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REVIEW
Integrating psychotherapy and psychopharmacology: psychedelic-assisted
psychotherapy and other combined treatments
Kyle T. Greenway
a
, Nicolas Garel
a
, Lisa Jerome
b
and Allison A. Feduccia
c
a
Department of Psychiatry, McGill University, Montreal, Quebec, Canada;
b
Data Services, MAPS Public Benefit Corporation;
c
Project New Day,
Psychedelic.Support
ABSTRACT
Introduction: Combinations of psychotherapy with antidepressants are gold-standard psychiatric
treatments. They operate through complex and interactional mechanisms, not unlike the reemergent
paradigm of psychedelic-assisted psychotherapy, which promising research suggests may also be
highly effective in even challenging populations.
Areas covered: We review the therapeutic mechanisms behind both conventional and psychedelic
paradigms, including the evolution of this knowledge and the associated explanatory frameworks. We
explore how psychedelics have provided insights about psychiatric illnesses and treatments over the
past decades. We discuss limitations to early explanatory models while highlighting and comparing the
psychological and biological mechanisms underlying many psychiatric treatments.
Methods: A narrative review was conducted based on a search in Medline/Pubmed up to January 1
st
,
2020, and iterative retrieval of references from recent reviews and clinical trials.
Expert opinion: The contextual model of the common factors of psychotherapy provides a powerful
perspective on psychotherapy, antidepressants, and psychedelics, as well as 3,4-methylenedioxy-
methamphetamine (MDMA) and ketamine. It aligns well with key tenets of psychedelic-assisted
psychotherapy. Conventional antidepressants and especially psychedelics may improve the efficacy of
psychotherapy via neurochemical changes and increased environmental sensitivity. Combined treat-
ments hold significant promise for advancing the knowledge and treatment of many forms of
psychopathology.
ARTICLE HISTORY
Received 27 January 2020
Accepted 18 May 2020
KEYWORDS
Psychedelics; mdma; lsd;
psilocybin; psychotherapy;
antidepressants; psychiatry;
psychedelic-assisted
psychotherapy; mdma-
assisted psychotherapy;
ketamine; ketamine-assisted
psychotherapy
1. Introduction
The global prevalence of psychiatric disorders and their socie-
tal impacts are increasing [1,2], and they are now responsible
for approximately 28% of illness morbidity worldwide – half of
which is attributable to anxiety and depression [2]. Major
depressive disorder is the most common psychiatric illness
[3], the leading cause of disability [3], and is associated with
extraordinary individual and societal costs [4]. Although exist-
ing treatments are generally considered effective [5], treat-
ment-resistance is a common and increasing clinical
phenomenon [6,7]. New psychiatric treatments are thus sorely
needed – particularly ones that are efficacious in patients who
have failed the existing treatments.
Developing central nervous system drugs is associated with
higher development costs, longer approval/development
times, and greater rates of costly failures than other drugs
[8–10]. In spite of these difficulties, the Food and Drug
Administration (FDA) has bestowed Breakthrough Therapy
designations on several emerging treatments for psychiatric
disorders due to their potential for ‘benefit above that of
available therapies for life-threatening illnesses’ [11]. Of those
that are not yet approved, all except for one are specific
combinations of psychoactive molecules with psychotherapy:
psilocybin-assisted psychotherapy for major depressive
disorder as well as treatment-resistant depression (being
developed by separate entities) [12,13], and 3,4-methylene-
dioxymethamphetamine (MDMA)-assisted psychotherapy for
posttraumatic stress disorder (PTSD) [14]. Additionally, esketa-
mine (Spravato™) has recently received FDA-approval for treat-
ment-resistant depression in conjunction with a conventional
antidepressant, after also receiving the Breakthrough Therapy
designation in August 2016 [15]. This is an intranasal formula-
tion of the s-enantiomer of ketamine, which has been
described by at least one expert as ‘arguably the most impor-
tant discovery in half a century’ [16]. With some notable
exceptions, like brexanolone infusions for postpartum depres-
sion and vortioxetine for major depressive disorder [17,18],
these developments appear to represent the only recent
major pharmacologic advances in the realm of mood and
anxiety disorders and the only treatments specifically being
developed in refractory populations [19].
All three molecules – psilocybin, MDMA, and ketamine –
have been described as ‘psychedelics’ [20]. This term is
a neologism coined in 1953 by psychiatrist Humphrey
Osmond from the Greek psyche (mind/soul) and delos
(reveal/manifest), primarily referring to lysergic acid diethyla-
mide (LSD) [21]. There is some confusion around terminology.
In keeping with the primary mechanism of action of LSD,
many authors reserve the term psychedelic for serotonin 2A
CONTACT Kyle T. Greenway kyle.greenway@mail.mcgill.ca McGill University, Department of Psychiatry, 1033 Avenue Des Pins, Montréal, Canada
EXPERT REVIEW OF CLINICAL PHARMACOLOGY
https://doi.org/10.1080/17512433.2020.1772054
© 2020 Informa UK Limited, trading as Taylor & Francis Group
(5HT
2A
) receptor agonists, whereas others describe this class as
classic (or classical) psychedelics [22,23]. In addition to – or
instead of – the label psychedelic, MDMA is classed as an
‘entactogen’ or ‘empathogen’ (empathy inducing) and keta-
mine is described as a ‘dissociative’. Their highly distinct prop-
erties are broached below, but they share the capacity to
engender powerful temporary alterations in consciousness
that may hold therapeutic potential [19,20]. When combined
with specific forms of psychotherapy that aim to translate
these non-ordinary experiences into healing, the term psyche-
delic-assisted psychotherapy (PAP) is generally employed [20].
The aim of this article is to review the principles, history, and
results of PAP, focusing on the prototypical psychedelic LSD
and another 5HT
2A
agonist, psilocybin. We begin with an
examination of conventional psychotherapy and psychophar-
macology, specifically the antidepressants, and their combina-
tion. The evolving understanding of how psychotherapy and
various pharmacotherapies interact holds significant promise
for improved conceptualizations and treatment of a wide
range of psychiatric conditions.
2. Methods
We performed two Medline/Pubmed searches: ‘psychedelic*’,
and ‘antidepressant AND psychotherapy AND review AND
(depression OR mood)’ restricted to English language pub-
lished before January 1
st
, 2020. The former yielded 1038
results and the latter 2122. The database Clinicaltrials.gov
was searched for completed trials on psilocybin, LSD, MDMA,
and ketamine. The identified publications were screened for
relevance, and additional articles were identified by iteratively
reviewing references contained within identified articles. In
total, some 239 have been selected for inclusion in this review.
3. Conventional treatments
The combination of psychopharmacological and psychother-
apeutic interventions is now considered the gold standard in
a wide variety of psychiatric conditions because of comple-
mentarity and potentially synergistic benefits [5].
Psychotherapy can address underlying unresolved psychologi-
cal issues and support behavioral modifications, while drugs
modulate neurochemical signaling and other downstream
processes. We elected to focus on how antidepressants
combine with psychotherapy as this combination has been
studied in depth [5,24], and its benefits are better established
than other psychotherapy-medication combinations, such as
benzodiazepines and antipsychotics [25,26]. Furthermore, anti-
depressants are of particular relevance as they are used to
treat a wide variety of conditions beyond depression, includ-
ing a wide range of anxiety disorders [27], neuropathic pain
[28], and irritable bowel syndrome [29].
3.1. Pharmacotherapies
The first drug to be described as an antidepressant was iso-
niazid, a tuberculosis treatment that was serendipitously
observed in the 1950s to improve various symptoms asso-
ciated with depression [30]. Further clinical and pharmacolo-
gical research led to the discoveries of a number of similar
molecules, now classed as monoamine oxidase inhibitors [30],
as well as the formulation of the ‘monoamine hypothesis’
which postulates that depression is a result of the depletion
of serotonin, norepinephrine, and/or dopamine [31]. The dis-
covery and study of psychedelics played a key role in this line
of investigation [32,33], as discussed below, as well as the
resultant overall shift toward a biomedical model of psychia-
try. The monoamine hypothesis was fruitful, yielding a number
of new classes of antidepressants that act primarily on mono-
amines, including the tricyclics, the selective serotonin reup-
take inhibitors (SSRIs), the serotonin-norepinephrine reuptake
inhibitors (SNRIs), and a variety of other molecules [30,34]. The
SSRIs and SNRIs are currently the most commonly prescribed
antidepressants by a significant margin, mostly because of
their superior safety and tolerability [34,35].
A large body of evidence demonstrates that these antide-
pressants are preferred and effective treatments for many
patients [27,34,36–38], fit well into a medical model of mental
healthcare [39,40], and are cost-effective treatments for anxi-
ety and depression [41–43]. Nevertheless, their short-term and
long-term efficacy are subject to some debate [44–48]. Their
disadvantages include both short-term and long-term side
effects [49], which possibly continue for years following drug-
discontinuation [50], and benefits that may not persist after
treatment discontinuation [50,51]. Relatively long medication
trials of weeks or months are needed to evaluate response
[52]. As with many medications, antidepressant treatment is
marked by poor adherence in approximately 50% of patients
[49], partly due to the delayed onset of benefits [53], the need
for daily dosing even after symptoms have improved [49,52],
impairments in motivation and self-care intrinsic to disorders
such as depression [54], and potential side-effects like
impaired sexual functioning [55]. Patients may also prema-
turely discontinue antidepressants due to fears of dependence
[56], rightfully or wrongfully.
A significant increase in antidepressant prescription rates
has been documented over the recent decades with 1 in 8
American adults estimated to have filled a prescription for an
antidepressant in 2013 [35,57]. This rise is partly attributable to
the increasing duration of antidepressant treatment courses
[58], which some attribute to antidepressant discontinuation
syndrome. That is, patients may be apprehensive about stop-
ping antidepressants due to challenging discontinuation
Article highlights
●Psychiatric treatments, including psychotherapy and antidepressants,
act both biologically and psychologically.
●Combinations of antidepressants with psychotherapy act through
interactional and potentially synergistic mechanisms.
●Though operating with greater acuity, similar mechanisms underly
the combinations of psychotherapy with psychedelics, MDMA, or
ketamine.
●This acuity presents significant therapeutic opportunities and
challenges.
●Research on conventional combinations can inform the optimal use
of these novel combinations, and vice versa.
2 K. T. GREENWAY ET AL.
symptoms [59,60]. Further, if such symptoms are mistaken for
a relapse of the original disorder, there may be inappropriate
re-initiation of the medication [61]. Some authors argue that
the rise in prescription is due to excessive biomedicalization of
psychiatric illness over the preceding decades [62].
These drawbacks aside, conventional antidepressants
remain extremely important treatments in psychiatry more
than six decades after their discovery. The monoamine
hypothesis, however, has fared less well [63]. The mechanism
of action of these medications is now understood to be more
complex than the correction of neurotransmitter abnormal-
ities. Although uncertainties remain, recent explanatory mod-
els tend to emphasize the roles of neuroplasticity [63],
inflammation [64], and glutamatergic systems in depression
[31]. Copious evidence that talk therapies are, much like anti-
depressants, effective treatments of a wide variety of psychia-
tric illnesses also challenges the monoamine hypothesis
[27,38,65,66], pointing instead to mechanisms that are shared
amongst various illnesses and treatments.
3.2. Psychotherapy
Evidence-based psychotherapies like Cognitive Behavioral
Therapy (CBT) are generally accepted to be equivalently effi-
cacious for depressive disorders as antidepressants, except for
persistent depressive disorder [67]. Psychotherapy offers
advantages in comparison to medication; harms and side
effects are less common [68], quality of life (as opposed to
symptomatology) may be more improved [69], and many
patients prefer psychotherapy [70]. For some conditions, like
specific phobia, psychotherapy is superior to all other treat-
ments [27]. Unfortunately, the availability of psychotherapy is
often lacking [71], partly because of greater upfront costs and
the (generally false) perception of policy-makers that it is not
cost-effective [71,72]. There are nevertheless notable counter-
examples, such as the highly successful Improving Access to
Psychological Therapies program in the United Kingdom
[73,74], which demonstrates that providing psychotherapy at
a population level is feasible. An additional difficulty with
psychotherapy is that the treatment requires greater patient
commitment than medications, in terms of appointments and
active efforts to engage, which can be challenging for ill
patients who often suffer from, for example, impaired cogni-
tion or low motivation [75]. Benefits of psychotherapy, like
antidepressants, typically appear after several weeks of treat-
ment [66,67,76], but are more likely to persist post-treatment
[77].
Psychotherapy has no single definition but may be under-
stood as an interpersonal intervention that relies on repeated
encounters, a healing relationship, and a particular explana-
tory model, all within a structured therapeutic frame
[65,78,79]. Its origins have been variously traced to Josef
Breuer and Sigmund Freud’s development of psychoanalysis
[80], Philippe Pinel’s moral treatment [81], or, more broadly, to
diverse traditions including Western philosophy [82], Eastern
religions [83], and shamanism [78].
Modalities and techniques of psychotherapy are numerous
and diverse. However, a significant portion of the therapeutic
benefits of psychotherapy may be due to components that are
generally shared amongst various approaches – the so-called
common factors – rather than ingredients that are unique to
a particular therapeutic model [84,85]. Indeed, the ‘dodo bird
verdict’ postulates that all psychotherapeutic approaches are
similarly efficacious in part because the systematic application
of any therapeutic theory by a skilled therapist is beneficial
regardless of that theory’s actual veracity [86]. It was first
described in 1936 and remains an important topic today
[87,88]. Some authors thus speak of the creation and applica-
tion of a ‘therapeutic myth’ between patient and therapist as
a key component of psychotherapy [78,89]. That is, establish-
ing a mutually acceptable rationale that explains an indivi-
dual’s psychopathology and guides its treatment.
One widely-referenced model for the common factors is
the contextual model, which posits three primary mechanisms
of action of psychotherapy: the real relationship, the creation
of expectations through explanation of disorders and treat-
ments, and the enactment of health promoting actions [84,85].
While these factors are shared between schools of psychother-
apy, their implementation can vary dramatically in terms of
how therapists and patients relate to each other, the explana-
tory frameworks (or therapeutic myths) that they employ, and
the tasks that they undertake. For example, CBT partly strives
to correct collaboratively identified maladaptive patterns of
thought and to facilitate engagement in behavioral exposure
and activation [90]. Psychodynamic psychotherapy, on the
other hand, partly aims to change patients’ problematic pat-
terns of relating to their selves and to others via developing
insight about past relationships and their relationship with the
therapist [90]. The contextual model also acknowledges that
a strong therapeutic alliance is a necessity of all pathways, as
is supported by research [85]. Exactly how – and how well –
this alliance is established varies amongst techniques and
individual therapists [85].
While the contextual model explains research findings of
equivalent benefits between various psychotherapies in most
psychiatric conditions, it fails to explain why particular
approaches are superior in treating other conditions. One
classic example is the clear superiority of CBT including
a specific technique known as Exposure Response Prevention
over psychodynamic psychotherapy in the treatment of obses-
sive-compulsive disorder (OCD) [91,92]. Nevertheless, the con-
textual model provides a powerful lens for understanding the
psychological underpinnings of psychiatric care, even beyond
psychotherapy.
3.3. Shared pathways
Combining antidepressants with psychotherapy to treat
depression is often framed in terms of additive benefits via
distinct mechanisms, and indeed response rates are typically
greater than either in isolation [24], especially in terms of
quality of life [67]. However, antidepressant treatment is
more than a biological modulator of neurotransmitters, and
combination treatment is highly interactional. For example,
adding psychotherapy to antidepressant therapy may actually
increase the tolerability of medication, as evidenced by
reduced trial drop-out rates [67,93]. Effective treatment with
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 3
antidepressants may even reduce the use of immature
defense mechanisms and dysfunctional thinking [94,95], key
concepts in psychodynamic therapy and CBT, respectively.
This may be due to decreased symptomatology (which fre-
quently includes cognitive changes [75]) increasing therapy
efficiency [96], amongst other biological or expectancy effects.
The contextual model may also be applied to antidepres-
sants in that a correctable chemical imbalance may be seen as
an (imperfect) explanatory model, or a therapeutic myth,
through which the real relationship between the prescriber
and the patient provides for healing [97]. The famously power-
ful placebo effects in studies on depression support this per-
spective [45], as placebos routinely achieve 50% to 85% of
antidepressant levels of efficacy [98]. Such benefits are mark-
edly reduced when a plausible explanatory model of illness
and treatment is not provided. For example, a three-arm trial
comparing blinded antidepressant or placebo treatment to
supportive care (theoretically delivering the common factors
except for explanation) demonstrated a 46% symptom reduc-
tion with antidepressant medication versus 36% for placebo
and 5% for supportive care [99]. This suggests that, given
a specific therapeutic context, acts like pill-taking (placebo or
antidepressant) can have major benefits.
Conversely, explanatory models can reduce the benefits of
real medications. One study demonstrated that presenting an
antidepressant as an ‘active placebo’ greatly reduced benefits
on anxiety [100]. In a testament to the power of expectation
and the complexity of mind-body interactions, functional
magnetic resonance imaging changes in this study were also
dependent on the provided explanatory model. Further sup-
port for the psychological importance of antidepressant pre-
scription is that their effectiveness is partly mediated by the
reported strength of therapeutic alliance [99,101], much like
psychotherapy [85]. Such findings have led some to argue that
the treatment of depression by antidepressants is primarily
a psychological treatment [102], but alternative explanations
better capture the rich complexity of simultaneous treatment
by psychotherapy and medication.
One possibility is that modulating neurotransmitters with
antidepressants increases sensitivity to the environment
[103,104]. This has been demonstrated in a reanalysis of the
Sequenced Treatment Alternatives to Relieve Depression
(STAR*D) trial – the largest prospective clinical trial on depres-
sion ever [105] – which found that higher doses of the anti-
depressant citalopram were associated with a much greater
positive impact from positive socioeconomic status markers,
like education, employment, and income. This finding con-
trasts with the remarkably flat dose-response curve of antide-
pressants found in many studies [106], which may partly result
from positive and negative environments being amplified at
higher doses and thus canceling out. An analogous result has
been shown in animals (free from expectations); in one study,
rat models of depression treated with fluoxetine improved in
enriched living conditions but worsened in stressful living
conditions on several biological and behavioral outcomes
[107]. In combination with therapy, antidepressant treatment
might similarly increase sensitivity to reparative interactions
with a psychotherapist.
This mechanism could also explain why antidepressants
with very distinct pharmacologic profiles tend to achieve
remarkably similar levels of efficacy. For example, in the
STAR*D study, after failing to respond to one SSRI (citalopram),
response and remission rates did not differ between patients
switched to another SSRI (sertraline), an SNRI (venlafaxine), or
a norepinephrine-dopamine reuptake inhibitor (bupropion)
[105]. On the surface, this would seem to suggest that seroto-
nin, norepinephrine, and dopamine abnormalities were
equally distributed in this large, real-world population.
Alternatively, any monoamine modulation may potentially
improve symptoms via a shared mechanism like environmen-
tal sensitization, rather than the correction of neurotransmitter
imbalances. This may partly account for the disappointing lack
of benefits of antidepressants in patients with medical issues
or addictions [108–110], given that their environments may be
relatively more negative. In contrast, antidepressants have
been found to be more efficacious than placebos in the treat-
ment of addiction when accompanied by psychosocial inter-
ventions [111].
Just as the mechanism of action of antidepressants is more
psychological than may appear at first glance, psychotherapy
acts more biologically than might be expected. Introspection,
challenging dysfunctional thoughts, cultivating self-
compassion, practicing adaptive behaviors, and healing inter-
actions with a therapist may all remodel dysfunctional neural
circuits [112]. Indeed, neuroimaging has demonstrated that
both psychotherapy and pharmacotherapy engender neural
reorganization to a similar extent across many conditions
[113]. Plasma markers of increased neuroplasticity and cellular
resilience have also been found with successful psychother-
apy [114], as have epigenetic changes in both children and
adults [115,116]. Psychotherapy’s capacity to modify gene
expression has prompted renowned psychopharmacologist
Stephen Stahl to analogize it as an ‘epigenetic drug’ [117].
These findings demonstrate that any effective treatment of
psychopathology, in all of its complexity, cannot be fully
understood from purely biological or psychological
perspectives.
4. Psychedelics, MDMA, and ketamine
4.1. How early research on psychedelics transformed
psychiatry
One new – or rather, resurgent – approach that thoroughly
integrates multiple paradigms is psychedelic-assisted psy-
chotherapy. The quintessential psychedelic LSD was first
synthesized by Albert Hoffman while working for Sandoz in
1938, and its psychoactive effects were discovered during his
accidental ingestion 5 years later [118]. Its unique psychologi-
cal effects inspired hope for potential therapeutic applications,
which Sandoz pursued by distributing LSD to investigators
and clinicians worldwide, free of charge [119].
Of those who began to grapple with LSD, some viewed its
effects as mimicking psychosis and therefore referred to it as
a psychotomimetic, a term used at the time to describe
another psychedelic, mescaline [120]. Others saw LSD as caus-
ing ‘an upsurge of unconscious material into consciousness’,
4 K. T. GREENWAY ET AL.
producing dream-like states that greatly interested psycho-
analysts [121]. Still others drew parallels between LSD and
delirium tremens, an often-terrifying altered state induced by
alcohol withdrawal [122].
In every case, psychedelics challenged the dominant psy-
chological conceptualizations of mental illness. The psychoto-
mimetic model, for example, conflicted with the view that
psychotic disorders like schizophrenia arose from ‘refrigerator
mothers’ [123]. Instead, researchers began to frame schizo-
phrenia in a more biological light, hypothesizing the etiology
to be pathological metabolism of endogenous molecules
resembling LSD or mescaline [124]. This hypothesis has since
been essentially discarded, but the shift toward a biological
perspective set the stage for the first commercial antipsycho-
tics in 1952 [32,125], which have since superseded psycho-
analytic approaches in the treatment of schizophrenia.
Similarly in the case of depression, LSD’s potency in combina-
tion with its structural similarity to the recently discovered
serotonin lead to the first proposal in 1954 that serotonin
might play a significant role in mental illness [33,126]. Thus
depression was also framed more biologically, a view that was
also consolidated by the appearance of a novel commercial
drug, imipramine, in 1959 and the propagation of the mono-
amine hypothesis discussed above [31].
Prior to the psychedelics, psychiatry had already seen other
efforts at integrating biological and psychological treatments.
For example, ‘narcoanlaysis’ referred to the practice of utilizing
barbiturates to facilitate psychoanalysis [127], and various
other agents were studied as adjuncts of psychotherapy,
such as nitrous oxide, ether, and carbon dioxide [128]. While
these agents rapidly fell out of fashion, research on psyche-
delics continued steadily. More than 1,000 scientific publica-
tions including 40,000 patients were published in this era
[129], and many mainstream figures described psychedelics
as offering new frontiers for psychiatry and neuroscience
[119]. However, until recently, psychiatry’s shift toward biome-
dical models and the political backlash against recreational
use led to this work being largely halted [62].
Before then, LSD inspired remarkably sophisticated reflec-
tion on the relationship between biology and psychology that
other psychoactive drugs did not, and even the earliest works
anticipated many later advances in the psychological under-
standing of conventional antidepressants [130]. For instance,
Sandison and colleagues described in 1954 how the drug
effects were highly influenced by the therapeutic relationship,
the environment, and the patient’s unique psychic structure
[131,132]. These reports and others stand in stark contrast to
more simplistic and reductionist explanatory models from the
same period.
4.2. Psychedelic pharmacology and phenomenology
LSD is a highly absorbable semi-synthetic tryptamine with
significant structural overlap with serotonin [33]. It has strong
affinity for a variety of receptors, binding potently to 5HT
2A
,
5HT
1A
, 5HT
2 C
, and various adrenergic and dopaminergic
receptors, amongst others [120]. Its pharmacology is complex
[33,120], but 5HT
2A
(partial) agonism is central to its effects, as
demonstrated by the nearly complete extinction of psycholo-
gical effects by 5HT
2A
antagonists like ketanserin [133,134].
A typical dose of 100–200 μg of LSD causes profound altera-
tions in cognition, sensory processing, and emotions [33],
usually lasting 8–12 hours and peaking around 2 hours post-
ingestion, roughly corresponding to maximal plasma
levels [120].
Other psychedelics like psilocybin/psilocin, dimethyltrypta-
mine (DMT), and mescaline are generally understood to differ
more pharmacokinetically than pharmacodynamically: agon-
ism of 5HT
2A
is the major feature shared by the family [33].
This commonality is remarkable given that the origins of
various psychedelics can be traced to pre-Columbian
Mesoamerican societies, North American native peoples, or
mid-20
th
century Switzerland [33]. Notable pharmacokinetic
differences include psilocybin’s shorter duration of effects (4–-
6 hours) compared to LSD [135], and the destruction of DMT
by liver monoamine oxidase enzymes, necessitating parenteral
administration (or smoking [136]) or simultaneous administra-
tion of monoamine oxidase inhibitors as are found in botanical
preparations such as ayahuasca [33]. One shared feature of
this class is a rapid buildup of tolerance and cross-tolerance,
often attributed to tachyphylaxis of 5HT
2A
receptors, after only
several consecutive days of dosing [33]. The molecules are
considered to be exceptionally safe when administered with
appropriate precautions though safety concerns include the
triggering of psychotic episodes and potentially lethal interac-
tions with other medications/substances [33,120,137].
The phenomenology of the profoundly altered state pro-
duced by 5HT
2A
agonism is multifaceted and heterogenous
between individuals and studies. Modern studies employing
psychometrically-valid questionnaires, like the Altered states
of Consciousness Scale and the Mystical Experience
Questionnaire [138,139], consistently find dramatic perceptual
changes like sensory distortions and synesthesia [133], feelings
of ego dissolution or oceanic boundlessness [140,141], and
mystical experiences that strongly resemble those arising
naturally [142]. Suggestibility is increased [143], and empatho-
genic effects on mood such as increased trust and openness
are common [144]. Emotional processing is altered, including
reduced recognition of facial expressions of fear [144], and
subjects may report facing challenging emotions and gaining
a newfound sense of resolution [145]. Meaning-making is
altered; e.g., music may evoke more wonder and transcen-
dence [146], and rapidly take on personal meaning [147].
Indeed, the experiences themselves are often described as
highly meaningful [135], even years later [148].
4.2.1. Psychedelics and neural networks
Various efforts aiming to explain these effects, or relating
them to known psychological concepts, focus on observed
changes in communication within and between neural net-
works. Psychedelics typically decrease the former and increase
the latter [120,149], resulting in novel pathways of neural
communication [120]. Emphasis is often placed on alterations
to the Default Mode Network (DMN), which is most active
when individuals are not focused on the immediate environ-
ment [150], but rather engaged in self-referential thought
[151], or mental time travel [152], for example. Its
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 5
disintegration may thus engender a more present-moment
state, as neuroimaging studies of meditators suggest [153].
Links have been made between the DMN and the Freudian
conception of ego given its role in one’s sense of self as well
as its suppressive effects on lower-level subcortical systems
[154]. Though such analogies are inherently imperfect, it has
been shown that the disintegration of the DMN correlates
with participant-reported ratings of ‘ego dissolution’ [140].
The disintegration of other networks, including the cortico-
striato-thalamo-cortical circuit of the salience network
[155,156], have also been hypothesized as important
mechanisms.
Other effects include decreased constraints on cognition
[149], which may account for their phenomenological descrip-
tion as amplifiers of mental processes [157]. Amongst the
changes within and between neural networks, reduced con-
textualization and filtering of sensorial information, and/or
increased communication involving visual/auditory systems,
may produce perceptual disturbances [158,159]. Several over-
arching models have been proposed, for instance describing
these states of less constrained cognition and perception as
‘high entropy’ [149], or as being liberated for bottom-up
information flow [158]. No consensus has yet been reached,
but psychedelic states continue to inspire significant funda-
mental and clinical interest [160].
4.3. MDMA pharmacology and phenomenology
MDMA, has a distinct pharmacological profile from psychede-
lics that induces alterations in normal consciousness consid-
ered by some to be ‘psychedelic’ [138]. MDMA reverses
monoamine re-uptake transporters to effectively increase pre-
synaptic concentrations of norepinephrine, dopamine, and
especially serotonin [161]. Subsequent release of hormones,
including oxytocin, prolactin, cortisol, and vasopressin, also
contribute to the subjective effects [141]. MDMA is known as
an empathogen or entactogen and a ‘heart opening’ sub-
stance [161], with effects typically lasting for 4 hours after
a standard dose of 75–125 mg. Visual hallucinations are not
common, but sensory and perceptual alterations do occur
[138]. MDMA acutely modulates emotional-memory circuits,
including decreasing activity in the amygdala and increasing
connectivity between the hippocampus and amygdala [162].
One of the results appears to be greater prosocial behavior
[163,164]. Before MDMA was classified as a schedule 1 con-
trolled substance in the United States in 1985 due to wide-
spread recreational use [165], it was employed in thousands of
therapy sessions [166]. These early therapists generally already
had experience working with psychedelics like LSD but found
the non-hallucinatory MDMA to be well-suited to particular
applications such as couple’s therapy.
4.4. Ketamine pharmacology and phenomenology
Ketamine’s history and pharmacology differ dramatically
from MDMA and LSD. It is primarily a N-methyl-D-aspartate
receptor (NMDA) antagonist that modulates glutamergic
transmission [167], though it is active at a large variety of
receptors [168]. It’s efficacy against depression is thought to
owe to enhanced neuroplasticity and reversal of stress-
induced neuronal changes [169,170]. Doses between 0.5
and 10.0 mg per kilogram of body weight can induce pro-
found alterations in consciousness characterized by signifi-
cantly decreased movement, bodily sensation, and
interactivity [138]. These properties led to the description
of ketamine as a ‘dissociative anesthetic’, a term coined by
the wife of one of the first pharmacologists to study keta-
mine, Edward Domino [171]. Domino and his colleagues had
initially settled on descriptions such as ‘dreaming’ for keta-
mine’s effects [171], similar to language employed for psy-
chedelics [133], and indeed the states induced by ketamine
overlap phenomenologically with those induced by MDMA
and especially psilocybin [138]. Comparable levels of experi-
ences of unity, spiritual experiences, insightfulness, visual
phenomena, and altered meaning are reported with all
three compounds.
Since its discovery in 1962 [171], ketamine found wide-
spread medical applications including anesthesia and pain
management [172], and thus was never listed as a Schedule
1 substance. Like the psychedelics, Ketamine has been
employed as a psychotomimetic, a use that lead Yale research-
ers to demonstrate in 2000 that a single subanesthetic dose
rapidly improved depressive symptoms within minutes or
hours [173]. Since then, ketamine has been increasingly
employed as a treatment of refractory unipolar and bipolar
depression [174], amongst psychiatric conditions including
anxiety disorders and PTSD [175,176]. Ketamine (and esketa-
mine) is generally employed much like conventional antide-
pressants [177], typically administered by repeated 40-minute
IV 0.5 mg/kg infusions twice to thrice weekly [178], for months
or years [179]. In contrast, ketamine’s first use in psychiatry
resembled psychedelic-assisted psychotherapy in that intense
experiences were intentionally engendered by relatively high
doses, within a psychotherapeutic frame [180]. Ketamine is
thus unique in that it has been – and continues to be – utilized
within both psychedelic and more conventional paradigms
[174,181].
5. Psychedelic-assisted psychotherapy
Soon after its discovery, LSD attracted the attention of psycho-
analysts who were deeply interested in internal mental pro-
cesses and concepts like ego [132]. Bringing unconscious
material into conscious awareness such that it may be ‘worked
through’ is a fundamental aim of insight-oriented psy-
chotherapies, and LSD thus found early uses as
a psychoanalysis catalyst [131,182]. From there, the approach
of PAP evolved beyond its psychoanalytic origins. As early as
1959, an increased emphasis was placed on patient autonomy,
with therapists taking less active roles in the therapeutic
process [130]. The common experiences of ego-death and
feelings of transcendence were explained with concepts
from thinkers like Jung, Maslow and others [130,183].
Contributing to the development of movements like transper-
sonal psychology [184], spirituality was often embraced rather
than seen as a regressive defense as Freud had [185]. The
effects of music within psychotherapy were discovered, and
music became an important component of the therapeutic
6 K. T. GREENWAY ET AL.
approach [130,186]. A different treatment rhythm from stan-
dard psychotherapy emerged, partly due to drug effects per-
sisting for 4–12 hours and tachyphylaxis complicating repeat
dosing [33]. Over time, principals that are relatively common
to modern psychedelic protocols were established.
5.1. Modern protocols
One of the most referenced clinical approaches is that of
Stanislav Grof, and his classic 1980 book LSD Psychotherapy
[157]. He worked extensively with LSD, supervising over 4500
LSD research sessions during the 1950–1960s [157]. Although
his book is not the first or only of its kind, it has been cited in
nearly all modern PAP studies including those employing
psilocybin, ketamine, and MDMA [187–189]. For example, the
MDMA Treatment Manual used in clinical trials investigating
MDMA-assisted psychotherapy for treatment of PTSD largely
draws from Grof’s work [188], and other early psychedelic
researchers. The most common tenets and their evolution
will thus be explored.
This protocol centers on carefully engendering powerful
non-ordinary states of consciousness, which are described in
terms such as peak experiences or mystical experiences
[135,190]. Efforts are then made to ‘integrate’ these unusual
experiences into long-term gains. This conceptualization dif-
fers significantly from both conventional pharmacological and
psychotherapeutic approaches. The former involves regularly
administering drugs to control symptoms and/or correct
pathological neurobiological states, while the latter aims to
create change via years or months of corrective experiences
[157]. The PAP protocol consists of three phases: preparation,
treatment, and integration. These roughly align with the con-
textual model’s primary mechanisms of action: establishing
a therapeutic relationship, creating expectations of healing,
and enacting health-promoting activities [84,85].
In the preparation phase, patients are assessed for their
appropriateness for the treatment, including readiness for
potentially intense and challenging experiences. The most
emphasized potential risks are psychiatric including histories
of psychosis or bipolarity [137], or immature psychological
defenses such as those found in borderline personality disor-
der [191]. Potentially dangerous interactions with medications
like antidepressants are identified, and medication adjust-
ments are made as needed to avoid unwanted interactions
such as serotonin syndrome [137]. Forming a therapeutic rela-
tionship, including discussing biographic, medical, personal,
and spiritual histories, is critical in increasing trust and thereby
reducing potential for anxiety or so-called ‘bad-trips’ [137]. In
addition to providing education regarding the specific com-
pound’s psychoactive effects, patients are typically encour-
aged to engage in intention setting [192]. By forming an
explicit rationale for the need and hopes for the treatment
[193], which may also be described as creating the therapeutic
myth or adopting an explanatory framework, patients begin to
set expectations around the experience and outcomes. As
discussed above, this is a critical component for healing in
essentially all psychiatric interventions and is especially so
with psychedelics, ‘amplifiers of mental processes’ [157],
given the increased suggestibility and acutely heightened
environmental sensitivity [130,143,183]. Finally, patients are
typically prepared with ‘flight instructions’ that can be traced
back to 1950s [130], including directions to ‘mentally surren-
der to the experience’ [137], or to ‘trust, let go, be open’ [194].
Experience has shown that cultivating such a mind-set reduces
anxiety and increases the probability of working through
challenging experiences to perhaps achieve therapeutic ‘emo-
tional breakthroughs’ [145,194]. These directions, rare excep-
tions to the typical stance of therapeutic non-directiveness
[20], are given in the spirit of allowing individualized experi-
ences to unfold.
The second phase is the actual treatment sessions of drug
administration, typically lasting 8–12 hours for LSD, and
4–6 hours for psilocybin and MDMA [157]. Treatments typically
involve two therapists or monitors to increase the safety of
patients in vulnerable states, and to permit brief breaks during
long sessions [137]. Theoretically, having both female and
male therapists or monitors present may better evoke diverse
expressions of unconscious patterns of interpersonal relation-
ships in a psychological process known as ‘transference’ [157].
The therapists/monitors are often referred to as guides as
a reflection of the desired stance of non-directiveness [137].
This is often explained with reference to Grof’s concept of the
inner healing intelligence [157], though similar ideas can be
found in very early works [130], which postulates that humans
heal psychologically much as they do physically: via innate
capacities that can be enhanced but not replaced by external
interventions. This framing differs significantly from conven-
tional pharmacotherapy’s emphasis on postulated neurotrans-
mitter pathology, and the emphases found in conventional
psychotherapy models, (e.g. dysfunctional thinking patterns in
CBT and unconscious psychic conflicts in psychoanalysis-
inspired approaches [94,95]), which require more active and/
or authoritative therapeutic stances. The emphasis on patient
autonomy and internal strengths may have partly arisen as
a necessary measure to avoid excessive influence of psy-
chotherapists given the increased suggestibility associated
with psychedelics [143]. However, the hypothesis that
a significant portion of psychiatric treatment efficacy arises
from patients’ innate capacities, independent of treatment-
specific aspects, is supported by the power of the common
factors in both pharmacotherapy and psychotherapy.
5.2. Set and setting
Sociological research on psychedelic use in populations ran-
ging from modern recreational users to traditional indigen-
ous communities suggests a near universal emphasis on the
importance of ‘set and setting’ [195]. This refers to the
patient’s mind-set and the treatment environment, respec-
tively, and is an important concept in clinical studies of
psychedelics for both safety and efficacy [137]. Set and set-
ting might otherwise be described as a patient’s immediate
internal and external environment, and even the earliest
studies recognized that psychedelics tend to amplify
thoughts and feelings about both [130,131]. The former is
optimized during the preparation phase, especially by estab-
lishing a strong therapeutic alliance and an intention for
healing [183,192]. The latter is typically optimized by
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 7
providing a less sterile and more aesthetically pleasing treat-
ment environment, often described as living room-like [137].
The much higher rates of anxiety and negative emotions that
were seen in early psychotomimetic psychedelic studies
attest to the importance of set and setting [196,197].
Influential psychotherapists like Donald Winnicot evoked
similar concepts, such as the creation of therapeutic ‘holding
environments’ [198], and evidence is mounting that even
aesthetic improvements to medical settings can improve
diverse patient outcomes [199–201].
5.3. Music
Music therapy is an effective treatment of mood disorders
[202,203], and music forms a core component of PAP in
a unique way, non-verbally supporting and enhancing patient
experiences [204]. Patients typically spend time during the
treatment sessions lying comfortably, wearing blindfolds, and
listening to music via headphones with minimal interaction
with therapists [137]. Qualitative and quantitative studies have
shown an important multidirectional relationships between
music and emotions, mental images, and association of mean-
ing [140,146,197,205]. Three music-specific variables have
been proposed to mediate therapeutic response to psilocybin:
appreciation versus rejection of its style and quality, corre-
spondence versus dissonance to the current emotional state,
and music-evoked openness versus resistance [206]. In some
ways, the presence of music can conflict with the desired non-
directive therapeutic stance as its qualities can induce specific
emotional and psychological states [206]. This can enhance
the holding environment or evoke intense resistance – much
like other directive therapeutic interventions. Resistance is
mitigated by the encouragement to approach negative reac-
tions to specific music with openness and acceptance, and
music is also frequently adapted by therapists during treat-
ment [206].
5.4. Integration
Finally, following treatment, several non-drug sessions of
‘integration’ take place [137,157], usually within a day of the
first treatment and lasting for up to several hours [187]. These
sessions often incorporate elements from various schools of
psychotherapy including CBT, psychodynamics [130], and
existential meaning-making therapies [187], amongst others.
Aspects more unique to PAP include generally encouraging
patients to write down detailed accounts of their (often
intense) experience to facilitate working through [183,187].
As with treatment sessions, therapists are encouraged to
allow for a patient’s own experience and meaning-making
to unfold as it will, without undue influence [130,188].
Patients are typically encouraged to engage in various health-
promoting activities, one of the major common factors of
psychotherapy [84]. Such behavioral interventions likely con-
tribute significantly to the long-lasting benefits obtained with
PAP, evidenced by the magnitude of therapeutic change seen
in therapies that consist entirely of behavioral activa-
tion [207].
6. Modern research, safety and addiction
6.1. Psychedelics
Aside from a few affinities of unknown clinical significance,
including 5HT
1A
or D
2
receptors, psilocybin is remarkably
pharmacologically similar to LSD, and thus it is generally
employed with similar methods [33,120]. One significant dif-
ference is its shorter half-life, which is one of the major rea-
sons that psilocybin is more widely utilized in modern
research than LSD, in that treatment sessions can be con-
ducted with 6-hours of therapist time versus approximately
12 [157,187]. The other major advantage of psilocybin is that it
is generally associated with less public stigma than LSD
[137,187]. Since the first modern study of psilocybin-assisted
psychotherapy in 2006 for OCD [208], promising results have
been published for applications in end of life anxiety
[148,187,209], smoking cessation [210], treatment-resistant
depression [211], as well as to initiate meditation/spiritual
practices [212]. Remarkable hallmarks of these studies include
rapid and large effect sizes, that have persisted during follow-
up periods ranging from 6-months to nearly 5 years. Lasting
effects extend beyond reduced symptomatology include
increased spirituality [212], increased nature-relatedness
[213], and enhanced personality measures of extraversion of
openness [214]. Of note, the patients enrolled in these studies
had often failed to respond to multiple existing psychother-
apeutic and pharmacologic treatments. These results have led
to two pharmaceutical sponsors, Usona Institute and
COMPASS Pathways, receiving FDA Breakthrough Therapy
designation and the go-ahead to proceed to phase 3 trials
for investigating psilocybin as a treatment for major depres-
sive disorder and treatment-resistant depression [12,13].
Modern research on both recreational users and healthy
controls provides additional evidence for the potential bene-
fits of psychedelics, possibly even without concurrent psy-
chotherapy [215,216]. For example, a prospective survey of
654 people who used psychedelics found significant improve-
ments in a measure of psychological well-being [216]. These
benefits were moderated by the traits of the individuals sur-
veyed as well as their attention to set and setting, supporting
the importance of this tenet of PAP. Retrospective surveys
have further shown a correlation between recreational psy-
chedelic use and less criminal recidivism (in contrast to all
other drugs [217]) and less intimate partner violence
[218,219]. Though these studies are unable to prove causality,
controlled studies of psilocybin administered without psy-
chotherapy have also found benefits to mood and well-
being [215]. These findings attest to the general safety of the
psychedelics, and indeed the rate of adverse events in PAP
studies is comparable to standard psychotherapy [220].
Nevertheless, there have been reports of injuries and deaths
resulting from recreational use of psychedelics, which typically
occurred in the setting of ingesting multiple substances and/
or dangerously uncontrolled environments [137]. These risks
appear to be substantially greater in relatively novel psyche-
delic analogs [221].
Overall, LSD and psilocybin appear to be amongst the least
dangerous drugs in recreational users, even in comparison to
8 K. T. GREENWAY ET AL.
those with well-established medical uses like benzodiazepines,
in terms of both harm to users and harms to others [222]. The
potential for addiction is considered to be especially low [33].
This may be in part due to tachyphylaxis of 5HT
2A
receptors,
though more psychological mechanisms may also be at play.
Indeed, some studies have found that recreational use of
psychedelics is associated with less abuse of other substances
[217], and psilocybin and LSD have been employed with
success as a treatment of alcohol and nicotine addictions
[210,223].
6.2. MDMA
Since 2000, MDMA-assisted psychotherapy has been under inves-
tigation as a treatment for chronic treatment-resistant PTSD. Six
phase 2 trials were sponsored by the Multidisciplinary Association
for Psychedelic Studies (MAPS) from 2004–2016, with results indi-
cating substantial improvements in PTSD symptoms and ade-
quate tolerability to the treatment protocol [224]. During MDMA
sessions, participants can more readily process traumatic mem-
ories and engage with the associated challenging emotions, due
to their ‘window of tolerance’ being increased [225]. Greater
introspection, enhanced compassion for oneself and others, and
a larger capacity to feel and talk about traumatic memories have
all been proposed as key psychological mechanisms induced by
MDMA in a therapeutic context [225]. As with classic psychedelics,
integrative non-drug therapy sessions are essential for contextua-
lizing the experience and applying insights to everyday life. Long-
term (12 or more months) reductions in PTSD symptoms and
other positive outcomes have been observed following treatment
[226]. After reviewing data from these trials, the FDA granted
a Breakthrough Therapy designation in 2017, and the first of two
phase 3 trials commenced in November 2018 [14]. An Expanded
Access program for 50 patients with PTSD to undergo MDMA-
assisted psychotherapy will start later in 2020. In addition, MDMA-
assisted psychotherapy has been explored for use in other indica-
tions, including social anxiety in autistic adults and anxiety related
to life-threatening illness [227], and current or planned trials will
evaluate its use for alcohol use disorders and eating disorders.
MDMA is considered to have a moderate abuse liability
amongst recreational users [222]. In research trials conducted in
controlled clinical settings, there have been no reports of drug
craving or substance use disorders (SUDs) arising after treatment
[224]. Therefore, the potential for problematic use is considered
low when administered under supervision with concurrent edu-
cation about risks of ‘Ecstasy’ use in non-medical contexts.
6.3. Ketamine
Ketamine is generally employed without application of the
tenets of PAP, such as concurrent psychotherapy or the opti-
mization of set and setting [179]. The altered states it engen-
ders are typically framed for both clinicians and patients as
side-effects to be mitigated [228]. However, ketamine has also
been employed in a PAP-like model to facilitate therapeutic
changes. Indeed, ketamine-assisted psychotherapy has been
successfully used in the treatment of depression/anxiety [181],
PTSD [229], as well as alcohol [230], heroin [231], and cocaine
addiction [232]. These latter results are somewhat surprising
given that ketamine is a substance of abuse [222], with sig-
nificantly more harm and potential for physiological depen-
dence than the psychedelics [233]. Pharmacological
explanations may partly underly these results [234], but can-
not fully explain how ketamine exerts anti-addiction effects
against multiple substances of abuse. Rather, evidence sug-
gest that the experiences induced by ketamine – much like
the psychedelics – within a psychotherapeutic frame least
partially mediate its efficacy against addiction [235].
Psychedelic-like experiences may also partially underly keta-
mine’s antidepressant effects even when employed in purely
biomedical contexts [236–238].
7. Expert opinion
Psychiatry has evolved considerably over the preceding dec-
ades from primarily biological or psychological models of dis-
ease to more nuanced, integrative frameworks. We have
discussed several key examples, such as how the contextual
model of psychotherapy applies to antidepressants and how
psychotherapy acts biologically. Combinations of psychother-
apy with antidepressants, psychedelics, MDMA, and ketamine
are even more complex, involving bidirectional and potentially
synergistic interactions. These combinations share much; the
contextual model’s three central common factors correspond
well to longstanding PAP approaches, and enhanced environ-
mental sensitivity may underly many diverse combinations.
This increased environmental sensitivity is much more
acute in PAP, giving rise to dramatically altered states that
may result in ‘therapeutic breakthroughs’ or ‘bad-trips’,
thereby presenting both significant opportunities and chal-
lenges. Emerging evidence suggests that PAP can engender
powerful and persistent benefits in highly refractory patients.
These can appear ‘ultra-rapidly’, thereby significantly reducing
the duration of suffering for responders. Likewise, non-
responders can pursue alternative treatments without requir-
ing weeks or months of medication/psychotherapy to evaluate
response. Remitters may thereafter require fewer daily medi-
cations, thereby reducing risks associated with side-effects and
drug-drug interactions. Fewer psychotropic medications may
also yield clearer clinical pictures that are less obfuscated by
uncertainty around compliance and discontinuation symp-
toms. Lastly, amongst psychiatry’s wide variety of ‘therapeutic
myths’, PAP’s explanatory frameworks that highlight patients’
inner healing capacities may increase feelings of autonomy
relative to frameworks that instead emphasize neuropatholo-
gical states.
Challenges include carefully selecting and preparing
patients, who may require medication adjustment or discon-
tinuation – associated with risks including suicide [59] – so as
to avoid potential interactions such as serotonin syndrome
[137]. Altered states require meticulous attention to set and
setting, as well as patient safety, and it is not clear if the high
standards of clinical trials will translate to the clinic.
Therapist-specific factors are known to be an important mod-
erator of clinical results, and current research has largely
been performed by experienced and highly motivated thera-
pists [85,97]. Rightfully or wrongfully, PAP is likely to be
viewed as excessively resource-intensive much like
EXPERT REVIEW OF CLINICAL PHARMACOLOGY 9
conventional psychotherapy. Dissemination of PAP will
require overcoming stigma and making significant changes
to biomedical models, in both conceptual and practical ways.
Accommodating psychotherapy sessions that last for multi-
ple hours, for example, would require different ways of orga-
nizing healthcare.
Whether or not psychedelic treatments become mainstream
remains to be seen. However, the scale of unmet needs in
psychiatry in conjunction with highly promising results, major
ongoing trials, and the FDA’s recent support, suggest that PAP
will find clinical niches. Despite its novelty, the underlying
approach of PAP has much in common with current psychiatric
treatments, and current psychiatric treatments could be
enriched through considering some of its key tenets. For exam-
ple, a clear emphasis on optimizing intentions and expectations
of healing could benefit all existing treatments.
Significant further research will be required to move PAP
into mainstream clinics and hospitals. The various
approaches utilized to date need to be actively compared
with a wider variety of treatments, and may benefit from
utilization of more conventional psychotherapies like CBT.
Medication protocols need to be optimized in terms of dose,
numbers of sessions, and follow-up or maintenance proto-
cols. The key mechanisms of psychotherapeutic change
should be characterized and optimized, potentially by com-
ponent analysis, for specific molecules and certain clinical
populations. Such studies should be demographically
diverse and include [239], but not be limited to, treatment-
resistant subpopulations. Much work also remains to be
done to better understand the neurological mechanisms of
psychedelics, MDMA, and ketamine. Finally, long-term stu-
dies will be necessary to demonstrate that the benefits
obtained from PAP can indeed be maintained, with or with-
out repeat treatments, for various conditions.
Funding
This paper was not funded
Declaration of interest
L. Jerome is an employee of the Multidisciplinary Association for
Psychedelics Studies (MAPS) Public Benefit Corporation, as was A. Feduccia
during the preparation of the manuscript. A. Feduccia is an owner and
employee of Psychedelic.Support and consultant for Project New Day,
a 501(c)(3) not-for-profit organization. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
Reviewers disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
ORCID
Kyle T. Greenway http://orcid.org/0000-0002-7829-493X
Nicolas Garel http://orcid.org/0000-0002-4031-9943
Lisa Jerome http://orcid.org/0000-0001-6209-8750
Allison A. Feduccia http://orcid.org/0000-0002-6918-0738
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