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Toward Synergies of Ketamine and Psychotherapy

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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, we review 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 field.
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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
DavidS.Mathai
1*, VictoriaMora
2 and AlbertGarcia-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, wereview 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 ketamines dreamlike and hallucinogenic properties, experienced by
patients as feeling “disconnected” from their environment, and leading to its classication as
a “dissociative anesthetic” (Domino et al., 1965; Reier, 1971). e subjective eects 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; Soa 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 dened, 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 etal., 2020). Psychotherapy may besimplied
even further, to denote any “communication between patients and therapists that is intended
to help people (American Psychological Association, 2017).” ese denitions will be used
hereaer 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 eects 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, wereview
historical and modern approaches to the use of ketamine with
psychotherapy, discuss the clinical relevance of ketamines acute
psychoactive eects, 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
specic parameters of treatment administration.
A BRIEF HISTORY
e rst known uses of ketamine as a therapeutic adjunct
date back to the early 1970s, soon aer 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
hecalled “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 conicts 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 Loy 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 eects
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 signicant explorations of ketamine as a
therapeutic agent occurred through the 1970s and 1980s (Lilly,
1972, 1978; Fontana and Loschi, 1974; Sappington etal., 1979;
Grof, 1980; Golechha et al., 1985), though the single most
comprehensive body of clinical research in this area can
becredited 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 etal., 1992; Sivolap and Savchenkov, 1994). Krupitsky
eventually realized that patients beneted similarly from positive,
transcendent experiences while on ketamine and shied 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 etal., 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 benets of ketamine are attributed
to a pharmacologic eect 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 etal., 2006, 2007;
Mathai et al. Ketamine and Psychotherapy
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TABLE1 | Characteristics of studies reviewed using ketamine and psychotherapy.
Study N Design Treatment
population
Drug parameters Psychotherapy parameters
Adams etal. (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 etal. (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 etal. (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., MBRP2 h post-infusion)
Dakwar etal. (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 etal. (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 unspecied);
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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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 etal. (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.
TABLE1 | Continued
Mathai et al. Ketamine and Psychotherapy
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Early, 2014; Ring etal., 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 etal., 2019; Halstead etal., 2021;
Ragnhildstveit et al., 2021; Dames et al., 2022). As with other
psychedelic therapies, KAP emphasizes attention to “set and
setting” (Dore etal., 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 dierent levels
of trance increasing to full out-of-body experiences” while
holding central “that some degree of mind alteration is necessary
for ketamines eects (Dore et al., 2019).” is framework
suggests the possibility of highly variable and dose-dependent
states of consciousness induced by ketamine that represent
dierent opportunities for therapeutic intervention (Kolp etal.,
2014; Dore etal., 2019). For example, the KAP context would
becompatible with both “psycholytic therapy,” typically involving
lower doses of psychoactive drug to facilitate the therapeutic
and relational quality of ongoing psychotherapy during acute
drug eects, 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 classied as “experience-oriented
approaches to treatment, for which the subjective quality of
drug eect is thought to have inherent value and bean integral
part of the therapeutic process (Mathai et al., 2020). In this
framework, the patient’s experiences under drug eects 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 eects (Rodriguez et al., 2016; Adams et al., 2017;
Wilkinson et al., 2017, 2021; Dakwar et al., 2019, 2020;
Ocker et al., 2020; Shiroma etal., 2020; Azhari etal., 2021;
Philipp-Muller etal., 2021; Grabski etal., 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 aer
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 aer drug administration without the need for marked
mind-altering eects (Olson, 2021). Consistent with this
understanding, predominantly plasticity-oriented approaches
to ketamine as a therapeutic adjunct dier 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
FIGURE1 | 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 signicant 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 efcacy of
behavioral interventions.
Mathai et al. Ketamine and Psychotherapy
Frontiers in Psychology | www.frontiersin.org 6 March 2022 | Volume 13 | Article 868103
of ketamine are emerging (Pradhan et al., 2018; Veen et al.,
2018; Bottemanne etal., 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 scientic
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 eect for ketamine absent some degree of
perceived psychoactivity (Dore etal., 2019). Several challenges
are inherent to such an undertaking, including the experimental
prospect of dening “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 suciently high doses of
ketamine. A “critical test” of this question has been proposed
(Yaden and Griths, 2021), wherein a psychedelic agent
demonstrates full and lasting therapeutic ecacy 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 etal.,
2002; Jiang et al., 2016; Xu et al., 2017). Among issues with
poor generalizability due to experimental design, it is unclear
if the demonstrated eects from these studies meet criteria
for “full and lasting therapeutic ecacy.” 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 ecacy.
e acute ketamine eect 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 etal., 2020). Several independent
reviews have identied experimental evidence of a positive
correlation between dissociation and antidepressant ecacy for
ketamine, although this relationship has been inconsistent when
examined across clinical trials (Ballard and Zarate, 2020; Grabski
etal., 2020; Mathai etal., 2020). Another large post-hoc analysis
of phase 3 clinical trial data found no mediating eect of
dissociation on the antidepressant eects of esketamine (Chen
et al., 2022). While these ndings are dicult to interpret, it
is notable that modern studies have classied 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
eects 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 bea useful
predictor of the therapeutic ecacy of ketamine. Other subjective
eects during drug administration, including ratings of
“happiness” (Chen et al., 2020) or the sensation of “lightness
(Stocker etal., 2019) have also been associated with antidepressant
benet. Conversely, anxiety experienced during ketamine
infusions appears to predict negative treatment response for
depression (Aust etal., 2019). ese ndings require replication
but together suggest that the aective quality of drug-induced
experience may also bepertinent to therapeutic outcomes with
ketamine. It is moreover possible that the benets of certain
subjective eects, such as drug-mediated increases in
connectedness (Kolp et al., 2014; Griths 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 eects, oen referred
to as mystical-type eects 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 etal., 2014; Griths et al., 2016;
Roseman et al., 2018). Interestingly, it has been hypothesized
that the same mechanisms that drive the ecacy of these
treatments may also beresponsible for dose-dependent psychiatric
risks, like that of psychosis (Haarsma et al., 2021). However,
the relevant psychoactive eects of classic psychedelics appear
to beoptimized in careful experimental conditions that consider
the benet, 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 benets (Dakwar
etal., 2014, 2018; Mollaahmetoglu et al., 2021; Rothberg etal.,
2021; Sumner etal., 2021). Regardless of whether these eects
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 eective 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 eects and subsequent decreases in depression
and anxiety (Close etal., 2020; Davis etal., 2020). Importantly,
it is also held that the quality and therapeutic value of
relevant psychedelic eects are inuenced by the specic
treatment context for classic psychedelics (Johnson et al.,
2008; Hartogsohn, 2016; Carhart-Harris etal., 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 bekey 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 eects than treatment as usual (TAU)
esketamine dosing? (2) will the AET treatment context produce
signicantly dierent subjective (e.g., dissociative-type) eects
than TAU esketamine dosing? and (3) Are esketamine-induced
subjective eects within either treatment context associated
with antidepressant ecacy?
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 aer
esketamine dosing provides a unique opportunity for
psychotherapy that coincides with the period of acute drug
eects. ACT sessions will be conducted approximately 1 h
aer drug administration, and weexpect 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 eects 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 dier 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 eects.
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 specic psychotherapies,
which are ultimately dened as “evidence-based” when research
FIGURE2 | 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., efcacy and tolerability). After
initial study procedures, participants will berandomized 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 eect (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 etal.,
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 bebased on “rm scientic rationale
and on sound medical evidence” (U.S. Food and Drug
Administration, 1998), such as eectiveness 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 specic therapeutic modalities.
Dierent 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 eects (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 eects, improved treatment
protocols, and multiple dimensions of benet (Muscat et al.,
2021a; Walsh etal., 2021). Much like the “abreactive” interventions
of old, ongoing applications of ketamine are expected to reect
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 draing 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 Heer Research Institute
and serves as a scientic 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 beconstrued as a potential
conict of interest.
Publisher’s Note: All claims expressed in this article are solely those of the
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or those of the publisher, the editors and the reviewers. Any product that may
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Background Traditional treatments for post-traumatic stress disorder (PTSD) often show limited success with high dropout. Ketamine, an N-methyl-D-aspartate antagonist known for rapid antidepressant effects, has decreased PTSD symptoms in some studies but not in others. Administering ketamine in ways that parallel psychedelic-assisted treatments—including preparatory, integration, sensory immersion, and psychotherapy sessions—could decrease PTSD symptoms meaningfully. Methods A retrospective sample of 117 screened outpatients with elevated PTSD Checklist for DSM-5 (PCL-5) scores received intravenous ketamine in supportive environments. The protocol included preparation, intention-setting, and integration sessions accompanying at least six administrations. Administration sessions included eye shades and evocative music paralleling typical psychedelic therapy trials. Results Mean PCL scores decreased from 52.54 (SD = 12.01) to 28.78 (SD = 16.61), d = 1.64. Patients tolerated treatment well, with no serious adverse events. Covariates, including age, gender, days between PCL assessments, number of psychiatric medications, and suicidal ideation were not significant moderators; concomitant psychotherapy did reach significance, d = 0.51. Of the 117 patients’ final PCL scores, 88 (75.21%) measures suggested clinically meaningful improvement and 72 (61.54%) suggested remission of PTSD symptoms. Conclusion Intravenous ketamine in supportive environments, with hallmarks of psychedelic therapy, preceded large reductions in PTSD symptoms. These results highlight ketamine’s potential when delivered in this manner, suggesting environmental factors might account for some variation seen in previous work. Given the molecule’s cost, minimal interaction with other psychiatric medications, and legal status, intravenous ketamine in a psychedelic paradigm may be a promising option for PTSD unresponsive to other treatments.
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Dissociative therapies are being increasingly explored for their psychiatric applications, although questions remain about how they work and how best to use them. In exploring these questions, this review highlights six key areas of clinical relevance: (1) The possible contributions of functional unblinding when interpreting efficacy data; (2) The degree to which the therapeutic effects of dissociative therapies can be distinguished from the transient forms of relief seen with recreational drug use; (3) Understanding the construct of dissociation as it is tasked with describing the function of dissociative drugs; (4) The investigation of subjective drug effects as predictors of therapeutic outcome; (5) Similarities and differences in the effects of dissociative and classic psychedelics; and (6) The anticipated need for judicious prescribing/deprescribing resources as dissociative therapies proliferate.
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Post-traumatic stress disorder (PTSD) is a mental health condition that can occur following exposure to a traumatic experience. An estimated 12 million U.S. adults are presently affected by this disorder. Current treatments include psychological therapies (e.g., exposure-based interventions) and pharmacological treatments (e.g., selective serotonin reuptake inhibitors (SSRIs)). However, a significant proportion of patients receiving standard-of-care therapies for PTSD remain symptomatic, and new approaches for this and other trauma-related mental health conditions are greatly needed. Psychedelic compounds that alter cognition, perception, and mood are currently being examined for their efficacy in treating PTSD despite their current status as Drug Enforcement Administration (DEA)- scheduled substances. Initial clinical trials have demonstrated the potential value of psychedelicassisted therapy to treat PTSD and other psychiatric disorders. In this comprehensive review, we summarize the state of the science of PTSD clinical care, including current treatments and their shortcomings. We review clinical studies of psychedelic interventions to treat PTSD, trauma-related disorders, and common comorbidities. The classic psychedelics psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT) and DMT-containing ayahuasca, as well as the entactogen 3,4-methylenedioxymethamphetamine (MDMA) and the dissociative anesthetic ketamine, are reviewed. For each drug, we present the history of use, psychological and somatic effects, pharmacology, and safety profile. The rationale and proposed mechanisms for use in treating PTSD and traumarelated disorders are discussed. This review concludes with an in-depth consideration of future directions for the psychiatric applications of psychedelics to maximize therapeutic benefit and minimize risk in individuals and communities impacted by trauma-related conditions.
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Amid an international pandemic and a worsening mental health crisis, ketamine-assisted therapy is emerging as a promising solution for those deemed “treatment resistant.” Post-traumatic stress disorder (PTSD) and depression are on the rise, with accelerating direct (e.g., burden of suffering) and indirect (e.g., disability/role impairment and impact on family) costs. Psychedelic-assisted therapies show significant promise in the treatment of a number of clinically challenging conditions, including depression, anxiety, PTSD, addiction, and end-of-life distress. Ketamine is currently the only safe, effective and legal widely available psychedelic-like medicine. To address the echo pandemic of health care provider distress, a multi-disciplinary team was charged with developing a ketamine-assisted psychotherapy program, delivered in a community of practice (CoP) group model and evaluated in a quality improvement framework. Program evaluation occurred through mixed methods. Quantitative mental health assessments included the PHQ-9 for depression, the PCL-5 for PTSD, GAD-7 for generalized anxiety disorder (GAD), and B-IPF for work/life functionality. Participant narrative feedback was collected to evaluate outcomes and for quality improvement purposes. Mean mental health scores were collected across three cohorts, totaling 94 patients. The mean aggregate scores of participants meeting the mental health assessment cut-off criteria (screening positive) were analyzed to assess clinical significance. Mean aggregate results comparing baseline vs. outcome measures (measured within 1–2 weeks after completion of the 12-week program) were clinically significant, demonstrating significant improvements in depression, post-traumatic stress disorder, generalized anxiety disorder and work/life functionality. In summary, 91% saw improvements in generalized anxiety, 79% saw improvements in depression, 86% of those who screened positive for PTSD now screen negative, and 92% had significant life/work functionality improvements. Qualitative feedback was overwhelmingly positive, with several unsolicited self-reports of transformation. Participant and team feedback enables the program to continue improving with each iteration. Results speak to the effectiveness of ketamine for psychedelic-assisted therapy, supported by a CoP framework. Outcomes are relevant for mental health programming, education and healthcare policy.
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Background In this post-hoc analysis, data from the positive pivotal phase 3 trials of esketamine nasal spray (ESK) in treatment resistant depression (TRD): short-term study (TRANSFORM-2) and maintenance study (SUSTAIN-1) were analyzed to evaluate the relationship between dissociation and antidepressant effects of ESK. Methods Analysis by responder status, correlation analysis and mediation analysis were performed to assess the relationships between peak Clinician Administered Dissociative States Scale (CADSS) scores after first (day-1) and last (day-25) ESK dose and change in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores at the first (day-2) and last assessments (day-28) in TRANSFORM-2 and peak CADSS after first maintenance ESK dose and time to relapse in SUSTAIN-1 (only for mediation analysis). Results In TRANSFORM-2 the percentage of responders (>50% reduction in MADRS) at day-2 and day-28 did not differ significantly between patients who did versus did not manifest significant dissociation (peak CADSS scores >4 or ≤4, respectively) following the first ESK dose. Spearman correlation coefficients between dissociation and depression improvement were nonsignificant and close to zero. CADSS scores did not significantly mediate the reduction in MADRS at day-2 or 28 in TRANSFORM-2 or the time to depression relapse in SUSTAIN1. The mean difference in MADRS between ESK and active-control arms persisted beyond day-2 without significant change across time, although the mean peak CADSS scores significantly decreased across consecutive doses and fewer patients experienced significant dissociation after the last ESK dose compared to the first. Conclusion Within the dose range tested, the dissociative and antidepressant effects of ESK were not significantly correlated.
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Background In the past two decades, subanaesthetic doses of ketamine have been demonstrated to have rapid and sustained antidepressant effects, and accumulating research has demonstrated ketamine's therapeutic effects for a range of psychiatric conditions. Aims In light of these findings surrounding ketamine's psychotherapeutic potential, we systematically review the extant evidence on ketamine's effects in treating mental health disorders. Method The systematic review protocol was registered in PROSPERO (identifier CRD42019130636). Human studies investigating the therapeutic effects of ketamine in the treatment of mental health disorders were included. Because of the extensive research in depression, bipolar disorder and suicidal ideation, only systematic reviews and meta-analyses were included. We searched Medline and PsycINFO on 21 October 2020. Risk-of-bias analysis was assessed with the Cochrane Risk of Bias tools and A Measurement Tool to Assess Systematic Reviews (AMSTAR) Checklist. Results We included 83 published reports in the final review: 33 systematic reviews, 29 randomised controlled trials, two randomised trials without placebo, three non-randomised trials with controls, six open-label trials and ten retrospective reviews. The results were presented via narrative synthesis. Conclusions Systematic reviews and meta-analyses provide support for robust, rapid and transient antidepressant and anti-suicidal effects of ketamine. Evidence for other indications is less robust, but suggests similarly positive and short-lived effects. The conclusions should be interpreted with caution because of the high risk of bias of included studies. Optimal dosing, modes of administration and the most effective forms of adjunctive psychotherapeutic support should be examined further.
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Research over the last two decades has established ketamine as a safe, effective, fast-acting, and sustained antidepressant that significantly reduces adverse symptoms associated with depression, even in patients who are treatment resistant. Much of this research has evolved within the framework of several independent branches of scientific inquiry: in addition to the study of ketamine is a non-selective NMDAR antagonist with rapid antidepressant effects, it has also been found effective as a psychoplastogen that stimulates synaptogenesis and increases neuroplasticity, as a powerful anti-inflammatory that may improve inflammation-related depressive symptoms, as a substance that induces beneficial high entropy brain states, and as a subjectively impactful psychedelic agent. Each branch of inquiry has generated independent evidence of ketamine's efficacy but has advanced without substantive coordination or communication with other lines of inquiry. Integrative research that considers these branches of research together may lead toward a better understanding of ketamine's effects and improved treatment protocols and clinical outcomes. Such an overview can inform more comprehensive patient care through: (a) informed patient psychoeducation that encompasses all of ketamine's mechanisms of action; (b) calibration of optimal dosage to ensure induction and maintenance of high entropy brain states during each ketamine session utilizing EEG measurement; (c) Improved management of emergence side effects through proper care for set and setting; (d) inclusion of pre-selected appropriate music to enhance the emotional experience; (e) increased monitoring of ketamine effects on cortical activity, inter-hemispheric imbalance, and inflammation-related levels of cytokines to further improvements in ketamine protocols; and (f) appropriate timing of any adjunctive psychotherapy sessions to coincide with peak neurogenesis at 24–48 h post ketamine treatment.
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Background: Bulimia nervosa is a disabling psychiatric disorder that considerably impairs physical health, disrupts psychosocial functioning, and reduces overall quality of life. Despite available treatment, less than half of sufferers achieve recovery and approximately a third become chronically ill. Extreme and enduring cases are particularly resistant to first-line treatment, namely antidepressants and cognitive behavioral therapy, and have the highest rate of premature mortality. Here, we demonstrate that in such cases, repeated sessions of ketamine assisted psychotherapy (KAP) is an effective treatment alternative for improving symptoms. Case Presentation: A 21-year-old woman presented with extreme and enduring bulimia nervosa. She reported recurrent binge-eating and purging by self-induced vomiting 40 episodes per day, which proved refractory to both pharmacological and behavioral treatment at the outpatient, residential, and inpatient level. Provided this, her physician recommended repeated KAP as an exploratory and off-label intervention for her eating disorder. The patient underwent three courses of KAP over 3 months, with each course consisting of six sessions scheduled twice weekly. She showed dramatic reductions in binge-eating and purging following the first course of treatment that continued with the second and third. Complete cessation of behavioral symptoms was achieved 3 months post-treatment. Her remission has sustained for over 1 year to date. Conclusions: To our knowledge, this is the first report of repeated KAP used to treat bulimia nervosa that led to complete and sustained remission, a rare outcome for severe and enduring cases, let alone extreme ones. Additionally, it highlights the degree to which KAP can be tailored at the individual level based on symptom severity and treatment response. While its mechanism of action is unclear, repeated KAP is a promising intervention for bulimia nervosa that warrants future research and clinical practice consideration.
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Objectives: Investigation into parental decision-making processes involving ketamine is of high priority, given the necessary role of parents in consenting to treatment. In this study, we examined parental attitudes toward the emerging use of ketamine in adolescent mood disorders and suicidality. Methods: Two hundred eighty-three English-speaking parents completed an online survey using Amazon Mechanical Turk on psychiatric use of ketamine, acceptability of treatment, and their perceptions of ketamine treatment. Data quality control measures were used to mitigate invalid reporting. Results: Parents reported high acceptability toward use of ketamine for suicidality, major depressive disorder, and bipolar disorder in adolescents. Primary concerns around ketamine involved its potential side effects and lack of United States Food and Drug Administration (FDA) approval. Responses indicated a preference for short-term applications and less invasive routes of administration for ketamine. Parent history of mental illness, familiarity with psychological treatments, and comfort using other mental health interventions in their children predicted greater acceptability of ketamine. Conclusion: Although ketamine is not currently approved by the FDA for psychiatric use in children nor recommended outside of research protocols, these findings suggest that parents have interest in the application of ketamine as a treatment for pediatric mood disorders and point to future directions for research and clinical orientation.
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As psychedelic compounds gain traction in psychiatry, there is a need to consider the active mechanism to explain the effect observed in randomized clinical trials. Traditionally, biological psychiatry has asked how compounds affect the causal pathways of illness to reduce symptoms and therefore focus on analysis of the pharmacologic properties. In psychedelic-assisted psychotherapy (PAP), there is debate about whether ingestion of the psychedelic alone is thought to be responsible for the clinical outcome. A question arises how the medication and psychotherapeutic intervention together might lead to neurobiological changes that underlie recovery from illness such as post-traumatic stress disorder (PTSD). This paper offers a framework for investigating the neurobiological basis of PAP by extrapolating from models used to explain how a pharmacologic intervention might create an optimal brain state during which environmental input has enduring effects. Specifically, there are developmental “critical” periods (CP) with exquisite sensitivity to environmental input; the biological characteristics are largely unknown. We discuss a hypothesis that psychedelics may remove the brakes on adult neuroplasticity, inducing a state similar to that of neurodevelopment. In the visual system, progress has been made both in identifying the biological conditions which distinguishes the CP and in manipulating the active ingredients with the idea that we might pharmacologically reopen a critical period in adulthood. We highlight ocular dominance plasticity (ODP) in the visual system as a model for characterizing CP in limbic systems relevant to psychiatry. A CP framework may help to integrate the neuroscientific inquiry with the influence of the environment both in development and in PAP.
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Ketamine therapy with culturally attuned trauma-informed psychotherapy in a collaborative cross-cultural partnership may provide a critical step in the operationalization and optimization of treatment effectiveness in diverse populations and may provide a foundation for an improved quality of life for Indigenous people. Decolonizing Indigenous health and wellbeing is long overdue, requiring an equal partnership between government and Indigenous communities, built upon an aboriginal culture holistic foundation of balance of mind, body, social and spiritual realms, and within the context of historical and lived experiences of colonialism. Culturally attuned trauma-informed psychotherapy paired with ketamine—a fast-acting antidepressant that typically takes effect within 4 hours, even in cases of acute suicidality—may be uniquely qualified to integrate into an Indigenous based health system, since ketamine’s therapeutic effects engage multiple neuropsychological, physiological, biological, and behavioral systems damaged by intergenerational complex developmental trauma. Ketamine holds the potential to serve as a core treatment modality around which culturally engaged treatment approaches might be organized since its brief alteration of normal waking consciousness is already a familiar and intrinsic element of healing culture in many Indigenous societies. There is great need and desire in Indigenous communities for respectful and sacred partnership in fostering more effective mental health outcomes and improved quality of life.
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Objective: Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control. Methods: In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up. Results: Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups. Conclusions: This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.
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Résumé La kétamine, un antagoniste non compétitif du récepteur NMDA, est utilisée aujourd’hui comme traitement antidépresseur d’action rapide dans les troubles dépressifs. Ce traitement provoque des effets psychodysleptiques dissociatifs associant une déréalisation et une dépersonnalisation, et déclenche des modifications synaptogéniques favorisant la plasticité cérébrale. Malgré plusieurs études préliminaires suggérant l’utilité de son association avec la psychothérapie, l’administration de kétamine n’est généralement pas combinée à des protocoles de psychothérapie per- et postperfusion dans le cadre de son utilisation clinique à visée antidépressive. Pourtant, la phénoménologie des expériences psychodysleptiques et l’effet synaptogénique pourraient potentialiser l’effet des psychothérapies cognitives et comportementales. Dans cet article, nous proposons un guide pratique de psychothérapie augmentée sous kétamine (KAP) synthétisant les données contemporaines de la littérature et notre expérience clinique. Nous détaillons des propositions de bonne pratique clinique et proposons quatre étapes importantes pour l’utilisation d’une molécule psychodysleptique à visée antidépressive : la préparation, l’administration, l’intégration, et la prolongation. Enfin, nous discutons les limites et les perspectives de cette combinaison dans la prise en charge des troubles de l’humeur.