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Frontiers in Psychology | www.frontiersin.org 1 March 2022 | Volume 13 | Article 868103
HYPOTHESIS AND THEORY
published: 25 March 2022
doi: 10.3389/fpsyg.2022.868103
Edited by:
Maria Beckman,
Karolinska Institutet (KI), Sweden
Reviewed by:
Ämma Tangen,
Karolinska Institutet (KI), Sweden
Hugo Bottemanne,
INSERM U1127 Institut du Cerveau
et de la Moelle épinière (ICM), France
*Correspondence:
David S. Mathai
pmathai1@jhu.edu
Specialty section:
This article was submitted to
Psychology for Clinical Settings,
a section of the journal
Frontiers in Psychology
Received: 02 February 2022
Accepted: 25 February 2022
Published: 25 March 2022
Citation:
Mathai DS, Mora V and
Garcia-Romeu A (2022) Toward
Synergies of Ketamine
and Psychotherapy.
Front. Psychol. 13:868103.
doi: 10.3389/fpsyg.2022.868103
Toward Synergies of Ketamine and
Psychotherapy
DavidS.Mathai
1*, VictoriaMora
2 and AlbertGarcia-Romeu
1
1 Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United
States, 2 School of Health Professions, Baylor College of Medicine, Houston, TX, United States
Ketamine is a dissociative drug that has been used medically since the 1970s primarily
as an anesthetic agent but also for various psychiatric applications. Anecdotal reports
and clinical research suggest substantial potential for ketamine as a treatment in conjunction
with psychological interventions. Here, wereview historical and modern approaches to
the use of ketamine with psychotherapy, discuss the clinical relevance of ketamine’s acute
psychoactive effects, propose a unique model for using esketamine (one isomeric form
of ketamine) with Acceptance and Commitment Therapy (ACT), and suggest considerations
for moving medication-assisted psychotherapy forward as a eld.
Keywords: ketamine, esketamine, therapy, psychotherapy, psychedelic, dissociation, ACT
INTRODUCTION
Ketamine emerged from the study of phencyclidine (PCP) derivatives suitable for anesthetic
use in humans, and its discovery in 1962 is attributed to Parke-Davis Labs and Dr. Calvin
Lee Stevens, a professor of organic chemistry at Wayne State University (Domino et al., 1965).
Early clinicians recognized ketamine’s dreamlike and hallucinogenic properties, experienced by
patients as feeling “disconnected” from their environment, and leading to its classication as
a “dissociative anesthetic” (Domino et al., 1965; Reier, 1971). e subjective eects associated
with ketamine were observed to be “pleasant” (Domino et al., 1965), and investigators soon
began to consider its broader value as an antidepressant and psychotherapeutic agent (Yensen,
1973; Fontana and Loschi, 1974; Soa and Harakal, 1975). e drug has since been explored
for a growing number of psychiatric applications both as a standalone medication and in
combination with supportive interventions.
A compelling and transdiagnostic body of clinical research has emphasized the use of
ketamine in combination with psychotherapy for mental health conditions. While psychotherapy
is not easily dened, it has been reasonably described as an interpersonal intervention that
relies on repeated encounters, a healing relationship, and a particular explanatory model, all
within a structured therapeutic frame (Greenway etal., 2020). Psychotherapy may besimplied
even further, to denote any “communication between patients and therapists that is intended
to help people (American Psychological Association, 2017).” ese denitions will be used
hereaer to discuss a range of psychotherapeutic modalities involving ketamine administration.
e idea of harnessing psychotherapy with pharmacotherapy has been considered before.
e additive and synergistic eects of combining conventional antidepressants and psychotherapy,
for example, are well-established (Cuijpers et al., 2014; Dunlop, 2016). Some precedent even
exists for the approval of drug-therapy combinations by regulatory bodies such as the U.S. Food
and Drug Administration [FDA; 21 CFR 201.57 (c)(2)(i)(A), 2022]. Medications such as
Frontiers in Psychology | www.frontiersin.org 2 March 2022 | Volume 13 | Article 868103
Mathai et al. Ketamine and Psychotherapy
naltrexone extended-release injectable suspension for alcohol
and opioid dependence, bupropion hydrochloride extended-
release for smoking cessation, and buprenorphine sublingual
tablets for opioid dependence are all labeled for use in conjunction
with therapy. is is also expected to be the case if psilocybin
and MDMA are approved as psychiatric treatments for major
depression and post-traumatic stress disorder (PTSD), respectively
(Yazar-Klosinski and Mithoefer, 2017; Johnson et al., 2018).
Combination strategies serve a variety of purposes, driven
largely by the limitations of single-modality interventions. ese
strategies serve to address treatment non-response, residual
symptoms, and relapse and recurrence involving psychiatric
illness (Dunlop, 2016). Others have further emphasized that
approaches to pharmacotherapy that include psychotherapy
have the potential to improve psychological exibility, quality
of life, and overall functioning, beyond symptom reduction,
in ways that are valuable to patients (Kamenov et al., 2017;
Watts and Luoma, 2020). Integrated approaches may also
promote drug safety and tolerability. For instance, a therapy-
oriented approach to psilocybin administration in research
settings is thought to mitigate the psychological risks that are
possible with treatment (Johnson et al., 2008). e use of
psychotherapy with ketamine could similarly address treatment
risks, for example, by allowing for drug-sparing treatment
paradigms that are of public interest and decrease the likelihood
of tachyphylaxis (Mathai et al., 2020, 2021).
What is perhaps most unique to the use of ketamine as a
therapeutic adjunct is its status as a highly psychoactive,
medically legal, and reliably perplexing agent. Here, wereview
historical and modern approaches to the use of ketamine with
psychotherapy, discuss the clinical relevance of ketamine’s acute
psychoactive eects, propose a unique model for working with
esketamine (the S-enantiomer of ketamine), and make suggestions
for moving forward as a eld. We emphasize a conceptual
understanding of ketamine and psychotherapy, rather than the
specic parameters of treatment administration.
A BRIEF HISTORY
e rst known uses of ketamine as a therapeutic adjunct
date back to the early 1970s, soon aer its approval as an
anesthetic agent. In Mexico, the psychiatrist Salvador Roquet
discovered that subanesthetic doses of the drug occasioned
mental states that could be combined with psychoanalytical
techniques and indigenous healing practices in an approach
hecalled “psychosynthesis” (Yensen, 1973; Wolfson, 2014). His
pioneering and controversial work incorporated the use of
multiple psychedelic substances and “sensory overload” in group
treatment settings with the goal of producing, and then
processing, extreme psychological experiences. rough this
method, Roquet believed that patients could confront existing
psychological conicts and achieve emotional catharsis.
Around the same time, physicians in Southern Iran were
exploring similar qualities of ketamine in the individual treatment
of hospitalized psychiatric patients (Khorramzadeh and Lotfy,
1973). Enayat Khorramzadeh and Atta Ollah Loy observed
that ketamine facilitated patients’ ability to engage in an
“abreactive” psychotherapy process involving the recollection
and processing of traumatic memories, which was ultimately
associated with enduring relief of depression, anxiety, and other
psychiatric symptoms (see Table 1 for characteristics of this
and other research trials involving ketamine and psychotherapy).
ey later conducted a follow-up study examining how
dimensions of personality contributed to the psychoactive eects
of ketamine and found that elements of “extraversion,”
“neuroticism,” and “psychoticism” could reliably predict drug
experiences, suggesting the importance of nonpharmacological
factors in treatment (Khorramzadeh and Lotfy, 1976).
Several other signicant explorations of ketamine as a
therapeutic agent occurred through the 1970s and 1980s (Lilly,
1972, 1978; Fontana and Loschi, 1974; Sappington etal., 1979;
Grof, 1980; Golechha et al., 1985), though the single most
comprehensive body of clinical research in this area can
becredited to the Russian physician, Evgeny Krupitsky. Krupitsky
rst used ketamine in a form of behavioral psychotherapy in
the former Soviet Union in 1985 (Kolp et al., 2014). In his
earliest studies, ketamine was combined with other agents to
induce unpleasant psychedelic experiences that were associatively
linked with alcohol toward the goal of decreasing alcohol use
(Krupitsky etal., 1992; Sivolap and Savchenkov, 1994). Krupitsky
eventually realized that patients beneted similarly from positive,
transcendent experiences while on ketamine and shied from
a model of aversive conditioning to one informed by existential
and transpersonal psychology. is model has been described
as Ketamine Psychedelic Psychotherapy (KPP) or Ketamine
Psychedelic erapy (KPT), and was used successfully in the
treatment of alcohol and opioid use disorders (Krupitsky and
Grinenko, 1997; Krupitsky et al., 2002, 2007). Moreover, these
studies indicated that ketamine could be combined with
psychotherapeutic interventions to produce meaningful and
enduring changes in psychological attitudes, concepts of self,
and overall functioning. Krupitsky’s research was ultimately
shuttered by the rescheduling of ketamine in Russia amidst
growing concerns around its recreational use (Kolp etal., 2014).
MODERN APPROACHES
Widespread psychiatric interest in ketamine accelerated with
positive ndings from the rst randomized controlled trial
(RCT; Berman et al., 2000) and a larger replication study
(Zarate et al., 2006) of ketamine as a standalone treatment
for depression. ese and most subsequent academic
investigations have assumed a “biochemical paradigm” (Bennett,
2019), wherein the therapeutic benets of ketamine are attributed
to a pharmacologic eect independent of perceived psychoactivity
or supporting interventions. is paradigm is, for example,
evident in current FDA-approved uses of esketamine as an
antidepressive and antisuicidal agent (McIntyre et al., 2021).
However, in the mid-2000s, it became apparent that some
community practitioners were continuing to work with ketamine
as had been done historically, using it as a tool to facilitate
psychological exploration and healing (Kolp etal., 2006, 2007;
Mathai et al. Ketamine and Psychotherapy
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TABLE1 | Characteristics of studies reviewed using ketamine and psychotherapy.
Study N Design Treatment
population
Drug parameters Psychotherapy parameters
Adams etal. (2017) 1Case study Refractory
obsessive
compulsive
disorder
50 mg IN ketamine; twice weekly for
4 weeks
16-week program of inpatient/outpatient ERP; for
inpatient weeks 3–6, therapy was accompanied by
twice-weekly administration of ketamine; unclear timing
of therapy relative to ketamine administrations
Azhari etal. (2021) 8Uncontrolled
trial
Cannabis
use disorder
1–2 IV ketamine infusions over 4 weeks;
Infusion 1: (0.71 mg/kg over 52 min) on
week 2; Infusion 2 (non-responders):
(1.41 mg/kg over 92 min) on week 4
6-week program of MET and MBRP with therapy
occurring outside of ketamine administrations (i.e., MET
therapy on the day before the infusion and the afternoon
of the infusion)
Dakwar etal. (2019) 55 Randomized
controlled trial
Cocaine use
disorder
Treatment group: Single IV ketamine
infusion (0.5 mg/kg over 40 min); Control
group: Single IV midazolam infusion
(0.025 mg/kg over 40 min); infusions on
day 2
5-week inpatient/outpatient program of MBRP; 1 MBPR
session daily during rst 5 days; followed by 8 sessions
of MBRP outpatient (twice-weekly for 4 weeks); Patients
received IV infusion on day 2 of inpatient stay; therapy
occurred outside of ketamine/ midazolam administration
(i.e., MBRP2 h post-infusion)
Dakwar etal. (2020) 40 Randomized
controlled trial
Alcohol use
disorder
Treatment group: Single IV ketamine
infusion (0.71 mg/kg over 52 min); Control
group: Single IV midazolam infusion
(0.025 mg/kg over 52 min); infusions on
week 2
5-week outpatient program of MET; 6 sessions of MET
over 5 weeks (1 session/ week); therapy occurred
outside of ketamine/ midazolam administration (i.e.,
MET session provided 24 h after infusion)
Dames etal. (2022) 94 Observational
study
Mixed 3 sessions of PO or IM ketamine (during
weeks 4, 5, and 7): either PO or IM
ketamine for session 1 (dose unspecied);
IM ketamine (1–1.5 mg/kg) for sessions 2
and 3
12-week treatment program including group meetings
and KaT with model of preparation, dosing, and
integration; therapy occurred outside of ketamine
administration (i.e., “initial sharing” began after 90 min,
and post-KaT group integration sessions occurred
within 36 h)
Dore etal. (2019) 235 Observational
study
Mixed SL, IM, (or both) ketamine; Average dose
range was 200–250 mg SL, and 80–
90 mg IM
Outpatient KAP with sessions typically 2 weeks apart, or
more frequently depending on acuity; number of sessions
ranged from 1–25, which were spread over variable time
periods from initial session, to visit evaluation, to
termination where applicable; therapy occurred before,
during and after ketamine administrations
Grabski etal. (2022) 96 Randomized
controlled trial
Alcohol use
disorder
Treatment group: 3 weekly IV ketamine
infusions (0.8 mg/kg over 40 min); Control
group: 3 saline infusions; Infusions
occurred at visits 2, 4, and 6 spaced
1–3 weeks apart
Treatment group: 7 sessions of MBRP; Control group: 7
sessions of AE; therapy began at visit 2 and continued
for the subsequent six visits; therapy occurred outside
of ketamine administration (i.e., infusion was always
preceded by MBRP or AE and followed by another
session about 24 h later)
Halstead etal. (2021) 1 Case study Persistent
depressive
disorder and
treatment-
resistant
post-
traumatic
stress
disorder
SL ketamine (150 mg); 4 administrations
over 13 days
13-day intensive outpatient therapy program consisting
of MBCT and FAP; therapy occurred before, during and
after ketamine administrations
Khorramzadeh and Lofty
(1973)
100 Non-
randomized
controlled trial
Mixed IV ketamine infusions in 3 dose ranges:
(1) 0.2–0.3 mg/kg; (2) 0.4–0.6 mg/kg; (3)
0.7–1.0 mg/kg; unknown duration of
infusion
“Abreactive” psychotherapy during drug administration
Krupitsky etal. (1992) 186 Randomized
controlled trial
Alcohol use
disorder
Treatment group: Single co-administration
of aethimizol (1.5% 3 ml, IM), bemegride
(0.5% 10 ml IV), and ketamine (3 mg/kg,
IM); Control group: Conventional aversive
therapy without ketamine administration
ACA method of alcoholism treatment with therapy
occurring before, during, and after ketamine
administration
(Continued)
Mathai et al. Ketamine and Psychotherapy
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Study N Design Treatment
population
Drug parameters Psychotherapy parameters
Krupitsky and Grinenko
(1997)
111 Non-
randomized
controlled trial
Alcohol use
disorder
Treatment group: Single co-administration
of aethimizol (1.5% 3 ml, IM), bemegride
(0.5% 10 ml, IV), and ketamine (2.5 mg/kg
IM); Control group: Conventional therapy
for alcoholism without ketamine
KPT method of treatment with therapy occurring before,
during, and after ketamine administration
Krupitsky etal. (2002) 70 Randomized
controlled trial
Heroin use
disorder
Treatment group: Single IM ketamine
injection (2 mg/kg: hallucinogenic dose);
Control group: Single IM ketamine
injection (0.2 mg/kg: non-hallucinogenic
dose)
KPT method of treatment with therapy occurring before,
during, and after ketamine administration
Krupitsky etal. (2007) 59 Randomized
controlled trial
Heroin use
disorder
Treatment group: 3 IM ketamine injections
(2 mg/kg); 1-month intervals between
doses; Control group: Single IM ketamine
injection (2 mg/kg)
Addiction counseling and KPT method of treatment with
therapy occurring before, during, and after ketamine
administration
Ocker etal. (2020) 1 Case study Opioid
medication
dependence
with opioid-
induced
hyperalgesia
5-day (inpatient) continuous IV infusion of
ketamine in combination with a
multimodal analgesia regimen; ketamine
dose titrated throughout admission (0.09–
0.59 mg/kg/h)
Outpatient CBT every 3–4 weeks after initial period of
ketamine administration
Pradhan etal. (2018) 20 Randomized
controlled trial
Treatment-
refractory
post-
traumatic
stress
disorder
Treatment group: Single IV infusion of
ketamine (0.5 mg/kg over 40 min); Control
group: Single IV infusion of normal saline
over 40 min
12 sessions of TIMBER; therapy occurred during and
then after single ketamine administration
Ragnhildstveit etal. (2021) 1 Case study Treatment-
resistant
bulimia
nervosa
18 IV ketamine infusions (0.5 mg/kg IV
over 40 min) over 3-month period
18 sessions of guided psychotherapy during ketamine
administrations and preceded by 30 min of preparatory
psychotherapy
Rodriguez etal. (2016) 10 Uncontrolled
trial
Obsessive
compulsive
disorder
Single IV infusion of ketamine (0.5 mg/kg
over 40 min)
10 sessions of ERP over 2-week period; therapy
occurred outside of ketamine administration (i.e., after
completion of single ketamine administration)
Sappington etal. (1979) 21 Randomized
controlled trial
Healthy
volunteers
Treatment group: IV ketamine infusion
(0.1 mg/lb); Control groups: No ketamine
“Induced-anxiety” therapy focused on induction of
negative affect prior to drug administrations, drug-
induced relaxation, and processing with therapist
Shiroma etal. (2020) 12 Uncontrolled
trial
Chronic,
moderate
post-
traumatic
stress
disorder
3 IV infusions of ketamine (0.5 mg/kg over
40 min); once weekly for the rst 3 weeks
of treatment; unclear if IV infusions
continued after week 3
10-week program of PE with therapy occurring during
ketamine administrations
Wilkinson etal. (2017) 16 Uncontrolled
trial
Major
depressive
disorder
4 IV infusions of ketamine (0.5 mg/kg over
40 min) over 2 weeks
10-week program of CBT with therapy occurring
outside of ketamine administrations
Wilkinson etal. (2021) 41 Randomized
controlled trial
Severe major
depressive
disorder and
treatment-
resistant
depression
6 IV infusions of ketamine (0.5 mg/kg over
40 min) over 3 weeks
Treatment group: 14-week program of CBT; Control
group: 14-week program of TAU; therapy occurred
outside of ketamine administrations
ACA, affective contra-attribution; AE, alcohol education; CBT, cognitive behavioral therapy; ERP, exposure response prevention; FAP, functional analytic psychotherapy; IM,
intramuscular; IN, intranasal; IV, intravenous; KaT, ketamine assisted therapy; KAP, ketamine assisted psychotherapy; kg, kilograms; KPT, ketamine assisted psychotherapy; lb,
pounds; MBCT, mindfulness based cognitive behavioral therapy; MBRP, mindfulness based relapse prevention therapy; MET, motivational enhancement therapy; mg, milligrams; min,
minutes; PO, per os; TAU, treatment as usual; TIMBER, trauma interventions using mindfulness based extinction and reconsolidation.
TABLE1 | Continued
Mathai et al. Ketamine and Psychotherapy
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Early, 2014; Ring etal., 2016). A new wave of ketamine-assisted
psychotherapy (KAP) began to emerge, attracting a growing
network of clinicians and informed theoretically by principles
of psychedelic therapy (Dore etal., 2019; Halstead etal., 2021;
Ragnhildstveit et al., 2021; Dames et al., 2022). As with other
psychedelic therapies, KAP emphasizes attention to “set and
setting” (Dore etal., 2019) – a broad conceptualization of the
nonpharmacological parameters that are thought to shape
hallucinogenic drug response, such as the degree of preparation
before, and the environment during, drug administrations
(Hartogsohn, 2016). Administrations of ketamine within KAP
follow “a dosage escalation strategy to achieve dierent levels
of trance increasing to full out-of-body experiences” while
holding central “that some degree of mind alteration is necessary
for ketamine’s eects (Dore et al., 2019).” is framework
suggests the possibility of highly variable and dose-dependent
states of consciousness induced by ketamine that represent
dierent opportunities for therapeutic intervention (Kolp etal.,
2014; Dore etal., 2019). For example, the KAP context would
becompatible with both “psycholytic therapy,” typically involving
lower doses of psychoactive drug to facilitate the therapeutic
and relational quality of ongoing psychotherapy during acute
drug eects, and “psychedelic therapy,” involving higher doses
of drug to facilitate the occurrence and integration of profound,
mystical- and peak-type experiences (Garcia-Romeu and
Richards, 2018). KAP, along with early uses of ketamine in
psychiatry, can then be classied as “experience-oriented”
approaches to treatment, for which the subjective quality of
drug eect is thought to have inherent value and bean integral
part of the therapeutic process (Mathai et al., 2020). In this
framework, the patient’s experiences under drug eects can
be considered meaningful and potentially insightful material,
which can then be utilized in collaboration with the therapist
to facilitate therapeutic progress.
Other recent and contrasting approaches have tended to
use behavioral therapies largely outside of the period of acute
drug eects (Rodriguez et al., 2016; Adams et al., 2017;
Wilkinson et al., 2017, 2021; Dakwar et al., 2019, 2020;
Ocker et al., 2020; Shiroma etal., 2020; Azhari etal., 2021;
Philipp-Muller etal., 2021; Grabski etal., 2022). is strategy
presumes that, beyond the period of its immediate psychoactive
function, ketamine produces a window of enhanced
neuroplasticity and other neural adaptations that facilitate
cognitive and behavioral interventions (Dakwar and Nunes,
2016; Wilkinson et al., 2019; Hasler, 2020). eoretically,
drug-facilitated psychotherapy could be optimized when
delivered during “critical periods” of neural development,
marked by exquisite sensitivity to environmental input and
potentially conducive to learning (Lepow et al., 2021). It
could be argued that this “plasticity-oriented” approach is
rooted most in the function of ketamine as a “psychoplastogen”
– a term used to describe small molecule neurotherapeutics
that produce rapid and measurable changes in plasticity aer
a single administration that are thought to support relatively
long-lasting changes in behavior (Olson, 2018). is logic
suggests the possibility of ketamine-like psychoplastogens
that might enhance psychotherapeutic processes in critical
periods aer drug administration without the need for marked
mind-altering eects (Olson, 2021). Consistent with this
understanding, predominantly plasticity-oriented approaches
to ketamine as a therapeutic adjunct dier from KAP in
how psychological support is allocated, with relatively less
emphasis on or engagement with drug-induced experiences
over the course of treatment (see Figure 1 for illustration
of these models).
e “experience-oriented” and “plasticity-oriented” uses of
ketamine outlined above could overlap but may be seen as
portrayals of two leading theories of treatment. ough not
described here, other nuanced psychotherapeutic applications
A
B
C
FIGURE1 | Functional units for existing models combining ketamine with
psychotherapy. Each circle indicates a single experience of ketamine, with
circle size corresponding to relative theoretical emphasis on the nature of the
experience. Bracketed lines are used to indicate optimal windows of
psychotherapeutic intervention. (A) shows the strategy of high-dose
“psychedelic therapy,” involving signicant preparation before and integration
after a limited number of drug sessions, which themselves are largely inner-
directed, rather than primarily relational, experiences. (B) shows the model of
low-dose “psycholytic therapy,” in which ongoing psychotherapy coincides
with ketamine administration, making use of acute drug effects that are
thought to facilitate the quality of therapy. The two former approaches are
examples of “experience-oriented” frameworks, such as KAP. (C) is
representative of “plasticity-oriented” strategies, wherein psychotherapy is
delivered after the period of acute drug effects but within “critical periods” of
neural adaptation that are thought to facilitate the uptake and efcacy of
behavioral interventions.
Mathai et al. Ketamine and Psychotherapy
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of ketamine are emerging (Pradhan et al., 2018; Veen et al.,
2018; Bottemanne etal., 2021; Bottemanne and Arnould, 2021;
Muscat et al., 2021b), and novel ways of using the drug will
continue to develop. For all approaches, there exist scientic
questions that can engage key theoretical assumptions. For
example, how do animal models of critical periods and adaptive
learning inform the timing and nature of complex, idiosyncratic
interventions using ketamine in humans? is research is still
in its infancy. Additionally, and of particular relevance to clinicians,
what is the role of the subjective ketamine experience in ketamine
therapy? Current ndings on this point are reviewed below.
THE RELEVANCE OF EXPERIENCE
It has been argued that no study to date has demonstrated
a therapeutic eect for ketamine absent some degree of
perceived psychoactivity (Dore etal., 2019). Several challenges
are inherent to such an undertaking, including the experimental
prospect of dening “psychoactivity,” which would seemingly
include experiences ranging from feeling “high,” “relaxed,”
“connected,” “happy” and “light” to the peak- and mystical-
type phenomena that occur at suciently high doses of
ketamine. A “critical test” of this question has been proposed
(Yaden and Griths, 2021), wherein a psychedelic agent
demonstrates full and lasting therapeutic ecacy when
administered to individuals while unconscious and who
subsequently report no memory of drug-related experience.
In counterpoint, Olson (2021) draws attention to several
interesting, albeit limited, studies suggesting that intraoperative
ketamine may improve mood in surgical patients even when
they are unconscious during drug administration (Kudoh etal.,
2002; Jiang et al., 2016; Xu et al., 2017). Among issues with
poor generalizability due to experimental design, it is unclear
if the demonstrated eects from these studies meet criteria
for “full and lasting therapeutic ecacy.” More suitable
investigations of the “critical test” are underway (Heifets, 2021),
but in the meantime, other types of correlational data can
provide insight into the relationship between subjective drug
experience and therapeutic ecacy.
e acute ketamine eect for which there is the most data
is “dissociation,” as measured by the Clinician-Administered
Dissociative States Scale (CADSS) and includes feelings such
as detachment from oneself and one’s environment and changes
in sensory perception (Grabski etal., 2020). Several independent
reviews have identied experimental evidence of a positive
correlation between dissociation and antidepressant ecacy for
ketamine, although this relationship has been inconsistent when
examined across clinical trials (Ballard and Zarate, 2020; Grabski
etal., 2020; Mathai etal., 2020). Another large post-hoc analysis
of phase 3 clinical trial data found no mediating eect of
dissociation on the antidepressant eects of esketamine (Chen
et al., 2022). While these ndings are dicult to interpret, it
is notable that modern studies have classied dissociation
primarily as an adverse event, suggesting that a major limitation
in the predictive ability of the CADSS, and similarly utilized
instruments, is prevailing research bias toward these psychoactive
eects as undesirable. Most studies of ketamine have also not
examined the relevance of dissociation in the context
of psychotherapy.
It is nonetheless worth considering that dissociation, as a
single metric and captured by the CADSS, may not bea useful
predictor of the therapeutic ecacy of ketamine. Other subjective
eects during drug administration, including ratings of
“happiness” (Chen et al., 2020) or the sensation of “lightness”
(Stocker etal., 2019) have also been associated with antidepressant
benet. Conversely, anxiety experienced during ketamine
infusions appears to predict negative treatment response for
depression (Aust etal., 2019). ese ndings require replication
but together suggest that the aective quality of drug-induced
experience may also bepertinent to therapeutic outcomes with
ketamine. It is moreover possible that the benets of certain
subjective eects, such as drug-mediated increases in
connectedness (Kolp et al., 2014; Griths et al., 2021;
Mollaahmetoglu et al., 2021), are not fully realized in the
absence of interpersonal therapeutic engagement.
Finally, it is valuable to recognize the similarities between
ketamine and classic (serotonergic) psychedelics such as
psilocybin and lysergic acid diethylamide (LSD), which produce
overlapping subjective phenomena in spite of diverging
pharmacological mechanisms of action (Bowdle et al., 1998;
Studerus et al., 2010). For classic psychedelics, it is well-
established that a subset of psychoactive eects, oen referred
to as mystical-type eects and characterized by a sense of
unity, predict greater therapeutic response across a variety of
conditions such as depression, existential distress, and substance
use disorders (Garcia-Romeu etal., 2014; Griths et al., 2016;
Roseman et al., 2018). Interestingly, it has been hypothesized
that the same mechanisms that drive the ecacy of these
treatments may also beresponsible for dose-dependent psychiatric
risks, like that of psychosis (Haarsma et al., 2021). However,
the relevant psychoactive eects of classic psychedelics appear
to beoptimized in careful experimental conditions that consider
the benet, safety, and tolerability of such (Johnson et al.,
2008; dos Santos et al., 2018). While similar optimization has
not been pursued for ketamine, increasing research suggests
that mystical- and peak-type experiences, such as measured
by the Hood Mysticism Scale (HMS) and 11D-ASC questionnaire,
increase the likelihood of various therapeutic benets (Dakwar
etal., 2014, 2018; Mollaahmetoglu et al., 2021; Rothberg etal.,
2021; Sumner etal., 2021). Regardless of whether these eects
are essential to treatment, there is mounting support for a
broader understanding of and attention to the spectrum of
experiences induced by ketamine.
A SPECIFIC PROPOSAL
In light of existing knowledge gaps, the authors and colleagues
have proposed a pilot investigation of esketamine with
Acceptance and Commitment erapy (ACT) for treatment-
resistant depression that is currently in the planning stage.
ACT has been recognized as a well-suited framework for
psychedelic-assisted treatment (Walsh and iessen, 2018;
Mathai et al. Ketamine and Psychotherapy
Frontiers in Psychology | www.frontiersin.org 7 March 2022 | Volume 13 | Article 868103
Sloshower et al., 2020; Wol et al., 2020). ACT is a form
of cognitive-behavioral therapy that emphasizes psychological
exibility (PF) and has been shown to be eective in the
treatment of depressive symptoms (Bai et al., 2020). PF is
a transdiagnostic construct that can be thought of as an
individual’s capacity to recognize and adapt to contextual
demands, shi mindset or behaviors during individual and
social experiences, maintain balance across important life
domains, and to be aware of and committed to behaviors
consistent with values (Kashdan, 2010). PF appears to predict
outcomes of psychotherapy for treatment-resistant depression
(Yasinski et al., 2020) and measurements of this construct,
like e Acceptance and Action Questionnaire (AAQ-II),
have been shown to mediate the relationship between acute
psychedelic eects and subsequent decreases in depression
and anxiety (Close etal., 2020; Davis etal., 2020). Importantly,
it is also held that the quality and therapeutic value of
relevant psychedelic eects are inuenced by the specic
treatment context for classic psychedelics (Johnson et al.,
2008; Hartogsohn, 2016; Carhart-Harris etal., 2018; Garcia-
Romeu and Richards, 2018), although this has not been
adequately explored with ketamine. Taken together, these
data indicate that PF-oriented models may bekey to supporting
processes of change when psychotherapy and psychedelic
experience are combined (Watts and Luoma, 2020).
While several published studies indicate the value of
psychotherapy alongside ketamine administration, none of
these investigations have utilized an ACT-based approach.
Furthermore, to our knowledge no studies have examined
the combination of esketamine and concurrent psychotherapy.
In this pilot study we propose to examine three research
questions: (1) will an augmented esketamine treatment protocol
(AET) involving preparatory counseling and ongoing ACT
during esketamine administration yield greater or more durable
antidepressant-type eects than treatment as usual (TAU)
esketamine dosing? (2) will the AET treatment context produce
signicantly dierent subjective (e.g., dissociative-type) eects
than TAU esketamine dosing? and (3) Are esketamine-induced
subjective eects within either treatment context associated
with antidepressant ecacy?
e study will randomly assign patients initiating esketamine
for treatment-resistant depression to either the TAU or AET
arm beginning with the rst dose and throughout the duration
of the 4-week induction phase (see Figure 2). e fact that
the FDA requires a two-hour monitoring window aer
esketamine dosing provides a unique opportunity for
psychotherapy that coincides with the period of acute drug
eects. ACT sessions will be conducted approximately 1 h
aer drug administration, and weexpect that standard dosages
of esketamine will facilitate a “psycholytic” and relational
model of therapy. Participant treatment response will
be tracked using standard measures of depression from
baseline through the end of the 4-week maintenance period,
and again at a 3-month follow-up. Subjective eects will
be assessed throughout esketamine dosing using a battery
of psychometric questionnaires. Other measurements of interest
include psychological exibility, therapeutic alliance, and need
for maintenance treatment that may dier between treatment
arms. ese data will provide needed empirical observations
regarding the impact of psychotherapeutic intervention in
conjunction with esketamine, and the mediating role of
subjective and contextually determined drug eects.
DISCUSSION
Ongoing study will help clarify the uses of ketamine as a therapeutic
adjunct. Notably, in contrast to pharmacotherapy development,
no formal approval process exists for specic psychotherapies,
which are ultimately dened as “evidence-based” when research
FIGURE2 | Proposed design for a pilot investigation of esketamine with Acceptance and Commitment Therapy (ACT) for treatment-resistant depression. Current
esketamine dosing protocols call for twice weekly dosing during a 4-week induction phase, followed by weekly dosing during a maintenance phase in weeks 5
through 8. Patients receive an initial dose of 56 mg, followed by repeated doses of 56 mg or 84 mg based on treatment response (i.e., efcacy and tolerability). After
initial study procedures, participants will berandomized to receive treatment as usual (plain circle) or esketamine in conjunction with ACT (circle with bracketed line)
during the induction phase of treatment. Both study arms will follow the same clinical procedures for maintenance treatment and subsequent follow-up.
Mathai et al. Ketamine and Psychotherapy
Frontiers in Psychology | www.frontiersin.org 8 March 2022 | Volume 13 | Article 868103
involving a substantial number of patients has provided evidence
of treatment eect (National Institute of Mental Health, 2021).
However, these lines of inquiry are unlikely to attract the funding
of pharmaceutical companies and will thus depend heavily on
the support of public agencies (Migone, 2017). Furthermore, with
the need for time-consuming and complex factorial study designs
to adequately compare drug x therapy interactions (Grabski etal.,
2022), standards of care for combinations of ketamine and
psychotherapy are expected to develop slowly.
For the time being, there is value to considering existing
and independent medical and psychological standards. Prescribing
of ketamine, particularly for o-label uses that may have
therapeutic utility, should bebased on “rm scientic rationale
and on sound medical evidence” (U.S. Food and Drug
Administration, 1998), such as eectiveness data collected from
controlled trials or documented in clinical settings (Radley
et al., 2006). Best psychological practice is informed not only
by existing research but also “clinical expertise in the context
of patient characteristics, culture and preferences (American
Psychological Association, 2008).” Additional parameters are
expected to be relevant to the interactions of ketamine and
therapy, including variables such as medication dosage and
the timing of psychological interventions, as described here,
along with other factors, such as the normative claims of
treatment, and provider training in specic therapeutic modalities.
Dierent paradigms for ketamine can coexist – the
“experience-oriented,” “plasticity-oriented,” and others still. Even
guidelines for strictly pharmacological uses of ketamine and
esketamine emphasize the importance of “a comfortable and
adaptable environment” for patients given that drug
administration “may amplify sensory experiences and/or result
in dissociation or psychotomimetic eects (McIntyre et al.,
2021).” An integrated approach to ketamine therapy, considering
both historical perspectives on subjective experience and modern
advances in neuroscience, may ultimately lead to a better
understanding of relevant drug eects, improved treatment
protocols, and multiple dimensions of benet (Muscat et al.,
2021a; Walsh etal., 2021). Much like the “abreactive” interventions
of old, ongoing applications of ketamine are expected to reect
the prevailing psychological zeitgeist. However, while the
mechanics, contexts, and explanations for our interventions
may shi, the therapeutic endeavor is the same as it has always
been – toward the vision of a better life for patients.
DATA AVAILABILITY STATEMENT
e original contributions presented in the study are included
in the article/supplementary material, further inquiries can
be directed to the corresponding author.
AUTHOR CONTRIBUTIONS
DM, VM, and AG-R made substantial contributions to the
conception, design, and draing of the manuscript. All authors
approved the nal version of this manuscript and agree to
be accountable for all aspects of the work.
FUNDING
Funding for this research was made possible by the Johns Hopkins
Center for Psychedelic and Consciousness Research and provided
by Tim Ferriss, Matt Mullenweg, Blake Mycoskie, Craig Nerenberg,
and the Steven and Alexandra Cohen Foundation. e funders
had no role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript.
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Conflict of Interest: AG-R receives support from the Heer Research Institute
and serves as a scientic advisor to ETHA Natural Botanicals and NeonMind Biosciences.
e remaining authors declare that the research was conducted in the absence
of any commercial or nancial relationships that could beconstrued as a potential
conict of interest.
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