:
Phantom limp pain: sub-hallucinogenic treatment with lysergic acid
diethylamide (LSD-25). \emph{Headache} . Jul 1977;17(3):118-9.
doi:10.1111/j.1526-4610.1977.hed1703118.x

80. Kuromaru S, Okada S, Hanada M, Kasahara Y, Sakamoto K. The effect of
LSD on the phantom limb phenomenon. \emph{J Lancet} . Jan
1967;87(1):22-7.

81. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces
substantial and sustained decreases in depression and anxiety in
patients with life-threatening cancer: A randomized double-blind
trial.\emph{J Psychopharmacol} . Dec 2016;30(12):1181-1197.
doi:10.1177/0269881116675513

82. Schindler EAD, Sewell RA, Gottschalk CH, et al. Exploratory
Controlled Study of the Migraine-Suppressing Effects of
Psilocybin.\emph{Neurotherapeutics} . Jan 2021;18(1):534-543.
doi:10.1007/s13311-020-00962-y

83. Medicine USNLo. Standardized Natural Psilocybin-assisted
Psychotherapy for Tapering of Opioid Medication. 2023.

84. McKenna DJ. Clinical investigations of the therapeutic potential of
ayahuasca: rationale and regulatory challenges. \emph{Pharmacol Ther} .
May 2004;102(2):111-29. doi:10.1016/j.pharmthera.2004.03.002

85. Bouso CSaJC. Ayahuasca: From the Amazon to the Global Villag.
Transnational Institute; 2015.

86. Jiménez-Garrido DF, Gómez-Sousa M, Ona G, et al. Effects of
ayahuasca on mental health and quality of life in naïve users: A
longitudinal and cross-sectional study combination. \emph{Sci Rep} . Mar
5 2020;10(1):4075. doi:10.1038/s41598-020-61169-x

87. Barbosa PC, Cazorla IM, Giglio JS, Strassman R. A six-month
prospective evaluation of personality traits, psychiatric symptoms and
quality of life in ayahuasca-naïve subjects. \emph{J Psychoactive Drugs}
. Sep 2009;41(3):205-12. doi:10.1080/02791072.2009.10400530

88. Goutarel RG, Otto; Sillans, Roger. Pharmacodynamics and Therapeutic
Applications of Iboga and Ibogaine. Psychedelic Monographs and Essays
1993 6 71-1111996.

89. Bagal AA, Hough LB, Nalwalk JW, Glick SD. Modulation of
morphine-induced antinociception by ibogaine and noribogaine.\emph{Brain
Res} . Nov 25 1996;741(1-2):258-62. doi:10.1016/s0006-8993(96)00938-9

90. Sunder Sharma S, Bhargava HN. Enhancement of morphine
antinociception by ibogaine and noribogaine in morphine-tolerant
mice.\emph{Pharmacology} . Nov 1998;57(5):229-32. doi:10.1159/000028246

91. Weleff J, Akiki TJ, Barnett BS. Bibliometric Analysis of Academic
Journal Articles Reporting Results of Psychedelic Clinical
Studies.\emph{J Psychoactive Drugs} . Sep-Oct 2023;55(4):434-444.
doi:10.1080/02791072.2022.2133757

92. Pisano VD, Putnam NP, Kramer HM, Franciotti KJ, Halpern JH, Holden
SC. The association of psychedelic use and opioid use disorders among
illicit users in the United States. \emph{J Psychopharmacol} . May
2017;31(5):606-613. doi:10.1177/0269881117691453

93. Argento E, Socias ME, Hayashi K, et al. Psychedelic use is
associated with reduced daily opioid use among people who use illicit
drugs in a Canadian setting. \emph{Int J Drug Policy} . Feb
2022;100:103518. doi:10.1016/j.drugpo.2021.103518

94. Jones G, Ricard JA, Lipson J, Nock MK. Associations between classic
psychedelics and opioid use disorder in a nationally-representative U.S.
adult sample. \emph{Sci Rep} . Apr 7 2022;12(1):4099.
doi:10.1038/s41598-022-08085-4

95. Medicine USNLo. Inpatient Buprenorphine Induction With Psilocybin
for Opioid Use Disorder (BIPOD-In). ClinicalTrials.gov2023.

96. Sobell LC, Sobell MB. Timeline Follow-Back. In: Litten RZ, Allen JP,
eds. \emph{Measuring Alcohol Consumption: Psychosocial and Biochemical
Methods} . Humana Press; 1992:41-72.

97. Medicine USNLo. Adjunctive Effects of Psilocybin and a Formulation
of Buprenorphine. 2021.

98. Medicine USNLo. Psilocybin for Opioid Use Disorder in Patients on
Methadone Maintenance With Ongoing Opioid Use. 2023.

99. Thomas G, Lucas P, Capler NR, Tupper KW, Martin G.
Ayahuasca-assisted therapy for addiction: results from a preliminary
observational study in Canada. \emph{Curr Drug Abuse Rev} . Mar
2013;6(1):30-42. doi:10.2174/15733998113099990003

100. Hamill J, Hallak J, Dursun SM, Baker G. Ayahuasca: Psychological
and Physiologic Effects, Pharmacology and Potential Uses in Addiction
and Mental Illness. \emph{Curr Neuropharmacol} . 2019;17(2):108-128.
doi:10.2174/1570159x16666180125095902

101. Fábregas JM, González D, Fondevila S, et al. Assessment of
addiction severity among ritual users of ayahuasca. \emph{Drug Alcohol
Depend} . Oct 1 2010;111(3):257-61. doi:10.1016/j.drugalcdep.2010.03.024

102. Argento E, Capler R, Thomas G, Lucas P, Tupper KW. Exploring
ayahuasca-assisted therapy for addiction: A qualitative analysis of
preliminary findings among an Indigenous community in Canada. \emph{Drug
Alcohol Rev} . Nov 2019;38(7):781-789. doi:10.1111/dar.12985

103. Mosca A, Chiappini S, Miuli A, et al. Ibogaine/Noribogaine in the
Treatment of Substance Use Disorders: A Systematic Review of the Current
Literature. \emph{Curr Neuropharmacol} . 2023;21(11):2178-2194.
doi:10.2174/1570159x21666221017085612

104. Mash DC, Kovera CA, Pablo J, et al. Ibogaine: complex
pharmacokinetics, concerns for safety, and preliminary efficacy
measures. \emph{Ann N Y Acad Sci} . Sep 2000;914:394-401.
doi:10.1111/j.1749-6632.2000.tb05213.x

105. Knuijver T, Schellekens A, Belgers M, et al. Safety of ibogaine
administration in detoxification of opioid-dependent individuals: a
descriptive open-label observational study. \emph{Addiction} . Jan
2022;117(1):118-128. doi:10.1111/add.15448

106. Noller GE, Frampton CM, Yazar-Klosinski B. Ibogaine treatment
outcomes for opioid dependence from a twelve-month follow-up
observational study. \emph{Am J Drug Alcohol Abuse} . 2018;44(1):37-46.
doi:10.1080/00952990.2017.1310218

107. Davis AK, Renn E, Windham-Herman AM, Polanco M, Barsuglia JP. A
Mixed-Method Analysis of Persisting Effects Associated with Positive
Outcomes Following Ibogaine Detoxification. \emph{J Psychoactive Drugs}
. Sep-Oct 2018;50(4):287-297. doi:10.1080/02791072.2018.1487607

108. Mash DC, Duque L, Page B, Allen-Ferdinand K. Ibogaine
Detoxification Transitions Opioid and Cocaine Abusers Between Dependence
and Abstinence: Clinical Observations and Treatment Outcomes.\emph{Front
Pharmacol} . 2018;9:529. doi:10.3389/fphar.2018.00529

109. Malcolm BJ, Polanco M, Barsuglia JP. Changes in Withdrawal and
Craving Scores in Participants Undergoing Opioid Detoxification
Utilizing Ibogaine. \emph{J Psychoactive Drugs} . Jul-Aug
2018;50(3):256-265. doi:10.1080/02791072.2018.1447175

110. Medicine USNLo. Preliminary Efficacy and Safety of Ibogaine in the
Treatment of Methadone Detoxification. 2022.

111. Medicine USNLo. A Study of Oral Ibogaine in Opioid Withdrawal.
2022;

112. Glue P, Lockhart M, Lam F, Hung N, Hung CT, Friedhoff L.
Ascending-dose study of noribogaine in healthy volunteers:
pharmacokinetics, pharmacodynamics, safety, and tolerability. \emph{J
Clin Pharmacol} . Feb 2015;55(2):189-94. doi:10.1002/jcph.404

113. Bornemann J, Close JB, Spriggs MJ, Carhart-Harris R, Roseman L.
Self-Medication for Chronic Pain Using Classic Psychedelics: A
Qualitative Investigation to Inform Future Research. \emph{Front
Psychiatry} . 2021;12:735427. doi:10.3389/fpsyt.2021.735427

114. Lipton RB, Buse DC, Friedman BW, et al. Characterizing opioid use
in a US population with migraine: Results from the CaMEO
study.\emph{Neurology} . Aug 4 2020;95(5):e457-e468.
doi:10.1212/wnl.0000000000009324

115. Paice JA, Bohlke K, Barton D, et al. Use of Opioids for Adults With
Pain From Cancer or Cancer Treatment: ASCO Guideline. \emph{J Clin
Oncol} . Feb 1 2023;41(4):914-930. doi:10.1200/jco.22.02198

116. Delorme J, Kerckhove N, Authier N, Pereira B, Bertin C, Chenaf C.
Systematic Review and Meta-Analysis of the Prevalence of Chronic Pain
Among Patients With Opioid Use Disorder and Receiving Opioid
Substitution Therapy. \emph{J Pain} . Feb 2023;24(2):192-203.
doi:10.1016/j.jpain.2022.08.008

117. Administration USFaD. Psychedelic Drugs: Considerations for
Clinical Investigations. 2023.

118. Johnson M, Richards W, Griffiths R. Human hallucinogen research:
guidelines for safety. \emph{J Psychopharmacol} . Aug 2008;22(6):603-20.
doi:10.1177/0269881108093587

119. Kiluk BD, Kleykamp BA, Comer SD, et al. Clinical Trial Design
Challenges and Opportunities for Emerging Treatments for Opioid Use
Disorder: A Review. \emph{JAMA Psychiatry} . Jan 1 2023;80(1):84-92.
doi:10.1001/jamapsychiatry.2022.4020

120. Mücke M, Cuhls H, Radbruch L, et al. Quantitative sensory testing
(QST). English version. \emph{Schmerz} . Nov 2021;35(Suppl 3):153-160.
Quantitative sensorische Testung (QST). doi:10.1007/s00482-015-0093-2

121. Georgopoulos V, Akin-Akinyosoye K, Zhang W, McWilliams DF, Hendrick
P, Walsh DA. Quantitative sensory testing and predicting outcomes for
musculoskeletal pain, disability, and negative affect: a systematic
review and meta-analysis. \emph{Pain} . Sep 2019;160(9):1920-1932.
doi:10.1097/j.pain.0000000000001590

122. Crombez G, Van Ryckeghem DML, Eccleston C, Van Damme S. Attentional
bias to pain-related information: a meta-analysis. \emph{Pain} . Apr
2013;154(4):497-510. doi:10.1016/j.pain.2012.11.013

123. Kiluk BD, Yip SW, DeVito EE, Carroll KM, Sofuoglu M. Anhedonia as a
key clinical feature in the maintenance and treatment of opioid use
disorder. \emph{Clin Psychol Sci} . Nov 2019;7(6):1190-1206.
doi:10.1177/2167702619855659

124. Saraiya TC, Jarnecke AM, Jones J, Brown DG, Brady KT, Back SE.
Laboratory-induced stress and craving predict opioid use during
follow-up among individuals with prescription opioid use
disorder.\emph{Drug Alcohol Depend} . Aug 1 2021;225:108755.
doi:10.1016/j.drugalcdep.2021.108755

125. Glue P, Cape G, Tunnicliff D, et al. Ascending Single-Dose,
Double-Blind, Placebo-Controlled Safety Study of Noribogaine in
Opioid-Dependent Patients. \emph{Clin Pharmacol Drug Dev} . Nov
2016;5(6):460-468. doi:10.1002/cpdd.254

126. Olson DE. The Subjective Effects of Psychedelics May Not Be
Necessary for Their Enduring Therapeutic Effects. \emph{ACS Pharmacol
Transl Sci} . Apr 9 2021;4(2):563-567. doi:10.1021/acsptsci.0c00192

127. Yaden DB, Griffiths RR. The Subjective Effects of Psychedelics Are
Necessary for Their Enduring Therapeutic Effects. \emph{ACS Pharmacol
Transl Sci} . Apr 9 2021;4(2):568-572. doi:10.1021/acsptsci.0c00194

128. Roseman L, Nutt DJ, Carhart-Harris RL. Quality of Acute Psychedelic
Experience Predicts Therapeutic Efficacy of Psilocybin for
Treatment-Resistant Depression. \emph{Front Pharmacol} . 2017;8:974.
doi:10.3389/fphar.2017.00974

129. Schindler EAD. Psychedelics in the Treatment of Headache and
Chronic Pain Disorders. \emph{Curr Top Behav Neurosci} .
2022;56:261-285. doi:10.1007/7854\_2022\_365

130. Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study
of the 5-HT2AR agonist psilocybin in the treatment of tobacco
addiction.\emph{J Psychopharmacol} . Nov 2014;28(11):983-92.
doi:10.1177/0269881114548296

131. Hoffman BM, Papas RK, Chatkoff DK, Kerns RD. Meta-analysis of
psychological interventions for chronic low back pain. \emph{Health
Psychol} . Jan 2007;26(1):1-9. doi:10.1037/0278-6133.26.1.1

132. Dutra L, Stathopoulou G, Basden SL, Leyro TM, Powers MB, Otto MW. A
meta-analytic review of psychosocial interventions for substance use
disorders. \emph{Am J Psychiatry} . Feb 2008;165(2):179-87.
doi:10.1176/appi.ajp.2007.06111851

133. Brennan W, Belser AB. Models of Psychedelic-Assisted Psychotherapy:
A Contemporary Assessment and an Introduction to EMBARK, a
Transdiagnostic, Trans-Drug Model. \emph{Front Psychol} .
2022;13:866018. doi:10.3389/fpsyg.2022.866018

134. Cavarra M, Falzone A, Ramaekers JG, Kuypers KPC, Mento C.
Psychedelic-Assisted Psychotherapy-A Systematic Review of Associated
Psychological Interventions. \emph{Front Psychol} . 2022;13:887255.
doi:10.3389/fpsyg.2022.887255

135. Yaden DB, Berghella AP, Regier PS, Garcia-Romeu A, Johnson MW,
Hendricks PS. Classic psychedelics in the treatment of substance use
disorder: Potential synergies with twelve-step programs. \emph{Int J
Drug Policy} . Dec 2021;98:103380. doi:10.1016/j.drugpo.2021.103380

136. Pronovost-Morgan C, Hartogsohn I, Ramaekers JG. Harnessing placebo:
Lessons from psychedelic science. \emph{J Psychopharmacol} . Sep
2023;37(9):866-875. doi:10.1177/02698811231182602

137. Henderson LA, Di Pietro F, Youssef AM, et al. Effect of Expectation
on Pain Processing: A Psychophysics and Functional MRI
Analysis.\emph{Front Neurosci} . 2020;14:6. doi:10.3389/fnins.2020.00006

138. Hovmand OR, Poulsen ED, Arnfred S, Storebø OJ. Risk of bias in
randomized clinical trials on psychedelic medicine: A systematic
review.\emph{J Psychopharmacol} . Jul 2023;37(7):649-659.
doi:10.1177/02698811231180276

139. Szigeti B, Nutt D, Carhart-Harris R, Erritzoe D. The difference
between 'placebo group' and 'placebo control': a case study in
psychedelic microdosing. \emph{Sci Rep} . Jul 26 2023;13(1):12107.
doi:10.1038/s41598-023-34938-7

140. Gukasyan N, Nayak SM. Psychedelics, placebo effects, and set and
setting: Insights from common factors theory of
psychotherapy.\emph{Transcult Psychiatry} . Oct 2022;59(5):652-664.
doi:10.1177/1363461520983684

141. Gukasyan N, Davis AK, Barrett FS, et al. Efficacy and safety of
psilocybin-assisted treatment for major depressive disorder: Prospective
12-month follow-up. \emph{J Psychopharmacol} . Feb 2022;36(2):151-158.
doi:10.1177/02698811211073759

142. Henningfield JE, Ashworth J, Heal DJ, Smith SL. Psychedelic drug
abuse potential assessment for new drug applications and controlled
substance scheduling: A United States perspective. \emph{J
Psychopharmacol} . Jan 2023;37(1):33-44. doi:10.1177/02698811221140004

143. Breeksema JJ, Kuin BW, Kamphuis J, van den Brink W, Vermetten E,
Schoevers RA. Adverse events in clinical treatments with serotonergic
psychedelics and MDMA: A mixed-methods systematic review. \emph{J
Psychopharmacol} . Oct 2022;36(10):1100-1117.
doi:10.1177/02698811221116926

144. Johnston CB, Mangini M, Grob C, Anderson B. The Safety and Efficacy
of Psychedelic-Assisted Therapies for Older Adults: Knowns and
Unknowns.\emph{Am J Geriatr Psychiatry} . Jan 2023;31(1):44-53.
doi:10.1016/j.jagp.2022.08.007

145. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-Dose Psilocybin
for a Treatment-Resistant Episode of Major Depression. \emph{N Engl J
Med} . Nov 3 2022;387(18):1637-1648. doi:10.1056/NEJMoa2206443

146. Halpern JH, Pope HG, Jr. Hallucinogen persisting perception
disorder: what do we know after 50 years? \emph{Drug Alcohol Depend} .
Mar 1 2003;69(2):109-19. doi:10.1016/s0376-8716(02)00306-x

147. Rocha JM, Reis JAS, Bouso JC, Hallak JEC, Dos Santos RG.
Identifying setting factors associated with improved ibogaine safety: a
systematic review of clinical studies. \emph{Eur Arch Psychiatry Clin
Neurosci} . Oct 2023;273(7):1527-1542. doi:10.1007/s00406-023-01590-1

148. McIntyre RS. Serotonin 5-HT(2B) receptor agonism and valvular heart
disease: implications for the development of psilocybin and related
agents. \emph{Expert Opin Drug Saf} . Jul-Dec 2023;22(10):881-883.
doi:10.1080/14740338.2023.2248883

\textbf{FIGURE LEGEND}

\textbf{Figure 1.} Pharmacological, psychological, and social mechanisms
for how psychedelics may influence pain and pain-related behaviours.

\textbf{Figure 2. Figure 2A.} Overview of neurocircuitry of
addiction.\textbf{Figure 2B.} Overlap of psychedelic mechanisms as they
may theoretically influence specific areas of the neurocircuitry of
addiction as relevant to both pain and opioid use disorder.

\textbf{FIGURES}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1.} Pharmacological, psychological, and social mechanisms
for how psychedelics may influence pain and pain-related behaviours.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2. Figure 2A.} Overview of neurocircuitry of
addiction.\textbf{Figure 2B.} Overlap of psychedelic mechanisms as they
may theoretically influence specific areas of the neurocircuitry of
addiction as relevant to both pain and opioid use disorder.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/FIgure-2/FIgure-2}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

