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Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy


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Currently, ketamine is the only legal psychedelic medicine available to mental health providers for the treatment of emotional suffering. Over the past several years, ketamine has come into psychiatric use as an intervention for treatment resistant depression (TRD), administered intravenously without a psychotherapeutic component. In these settings, ketamine’s psychedelic effects are viewed as undesirable “side effects.” In contrast, we believe ketamine can benefit patients with a wide variety of diagnoses when administered with psychotherapy and using its psychedelic properties without need for intravenous (IV) access. Its proven safety over decades of use makes it ideal for office and supervised at-home use. The unique experience that ketamine facilitates with its biological, experiential, and psychological impacts has been tailored to optimize office-based treatment evolving into a method that we call Ketamine Assisted Psychotherapy (KAP). This article is the first to explore KAP within an analytical framework examining three distinct practices that use similar methods. Here, we present demographic and outcome data from 235 patients. Our findings suggest that KAP is an effective method for decreasing depression and anxiety in a private practice setting, especially for older patients and those with severe symptom burden.
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Journal of Psychoactive Drugs
ISSN: 0279-1072 (Print) 2159-9777 (Online) Journal homepage:
Ketamine Assisted Psychotherapy (KAP): Patient
Demographics, Clinical Data and Outcomes in
Three Large Practices Administering Ketamine
with Psychotherapy
Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed, Julane
Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole
Strauss & Phil Wolfson
To cite this article: Jennifer Dore, Brent Turnipseed, Shannon Dwyer, Andrea Turnipseed,
Julane Andries, German Ascani, Celeste Monnette, Angela Huidekoper, Nicole Strauss & Phil
Wolfson (2019): Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data
and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy, Journal of
Psychoactive Drugs, DOI: 10.1080/02791072.2019.1587556
To link to this article:
© 2019 The Author(s). Published with
license by Taylor & Francis Group, LLC.
Published online: 27 Mar 2019.
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Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data
and Outcomes in Three Large Practices Administering Ketamine with
Jennifer Dore
, Brent Turnipseed
, Shannon Dwyer
, Andrea Turnipseed
, Julane Andries
, German Ascani
Celeste Monnette
, Angela Huidekoper
, Nicole Strauss
, and Phil Wolfson
Helios Psychiatry, Woodside, CA;
Roots Behavioral Health, Austin, TX;
Center for Transformational Psychotherapy, San Anselmo, CA;
Ketamine Research Foundation, San Anselmo, CA
Currently, ketamine is the only legal psychedelic medicine available to mental health providers for
the treatment of emotional suffering. Over the past several years, ketamine has come into
psychiatric use as an intervention for treatment resistant depression (TRD), administered intrave-
nously without a psychotherapeutic component. In these settings, ketamines psychedelic effects
are viewed as undesirable side effects.In contrast, we believe ketamine can benefit patients with
a wide variety of diagnoses when administered with psychotherapy and using its psychedelic
properties without need for intravenous (IV) access. Its proven safety over decades of use makes it
ideal for office and supervised at-home use. The unique experience that ketamine facilitates with
its biological, experiential, and psychological impacts has been tailored to optimize office-based
treatment evolving into a method that we call Ketamine Assisted Psychotherapy (KAP). This article
is the first to explore KAP within an analytical framework examining three distinct practices that
use similar methods. Here, we present demographic and outcome data from 235 patients. Our
findings suggest that KAP is an effective method for decreasing depression and anxiety in
a private practice setting, especially for older patients and those with severe symptom burden.
Received 13 December 2018
Accepted 15 February 2019
Depression; ketamine;
psychedelic psychotherapy;
psychedelics; psychotherapy;
The development of a psychotherapy that uses keta-
mine as a medicine for conscious awareness is new and
groundbreaking (Wolfson and Hartelius 2016). It coin-
cides with promising clinical research with psilocybin
and MDMA embedded in psychotherapies that are
entering Phase III FDA trials (Feduccia, Holland, and
Mithoefer 2018; Mithoefer, Grob, and Brewerton 2016).
For now, ketamine is the only legally available psyche-
delic medication, along with cannabis.
Ketamine originated as an anesthetic drug in the late
1960s as an analog of phencyclidine. It has been
a successful anesthetic and analgesic agent with far fewer
adverse effects than the parent compound. Early in keta-
mines use, there were reports of an unusual side effect,
a dissociative/hallucinatory state referred to as the emer-
gence phenomenon.This was concerning because patients
were not prepared for these vivid experiences and found
them disturbing. It was dubbed a dissociative anesthetic
clinician (Matthew and Zarate 2016).
Ketamines potential to treat psychological or psychia-
tric problems was first reported in Khorramzadeh and
Lofty (1973), and in Argentina as an adjunct for antide-
pressant psychotherapy (Fontana 1974). In Mexico, the
psychiatrist Salvador Roquet introduced ketamine to
patients in group settings as a component of his approach
to psychedelic psychotherapy (Kolp et al. 2007; Yensen
2016). From Russia came reports of using ketamine for
the treatment of addictions (Krupitsky and Grinenko
1997). Duly noted by those involved with psychedelic
substances during this period prior to the Drug
Enforcement Administrations scheduling of substances,
use of ketamine for self-exploration and in psychothera-
peutic contexts had an ongoing but not extensive profile
(Jansen 2004; Wolfson and Hartelius 2016).
Anecdotally, some practitioners noted that intramus-
cular ketamine sessions were followed by periods of relief
from depressive and anxious states (Kolp et al. 2007). In
the late 1990s, investigators at the National Institute of
Mental Health began exploring the antidepressant poten-
tial of ketamine while searching for alternatives to the
limited benefits of SSRIs and SNRIs (Berman et al. 2000;
CONTACT Phil Wolfson The Ketamine Research Foundation, 6 Crest Avenue San Anselmo, CA 94960
Color versions of one or more of the figures in the article can be found online at
© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (
nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built
upon in any way.
Krystal et al. 1994). Notably, however, their effort was
focused on eliminating the psychedelic effects while
retaining or enhancing the antidepressant properties.
They concentrated on patients failing treatment on two
or more conventional antidepressants (labeled Treatment
Resistant Depression [TRD]), viewing this as a potential
market with a social responsibility to provide effective
treatment. Subsequently, a protocol for medicalized use
involving an intravenous (IV) route of administration in
which ketamine was infused at a rate of 0.5 mg/kg over 40
minutes emerged. After a single session of IV ketamine,
investigators noted remission of TRD and a reduction of
suicidality ((Krystal 2007). However, the benefit was
short-lived. This led to a more intensive approach to
providing treatment, tending towards an induction
phase of six sessions over about two weeks' time, with
further sessions occurring at various times depending on
the practitioner. The strategy focused on dosing and
frequency of ketamine administration to extend the dura-
tion of affective benefit (Cusin et al. 2012; Rot et al. 2015;
Zarate et al. 2013).
Although researchers attempted to minimize ketamines
unwanted dissociative effects, some degree of mind altera-
tion would generally occur. However, studies from the IV
researchers indicated enhanced benefit from the presence
of psychedelic experiences (Luckenbaugh et al. 2014). These
findings parallel the relationship between mystical experi-
ence and treatment outcome in the psilocybin studies
(Griffiths et al. 2011), with both medicines providing
altered, often profound psychedelic experience. This asso-
ciation suggests that profound psychedelic experiences,
regardless of the medicine facilitating them, may improve
mental health and overall well-being (Sullivan 2018). The
psychiatric establishment has tended to avoid this under-
standing, and instead has attempted to discover
a metabolite or analog of ketamine that lacks the psyche-
delic effects yet retains antidepressant effects. Ketamine
Assisted Psychotherapy (KAP) utilizes a dosage escalation
strategy to achieve different levels of trance increasing to
full out-of-body experiences. We believe that some degree
of mind alteration is necessary for ketamineseffects.No
study to date has demonstrated that, absent some degree of
perceived psychoactivity, there is an antidepressant effect
(for a review of ketamine research for depression and other
disorders, see Ryan, Marta, and Koek 2016).
In the mid-2000s, several office-based psychiatrists
began administering intramuscular (IM) ketamine within
a psychotherapeutic framework, in collaboration with
referring therapists, or providing therapy themselves
(Early 2016). With Stephen Hydes(2015) publication of
Ketamine for Depression in 2015, it became clear that keta-
mine could be administered using the sublingual, intrana-
sal, or intramuscular routes (Chilukuri et al. 2014), raising
the prospect that IV administration was unnecessary. In
fact, other routes of administration allow the entire thera-
peutic dosing spectrum to occur in a non-medicalized office
setting with full psychotherapeutic support (Jaitly 2013;
Over decades, ketaminesrecordofclinicalsafetyin
anesthesia and for analgesia, in emergency room settings,
in outpatient pain management clinics, and now for psy-
chiatric use, has produced an extensive body of clinical
experience that supports its safety (Collins et al. 2010)for
use in the office and for prescription use by patients at
home. We use ketamine both in lower-dose sublingual
administration for a trance experience that promotes inter-
action during the session and the transformational IM
experience with its preparation, journey, and subsequent
For over five years now, KAP has been in clinical
development evolving a set of basic strategies and accu-
mulating experience from several hundred patients and
thousands of KAP sessions. We report here the results of
three distinct KAP practices, each having matured in con-
secutive time frames. Given the evolving nature of KAP,
there is a development of reporting as practices have
settled on particular assessment measures and criteria.
Over time, there has been an increase in available data
and emphasis on patient self-reports. This has enabled the
maturation of a dosing strategy into a replicable protocol.
What is provided here is both a qualitative and quantita-
tive expression and evaluation of our work to date.
The practices reporting here do not limit the use of
KAP to only patients with TRD. KAP has been used for
patients suffering from a variety of problemsrelation-
ship and existential issues including post-traumatic stress
disorder (PTSD), Bipolar I and II depressive phases,
obsessive-compulsive disorder (OCD), psychological
reactions to physical illness, personality disorders, life-
threatening illnesses, and substance use co-occurring
with a primary psychiatric disorder. We do not view
ketamine as a stand-alone medicine fitting all possibili-
ties. The encounter here is with practices addressing the
human gamut with all the available tools of psychiatry
and psychotherapy.
Ketamine as a medicine: A brief review
Ketamine is available in two enantiomers: the S (+) and
the R () configurations. The S isomer is estimated to
be approximately twice as powerful as the R (Weber
et al. 2004). There is controversy in distinguishing
a pattern of different effects between the two. Current
pharmacological preparations include an equimolar
racemic mixture of the two enantiomers. S (+) keta-
mine has just come to market with FDA approval as
a patented antidepressant nasal preparation for in-
office psychiatric use.
Multiple routes of administration are used by practi-
tioners treating depression and other psychiatric con-
ditions, each with its own unique pharmacokinetics.
These include IV, IM, intranasal (IN), sublingual (SL),
anal, and oral delivery. Each has its own rate of absorp-
tion and timing of onset. In our practices, new patients
tend to begin with the SL method for assessment of
sensitivity to the medicine.
Ketamines antidepressant activity is believed to stem
from its antagonism of NMDA receptors within the gluta-
mate neurotransmitter matrix. Based on animal models, it
is believed that ketamine-induced synaptic potentiation
and proliferation may play a key role in eliciting antide-
pressant effects. Ketamine also impacts other neurotrans-
mitter systems, affecting cholinergic, monoaminergic,
kappa opioid, and GABAergic function, most likely as
downstream indirect effects (Wallach 2018). A recent
paper describing the use of naltrexone in six patients receiv-
ing low-dose ketamine infusions (Williams et al. 2018)has
created controversy as to the putative effects of ketamine on
opiod receptors and the possible clinical implications. This
has been contradicted by earlier, more thorough work by
Krystal et al. in 2007; and by receptor research (Wallach
2018). It is our view that the antidepressant effect of keta-
mine is not the direct result of signaling via the opiate
The bioavailability of IM ketamine is similar (93
95%) to IV ketamine. SL ketamine absorption is vari-
able and difficult to estimate but most likely in the
range of 1525%. IN ketamine absorption is higher at
about 2535%, depending on person and preparation.
Oral absorption is much less efficient, at 10% or less,
and takes more time to have its effect (Wieber et al.
1975). The swallowing of ketamine from SL or IN
administration may result in a remote onset of keta-
mines effect when it does occur somewhere in the
range of 4575 minutes later.
Ketamines tolerability and safety have been demon-
strated over almost five decades (Jaitly 2013). A pooled
data study from three different clinical trials of subanes-
thetic IV ketamine administration in major depressive dis-
order (MDD) patients found that adverse effects common
within the first four hours of administration included dizzi-
ness, derealization, and drowsiness (McGirr et al. 2014).
Whethertheseareconsideredadverseor as part of keta-
mines actual effects that result in therapeutic benefit is the
subject of debate. One third of all patients experienced
transient hemodynamic changes, particularly elevated
blood pressure. There have been no cases of persistent
neuropsychiatric sequelae, medical effects, nor increased
substance abuse in clinical practice. Use of a body weight
schema for a determination of ketamine dosage is of limited
clinical utility, as sensitivity to the medicine is idiosyncratic
and only fully predictable with patient experience.
Increasing the dosage of ketamine utilizing any of the routes
of administration will result in an increase in dissociative
The KAP experience: Trance and transformation
KAPs effectiveness lies in several factors. Depending
upon dose, ketamine promotes a time-out from ordin-
ary, usual mind, relief from negativity, and an openness
to the expansiveness of mind with access to self in the
larger sense. These effects enhance a patients ability to
engage in meaningful psychotherapy during and after
administration. Ketamine is potent for respite, analysis,
and meditative presence, and potent for recovery from
depression and the lingering effects of trauma. For
most patients, we begin with the sublingual induction
of the trance state to find an individual sweet spot
with respect to dosage that can be replicated at home
under supervision and used in future in office sessions
to aid in psychotherapy. We may then move to the IM
experience of transformation based on the patient, pro-
ducing an out-of-body experience which allows for
a unique but related approach to healing. These two
modes of treatment are outlined in Table 1.
KAP is intensive, demanding, and rewarding for its
practitioners and their patients. The long sessions, up to
three hours, plus provision of supervised recovery for
patients, can be fatiguing. As with any mind-altering
experience, there are set and setting considerations. In
our offices, we make every effort to provide a nest in the
Winnicott sense, a place of safety and warmth (Carhart-
Harris et al. 2018). Since the breakage of trust or the lack of
its acquisition are so much at the core of trauma persis-
tence, the behavior of therapists and their ability to bond
with patients are at the heart of our psychotherapy (Van
Der Kolk 2014). Long exposure to each other requires
a more human, intimate, and disclosing posture by thera-
pists while maintaining the boundary of not needingof
our patients. Attachment wounds are best healed in
a therapeutic environment that is reliable, compassionate,
appears safe, and recognizes the vulnerability of its patients
(Brown and Elliott 2016). An altered state is a vulnerable
state. In recognition of this, we frequently work dyadically,
enabling our patients to let down vigilance and journey
freely and without concern for intrusion or violation. If two
therapists (including an MD, FNP, or NP) are not available,
we have another therapist present on premises. This prac-
tice is in accord with the method of MAPS MDMA-
assisted psychotherapy. Adaptation of different methods
to psychedelic psychotherapy, such as Internal Family
Systems (Schwartz 1995), is an opportunity for growth and
creativity and for expansion of the theory and practice of
such methods.
Maintenance of the observing self is fundamental to
the success of our work and guides dosage selections.
Our monitoring consciousness rides with the journey
and comments at a fundamental level. It is accentu-
ated and deepened as in profound meditative states.
The journey tends to augment meditative ability and
stability (Millière et al. 2018).
Table 2 highlights the signatureof the ketamine
experience and therapeutic integrations.
In the freedom of an inward journey, absent the
emotional constraints of ordinary mind and free of
ones sense of inherent form, a sense of vast space arises.
The journey unfolds in different realities that may seem
the truth of being, outside of time and space, as if
observing our being in different realities. At times, this
may be confusing as the experience may be intense with
only the observing mind connecting to a sense of self.
This study is of KAPs effectiveness in providing the
means to personal elucidation which results in decrease
in symptomatology. We call this anchoring the essential
elements gained from the experience. This can take
many forms, including slogans, mantras, visions, inter-
nal movies, feelings, metaphors, and understandings.
This is about learning from the experience, bringing it
Table 1. The KAP experience: Trance and transformation.
Trance State SL with dose ranges
25400 mg varying with
individualslower onset 820 min
Promotes communication, access
to difficult states of mind with less
fear of those encounters, and
a relief from obsessive and
depressive concerns. Conscious
awareness and an ability to
communicate with attending
and involved relatives is
maintained throughout the
experience, often with a reduction
in direct verbal output. Integrate
a sense of newness and healing,
this occurring as the main
experience diminishes. Working
with this state is usually a multiple-
session process that can last
anywhere from two weeks to many
Transformational State IM
with dose ranges of 25130 mg
varying with the individualfast
onset 24 min, patients with less
sensitivity may receive higher
Reduction of body and sensory
awareness of an ego reductive,
spiritual and liberatory nature
from our usual sense of our
constitution. While the full out-of-
body experience is primarily
reached with an IM injection, it
may also be accessed with the
sublingual lozenge, depending on
individual sensitivity and dose.
With diminution of tactile and
visual sensation, and alteration of
auditory receptivity, the internal
visual realm is activated. Verbal,
intellectual description is limited.
Note: In our practices, we use the first KAP session to determine an
individual patients dose response curve and thus their individual dose
range that will allow them to reliably access the trance state in office
sessions and at home. The trance state is ideal for psychotherapy and
meditative self-reflection. The deep or peak experience tends to last
2560 minutes with a period of lesser intensity following, usually lasting
less than an hour. Set and setting and the presence of skilled therapists in
the KAP process make for integrations of powerful experiences that are
healing and rectifying. The role of the therapist is to support the indivi-
dual to find their own path, their own peaceor wrath, their own
accommodation and acceptance of the life livedor not. KAP is an
experience of self that is mediated by contact with administering thera-
pists and attendant loved ones, but without imposition of values and
Table 2. The ketamine signature.
Psychopharmacology Rapid onset
Rapid metabolism
Dosage escalation enables, then reduces,
therapeutic sharing
Dose-related reduction or elimination of external
sensations, particularly visual, tactile, and auditory
Effects Sensualas connectedness and appreciation.
Physically sensually stimulating for some. Recall
may be limited and is dose-dependent.
Observing self present throughout, independent of
recollection. Awareness consciousness heightened.
Fluid connectivity and thematic movement =
unique experiences. The mind roams freely while
being observed.
Little ability to direct the experience.
Heightened internal visual experience; reduction
of verbal thinking. Entering a different realitytotal
at higher doses; can be confusing. Transition to
a state separate from obsessions, circularity, and
Qualia Out-of-body experience; out of bounded time; out
of bounded space. Ego dissolution.
Humilityas situating ones self in time and space
a larger view of ones smallness. Cosmic
Love as connectedness. Formlessness.
Experience of being an energy format.
Apprehension of death from the perspective of
Spacious Presence Absence of negative emotions. A peaceful
Effortless self-acceptance. Possibility for highly
positive affect. Self-appreciation.
Therapeutic Goals
Breakage of patterns and circularity.
Perception of the depressive door opening to new
experience. Remodeling of sense of self.
Enhanced flexibility. Discrimination of wisdom.
Trust in the stability of the mind. Discrimination of
Putting trauma in the past. Moving towards
A relaxation of habitual vigilance and distrust of
self. A tendency to accept impermanence.
Reduction of negativity.
Enhanced capacity for meditative mindfulness.
New mental formations.
Enhanced creativity.
Respect for mental capacities. Diminution in the
fear of going crazy. Awe.
Ego dissolution, opening the mind to
wonderment. Reduction of negative narcissism
and self-obsession. Trust in self and others.
Sense of spaciousness and capaciousness of mind.
Trust in the intuitive self and spontaneity.
Relaxation and openness to experience and to
as method to everyday life. In essence, we use the
experiential component of the medicine to bring new
perspective and the direct experience of seeing our-
selves in a new waythe missing link that gives hope
to many sufferers of mental illness and others who
cannot achieve this critical reframing by other means.
All participants provided written informed consent.
Three forms were developed for data collection by the
Ketamine Research Foundation (KRF) Ketamine Data
Project (KDP) using a Redcap research database:
Intake, Visit, and Termination (when applicable).
Chart data were inputted consecutively from all three
practices. Where charts were incomplete, or the work
was too limited to input, a list of these was generated
with rationales for exclusion.
The forms contain demographic, diagnostic, medica-
tion, psychoactive history, psychiatric history, medical
history, and family data. Rater views of personality
rigidity, recommendations for ketamine administra-
tion, and concerns are included in the intake form. Self-
report data collected before KAP treatment (baseline/
intake) included the Beck Depression Inventory (BDI),
Hamilton Anxiety Scale (HAM-A), Patient Health
Questionnaire9 (PHQ-9), Childhood Resilience Scale
(CRS), and Adverse Childhood Event Score (ACE).
Follow-up self-report measures from the last
available office visit included BDI, HAM-A, PHQ-9,
and Levine Depression Scale Ratings. Rater view of
patients symptoms as well as the quality of the KAP
session experience were recorded. Change of State,
Mystical Experience Questionnaire (MEQ), and Ego
Dissolution Index (EDI) (Nour et al. 2016) were used
to assess KAP sessions.
During KAP treatment, patients received ketamine SL,
IM, or both during their treatment course. SL ketamine
was administered as either troche or a rapid-dissolve
tablet during the initial in-office session to determine
sensitivity and dose for the individual. Dose ranges were
titrated in office and then adjusted at home to achieve and
maintain access to the trance state described. This state
facilitates psychotherapy sessions and individual reflec-
tion at hometo maintain the therapeutic momentum, and
cannot be determined by a weight-based protocol in our
experience. Subsequently, SL ketamine was prescribed in
a limited amount without refills for at-home use with
instructions to use SL ketamine up to but not exceeding
six sessions over a two-week period, with less frequency
thereafter, depending on severity. Patients were instructed
to replicate the setting and procedure demonstrated by
the clinicians in the initial session at home. KAP sessions
were generally held in the office usually two weeks apart,
or more frequently depending on acuity. Different diag-
noses have different frequencies for KAP and all of our
practices are individualized. IM ketamine was adminis-
tered during in-office sessions only, usually supported by
ongoing SLsessions at home. IM doses were used to reach
the transformational state described earlier in which out-
of-body experiences are common and therapeutic. Not all
patients moved on to use the IM route of administration,
and this was determined at the discretion of the provider
based on therapeutic progress and symptom relief.
Rater views of KAP effects proceed through the Visit
and Termination forms, as does the history of admin-
istration. Raters provide their estimates of the presence
and intensity of psychedelic effects and their impacts,
sensitivity to ketamine, changes in symptoms and well-
being, plus adverse effects, drug interactions, changes in
medications, changes in diagnosis, and commentary of
a psychodynamic and qualitative nature.
SAS software was used to analyze the data. Statistical
tests used include correlations and moderation ana-
lyses. P-values were recorded and reviewed for clinical
relevance by the authors.
Data from 235 patients from three distinct private
general psychiatric practices located in Northern
California (Wolfson and Dore) and Austin, Texas
(Turnipseed) from 20132018 were collected prospec-
tively and analyzed retrospectively. Diagnoses among
these KAP patients at intake are shown in Figure 1.
Frequency of Adverse Effects is shown in Figure 2.
The sample had a mean age of 42.7 years, 48.9% were
women, and 85.5% had either a bachelorsdegreeor
postgraduate degree. Patients initiating KAP treatment
were taking an average of 2.84 medications for psychiatric
complaints at intake. These included antidepressants, sti-
mulants, mood stabilizers, antipsychotics, sedatives/
anxiolytics, and other medications. On average, indivi-
duals fell in the moderate depression category as per BDI
(mean = 26.55) and moderate anxiety category as per
HAM-A scale (mean = 20.35) before treatment and had
a significant ACE score (mean = 3.63). Average resilience
score at baseline was 8.27. About one-third (35%) of our
population had previous experience with psychoactive
substances. These included MDMA (n=34),LSD(n=
34), psilocybin (n= 29), ayahuasca (n=6),andketamine
(n= 6). Usual number of years in psychotherapy for our
KAP patients was 35 years. Total number of people who
received IM ketamine was 61.5%. The average dose range
of ketamine during KAP sessions was 200250 mg for the
SL route and 8090 mg for the IM route in our sample.
Outcomes included decreases in anxiety and depres-
sion. Figure 3 demonstrates clinically significant
improvements in depression and anxiety as measured
by BDI and HAM-A. Subset analysis of the improve-
ment in depression and anxiety demonstrates that
patients with developmental trauma (cPTSD) or devel-
opmental trauma have greatest improvement in depres-
sion and anxiety scores. Patient self-reported measures
(HAM-A, BDI, change of state scores) correlated with
clinician rater views on visit and termination forms
(including depression, anxiety, PTSD, well-being), con-
firming internal consistency between clinician report
and patient self-report. Pvalues for all of these correla-
tions were significant at p< 0.0001.
Number of in-office KAP sessions ranged from 1 to
25 sessions, which were spread over variable time peri-
ods from initial session to visit evaluation to termination
where applicable. The number of ketamine sessions posi-
tively correlated with improvements in the Levine Rapid
Depression Scale (p<0.001),andimprovementsinBDI
from pre- to post-treatment (p< 0.01), indicating that
a higher number of visits was correlated with greater
improvements in depression post-treatment. Treatment
duration positively correlated with Depression Rater
View (p< 0.05) and Anxiety Rater View (p<0.05),
showing that those with a longer total duration of treat-
ment also showed greater improvements in depression
and anxiety.
Figure 1. Distribution of most common diagnoses in our sample population. At intake, patients underwent a full psychiatric
evaluation by licensed mental health providers (MD/NP/therapist teams) who assessed whether patients meet diagnostic criteria
according to the DSM-V. Diagnosis are listed: Major Depressive Disorder (MDD), Developmental Trauma (cPTSD), Attention Deficit
Hyperactivity Disorder (ADHD), Post Traumatic Stress Disorder (PTSD), Generalized Anxiety Disorder (GAD), Substance Use Disorder
(SUD including Alcohol n= 14, Cannabis n= 11, Opioid n= 3, Inhalant n= 3, Cocaine n= 1, Nicotine n= 1, Stimulant n= 1, and
Other psychoactive n= 5), Other anxiety disorder (Unspecified, Due to physiological cause, SAD, Agoraphobia, Panic), Other mood
disorder (Bipolar Disorder, Unspecified, Premenstrual Dysphoric Disorder, Dysthymia).
Figure 2. The most common side effects seen in our KAP population are nausea, vomiting, and agitation, which occur only in a small
percentage of patients undergoing KAP treatment and rarely lead to discontinuation of the treatment.
Patients with severe symptom burden (including
higher BDI at intake, suicidality at intake and within
past year, history of psychiatric hospitalization, and
higher ACE scores) had more significant improvements
with KAP treatment, as demonstrated by greater
improvement in anxiety scores, well-being scores, BDI,
PTSD scores, drug and alcohol use scores with treatment,
p< .01 for all correlations. Additionally, increased age was
correlated with greater improvement of depression as per
rater view (p< .05), lower HAM-A with treatment (p<
.01), and lower BDI with treatment p< .05.
KAP is a unique, ground-breaking treatment with two
essential modalities that have led to successful treatment
outcomes in our clinical practices. We have presented
these two modalities as tranceand transformation.
Ketamine has a dose-related continuum of psychoactivity
that modifies therapeutic communication and interac-
tion, and which provides a range of effects from one
medicine decreasing symptoms and facilitating new
ways of being for our patients. Our view is that the
psychedelic, or dissociative, effects are an integral part of
KAP, not to be feared or avoided, but instead that offer
benefit to our patients when supported and integrated in
a psychotherapeutic context. This benefit occurs not only
across a range of doses but also for a range of diagnoses
and human difficulties that present within the context of
a general psychiatry private practice. KAP stands at the
forefront of legal psychedelic psychotherapies as MDMA
and psilocybin enter Phase 3 Studies. The practice of KAP
has thus laid the groundwork for a growing body of
practitioners who will adopt the principles of psychedelic
psychotherapy as a part of the future of mental health
In this study, we present a portrait of KAP which
combines patient experiences from three practices of
different maturity. Importantly, we found significant
benefits for many diagnoses. The population we present
reflects the interest from the general population in
ketamine work, often stemming from failed prior treat-
ments. Our patients come to KAP with moderate levels
of depression and anxiety, and a significant amount of
adverse childhood events.
given that the most common reason for discontinuing
conventional pharmacological treatment for depres-
sion and anxiety is the inability to tolerate side effects
such as nausea or sexual dysfunction. Ketamine can be
administered frequently when symptoms are acute (up
to every 48 hours), or periodically in a maintenance
format, depending on the needs of the patient.
Episodic, intermittent use of a medication is, for
many patients, preferable to constant exposure, as
with daily antidepressants. Intermittent use of medi-
cation also decreases the potential for adverse effects.
We also note that, despite the stigma of recreational
use and concerns regarding addiction, ketamine used
in KAP practice does not produce any physical depen-
dence. Importantly, we have not had patients seek
ketamine outside of our clinical practices or encoun-
tered any other indication of addictive behavior.
Figure 3. Average BDI and HAM-A scores at baseline compared with follow-up reveal a statistically significant decrease in anxiety
and depression with treatment. Intake BDI scores on average fell in the range of moderate depression (2028) and decreased an
average of 11.24 points to mild depression range. Intake HAM-A scores fell in the moderate anxiety category and decreased on
average 5.5 points to the mild anxiety category.
Despite the fact that much of our cohort was naive
to psychoactive experiences (65% naive to psychoac-
tives), patients were open to their future ketamine
experiences having psychedelic aspects. Psychedelic
experiences were well-tolerated and sought after as an
essential component of their healing process. Our
patient population, in their at-home administration,
under close supervision, adjusted their dosage to
a balance between trance depth and recollection of
their experiences. This aspect of our work is unique
in that it requires patients to be more engaged and
creative in their own settings.
Our patients experienced a clinically significant decrease
in anxiety and depression with treatment as compared to
baseline at intake. We also found that patients who have
more severe symptoms, including current suicidality, high
BDI at intake, and higher ACE score, tend to show the
most significant benefit. These correlations help us to begin
to form hypotheses about which types of patients benefit
most from KAP and will help guide treatment decisions
and the integration of this modality into general psychiatric
practice. Findings are limited by the instruments we have
used to measure change. In our clinical experience, we have
observed significant benefit even in the patients who
appear to function relatively well and report less sympto-
matology. Future studies are needed to characterize these
Ketamine is not for everyone. Some patients are
sickened by ketamine and a subset (< 5%) cannot
tolerate the nausea and vomiting experienced even
with preventative medication. A small percentage
(12%) do not respond to ketamine even at high IM
doses. Others, particularly those with rigid personality
structures, such as those with severe OCD or person-
ality disorders and perhaps severe PTSD, find entering
the trance state difficult and are not able to sustain the
benefits they experience during the actual sessions,
even if they do indeed experience some relief.
While we are unable to comment on neurobiological
mechanisms of action, there is the suggestion that neu-
roplastic changes may be at work, as well as possible
anti-inflammatory effects. Our finding that older
patients have more significant improvement in depres-
sion over the course of their treatment tends to support
this. We thought at first that increased benefit with age
might reflect the amount of psychotherapy that
a patient had upon entering KAP treatment; however,
this variable was not significant.
KAP differentiates itself from the IV practices that have
burgeoned in recent years. We have presented our office-
based practices and our controlled prescriptions for at-
home use. While we follow the protocol that includes
frequent sessions in the first stage of ketaminesapplication
for depression and TRD (most commonly six sessions in
two weeks, which may be repeated until remission is
achieved), our work embeds ketamine administration
within a psychotherapeutic framework for both in-office
sessions and home use. As therapy proceeds, we move to a
maintenance approach with less frequent ketamine ses-
sions, or sessions that are conducted to prevent significant
relapes. We provide treatment plans that include varied
frequencies and doses of administration for other psychia-
tric diagnoses, adapting our KAP treatment to each
patients individual needs through frequent contacts and
close communication.
Comparison of outcomes and effects between the IV
practices and KAP are difficult to obtain at this point.
Our data set appears to be more complex than what is
reported by the IV practices and we have the benefit of
experience in diagnosing and treating psychiatric dis-
orders and combining treatment modalities. We antici-
pate showing a more complete set of our emerging data
in the next year as uniformity in reporting enables this.
Presently, the use of ketamine with KAP versus the IV
practices differentiate in methodology, as well as in
economics. KAP, even with its intensity and long ses-
sions, is significantly less expensive overall.
Table 1 describes our approach for achieving both the
Trance and Transformation experiences in individual
patients, this method having been developed over the five
years that KAP has been practiced. Thus, our positive
findings in this article reflect an evolving methodology
using ketamine with psychotherapy as described, as
opposed to a specific protocol. We have now developed
a step-by-step approach that is manualized and taught in
our trainings (In trainings conducted by KRF). Further
research is required to refine, validate, and test the compo-
nents of this protocol, and to compare outcomes of the
protocol with those of IV ketamine interventions and with
standard of care interventions in mental health treatment.
In addition, affordability and access to treatment are
a major concern for both practitioners and potential
Ketamine Assisted Psychotherapy is a new and unique
methodology with a rapidly growing group of practi-
tioners participating in its development and practice.
We have presented a view of its current status combining
data from three different related centers, with
attendant outcomes with correlations. Psychedelic experi-
ence is an inherent, valued, and well-tolerated part of our
methodology. Our data support the efficacy of KAP for
a wide variety of psychiatric diagnoses and human
difficulties, significantly diminishing depression, anxiety,
and PTSD and increasing well-being.
None of the authors of this paper have a financial interest or
benefit arising from the direct applications of this research.
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... Given the lack of clinical trials employing psychedelic models for ketamine [despite encouraging retrospective reports (111)(112)(113)], we provide a concise review of the prevailing psilocybin-assisted psychotherapy (PAP) protocols which serve as the basis for most contemporary psychedelic ketamine models (112). We focus on the most common and distinctive approach involving one or two high doses of psilocybin, rather than the less common "psycholytic" approach-smaller doses used in conjunction with relatively frequent psychotherapy sessions (114)-or microdosing, the regular use of subperceptual doses of psychedelics without psychotherapy in a manner resemblant of oral antidepressants (115). ...
... Given the lack of clinical trials employing psychedelic models for ketamine [despite encouraging retrospective reports (111)(112)(113)], we provide a concise review of the prevailing psilocybin-assisted psychotherapy (PAP) protocols which serve as the basis for most contemporary psychedelic ketamine models (112). We focus on the most common and distinctive approach involving one or two high doses of psilocybin, rather than the less common "psycholytic" approach-smaller doses used in conjunction with relatively frequent psychotherapy sessions (114)-or microdosing, the regular use of subperceptual doses of psychedelics without psychotherapy in a manner resemblant of oral antidepressants (115). ...
... In sum, PAP can generally be understood as synergistic mindbody interventions typically conducted in three phases: preparatory sessions, one to two doses of psilocybin administered with careful attention to set and setting, non-directive psychological support, and post-experience integration (80). Actual practices vary significantly, and this is particularly true for psychedelic approaches to ketamine, where the numbers of treatment sessions range from one to dozens (112), dosages range from 0.1 mg up to and beyond 4 mg/kg parenterally (123), and routes of administration include intravenous, sublingual, intramuscular, and oral (112). ...
Full-text available
Background: Subanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine’s mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties. Methods: This article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives’ strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model’s various components, which are presented in detail. Results: The Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support. Discussion: Our integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model’s effectiveness and hypothesized psychological mechanisms.
... The expansion of the use of ketamine/esketamine has led to a variety of therapeutic approaches including ketamine assisted psychotherapy (Bennett, Yavorsky, and Bravo 2022;Dore et al. 2019). Nevertheless, despite its growing use, there have been few attempts to summarize clinical protocols and the setting in which these medications have been used. ...
... These findings suggest a predominantly biomedical paradigm for the study of ketamine and esketamine in the treatment of depressive disorders. This is reinforced by the fact that altered states of consciousness, such as the psychedelic dissociative experience, are interpreted as an adverse event in some modern studies (Mathai, Mora, and Garcia-Romeu 2022), especially in settings where psychotherapy is not offered (Dore et al. 2019). Historically, initial attempts investigating the antidepressant potential of ketamine did not focus on the psychedelic effects of the substance (Dore et al. 2019). ...
... This is reinforced by the fact that altered states of consciousness, such as the psychedelic dissociative experience, are interpreted as an adverse event in some modern studies (Mathai, Mora, and Garcia-Romeu 2022), especially in settings where psychotherapy is not offered (Dore et al. 2019). Historically, initial attempts investigating the antidepressant potential of ketamine did not focus on the psychedelic effects of the substance (Dore et al. 2019). This is in contrast with findings which suggest that subjective effects may be correlated with the antidepressant response (Luckenbaugh et al. 2014;Mathai et al. 2020;Niciu et al. 2018;Sos et al. 2013). ...
Depression is one of the most prevalent mental health disorders globally, causing severe emotional suffering, reducing life expectancy and increasing the risk of suicide. Recently, the use of dissociative psychedelic substances such as ketamine and esketamine for depressive disorders has expanded treatment options. We sought to analyze, through a systematic review, the existing protocols for the treatment of depression with ketamine and esketamine. The search adopted PRISMA criteria and was performed using PubMed and Web of Science databases. Procedures in each study were compared, focusing on the sample recruited, therapeutic approaches, including the clinical team and professionals engaged in treatment, medical procedures, description of the setting (including music) and factors such as specific medication (ketamine or esketamine), route of administration and dosage employed. Results indicated the predominance of a medical approach, with a limited number of studies on ketamine assisted psychotherapy (KAP) and other modalities of psychedelic assisted therapy. Additionally, there is limited information on psychosocial elements such as preparation, psychological support during session and integration of experience. Altogether these findings suggest that treatment of depression with ketamine or esketamine diverges in relation to the practices employed with psychedelic substances. This is discussed considering future research directions in the field.
... To date, no psychedelic substances have been approved for the treatment of any condition outside of research studies. The lone exception to this is the legal anesthetic ketamine, which is approved for the treatment of severe depression and has been used for other mental health conditions as well (e.g., Dore et al., 2019). Notably, studies of ketamine have largely excluded people of color (Michaels et al., 2022) One exception is a case study conducted at our clinic in Connecticut, we described the use of ketamine-assisted therapy for the treatment of racial trauma in a person of color (Halstead et al., 2021). ...
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Psychedelics are being studied for the treatment of numerous mental health disorders, as well as a means of bringing people together. Nonetheless, people of color and those with other marginalized identities have not been fully included. Studies and research on psychedelic-assisted therapies have largely excluded people of color, leaving out fundamental clinical issues for these populations. This paper provides a narrative review of relevant research on this topic, racial trauma, ethnic minority mental health, and how psychedelic therapies can advance recovery for people of color. It also discusses potential harms and steps needed to promote culturally inclusive access to care. Many psychedelic therapy trials are in their final stages and access is being expanded, making it important to consider equitable practices in research that can foster inclusion, such as community-based participatory research and culturally informed research design.
... Given that ketamine treatment shows efficacy with a substantive percentage of TRD patients (7)(8)(9)(10)(11), an added psychotherapy component may prove to be highly effective in selected patient populations. To date, the most robust evidence for the efficacy of KAP using a psychedelic protocol applied to a wide range of mood and trauma-related conditions comes from a retrospective study of 235 adult patients in three separate private general psychology practices in Northern California and Texas (12). The most common diagnoses in this varied group were MDD and complex posttraumatic stress disorder (cPTSD), and the treatment varied from 1 to 25 sessions. ...
... These data suggest that therapeutic responses can be driven by drug effect alone (consistent with the psychoplastogen model of efficacy), though these effects may be enhanced in the context of psychedelic-style psychotherapy. Unfortunately, there are still few controlled studies investigating ketamine in this latter context [252][253][254], and no head-to-head comparisons of intravenous ketamine with and without integration (or other psychotherapy components) have been published. Preclinical studies on the mechanism of ketamine support a ketamine-aspsychoplastogen model [48,109]. ...
Recent clinical and preclinical evidence suggests that psychedelics and entactogens may produce both rapid and sustained therapeutic effects across several indications. Currently, there is a disconnect between how these compounds are used in the clinic and how they are studied in preclinical species, which has led to a gap in our mechanistic understanding of how these compounds might positively impact mental health. Human studies have emphasized extra-pharmacological factors that could modulate psychedelic-induced therapeutic responses including set, setting, and integration-factors that are poorly modelled in current animal experiments. In contrast, animal studies have focused on changes in neuronal activation and structural plasticity-outcomes that are challenging to measure in humans. Here, we describe several hypotheses that might explain how psychedelics rescue neuropsychiatric disease symptoms, and we propose ways to bridge the gap between human and rodent studies. Given the diverse pharmacological profiles of psychedelics and entactogens, we suggest that their rapid and sustained therapeutic mechanisms of action might best be described by the collection of circuits that they modulate rather than their actions at any single molecular target. Thus, approaches focusing on selective circuit modulation of behavioral phenotypes might prove more fruitful than target-based methods for identifying novel compounds with rapid and sustained therapeutic effects similar to psychedelics and entactogens.
... In the present study, we focus on classic psychedelics such as dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and psilocybin which are as Johnson et al. (2019, p. 84) stated 'psychoactive compounds that exert effects through agonist (including partial agonist) activity at the serotonin 2A receptor (5-HT 2A R)'. Moreover, we focus on ketamine, even though pharmacologically it is a dissociative anesthetic, it is sometimes labelled as a non-serotonergic psychedelic, or some of its effects are described as psychedelic or psychedelic-like (Bowdle et al., 1998;Dore et al., 2019;Krupitsky & Grinenko, 1997). ...
Objective To map the studies reporting the use of psychedelics in clinical and non-clinical settings by people reporting an eating disorder (ED) and their outcomes. Method To be included, peer-reviewed articles had to be written in English or Spanish and had to address the usage of psychedelics by people reporting an ED. Searches were conducted on PubMed, Scopus, and Web of Science. Data on key study characteristics and the findings from the studies were charted using a standardised form. Two reviewers independently charted the data from the included articles. Quality appraisal was conducted for all included studies. Results Six studies reporting the use of ayahuasca, DMT/5-MEO-DMT, LSD/1P-LSD, San Pedro/mescaline, psilocybin, and ketamine were included. After the psychedelic experiences, many participants reported diminished ED symptoms, reductions in anxiety, self-harm, suicidality, and problematic substance use, significant improvements in depression and wellbeing, and changes in self-perception, and some showed complete remission. Several participants felt profound spiritual healing and reported achieving deep insights into the psychological origins of their ED. All the qualitative studies met 100% of the quality appraisal criteria, whereas the quantitative studies were rated from between 20% and 60%. Discussion All included studies suggest that psychedelics promise therapeutic value for eating disorders. These findings are preliminary, and randomised controlled trials are necessary to prove psychedelic-assisted psychotherapy efficacy and long-term implications for eating disorders. Major changes in drug policy are urgent to facilitate research about psychedelics.
The prevalence of depression, anxiety, and post-traumatic stress disorder (PTSD) has increased among healthcare providers, while the effectiveness of conventional treatments remains limited. Ketamine-assisted therapy offers a promising alternative; however, few have integrated ketamine with a group-based therapeutic modality. We report a retrospective, secondary analysis of a 12-week pilot of a Community of Practice (CoP) oriented group therapy program with optional, adjunct ketamine for depression, anxiety, and PTSD in a sample of 57 healthcare providers. All participants moved through the treatment as one group, with 38 electing to also receive three adjunct ketamine sessions in addition to the weekly CoP. Symptoms were assessed at baseline and pilot completion with the PHQ-9 for depression, GAD-7 for anxiety, and PCL-5 for PTSD. We observed significant reductions in the mean change among all participants, suggesting that benefit was derived from the CoP component, with or without ketamine as an adjunct. PHQ-9 scores decreased by 6.79 (95% CI: 5.09-8.49, p < .001), GAD-7 scores decreased by 5.57 (CI: 4.12-7.00, p < .001), and PCL-5 scores decreased by 14.83 (CI: 10.27-19.38, p < .001). Reductions were larger, but statistically nonsignificant, among those receiving ketamine. Further research is required to assess the impact of ketamine as an adjunct in group-based therapies.
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Background: Psychedelic drug experiences are shaped by current-moment contextual factors, commonly categorized as internal (set) and external (setting). Potential influences of past environments, however, have received little attention. Aims: To investigate how previous environmental stimuli shaped the experiences of patients receiving ketamine for treatment-resistant depression (TRD), and develop the concept of "imprinting" to account for such time-lagged effects across diverse hallucinogenic drugs. Methods: Recordings of treatment sessions and phenomenological interviews from 26 participants of a clinical trial investigating serial intravenous ketamine infusions for TRD, conducted from January 2021 to August 2022, were retrospectively reviewed. A broad literature search was undertaken to identify potentially underrecognized examples of imprinting with both serotonergic and atypical psychedelics, as well as analogous cognitive processes and neural mechanisms. Results: In naturalistic single-subject experiments of a 28-year-old female and a 34-year-old male, subjective ketamine experiences were significantly altered by varying exposures to particular forms of digital media in the days preceding treatments. Higher levels of media exposure reduced the mystical/emotional qualities of subsequent psychedelic ketamine experiences, overpowering standard intention-setting practices and altering therapeutic outcomes. Qualitative data from 24 additional patients yielded eight further spontaneous reports of past environmental exposures manifesting as visual hallucinations during ketamine experiences. We identified similar examples of imprinting with diverse psychoactive drugs in past publications, including in the first-ever report of ketamine in human subjects, as well as analogous processes known to underly dreaming. Conclusions/interpretation: Past environmental exposures can significantly influence the phenomenology and therapeutic outcomes of psychedelic experiences, yet are underrecognized and understudied. To facilitate future research, we propose expanding the contextual model of psychedelic drug actions to incorporate imprinting, a novel concept that may aid clinicians, patients, and researchers to better understand psychedelic drug effects.
Full-text available
Suicide is a pressing public health issue, with over 700,000 individuals dying each year. Ketamine has emerged as a promising treatment for suicidal thoughts and behaviors (STBs), yet the complex mechanisms underlying ketamine's anti-suicidal effect are not fully understood. Computational psychiatry provides a promising framework for exploring the dynamic interactions underlying suicidality and ketamine's therapeutic action, offering insight into potential biomarkers, treatment targets, and the underlying mechanisms of both. This paper provides an overview of current computational theories of suicidality and ketamine's mechanism of action, and discusses various computational modeling approaches that attempt to explain ketamine's anti-suicidal effect. More specifically, the therapeutic potential of ketamine is explored in the context of the mismatch negativity and the predictive coding framework, by considering neurocircuits involved in learning and decision-making, and investigating altered connectivity strengths and receptor densities targeted by ketamine. Theory-driven computational models offer a promising approach to integrate existing knowledge of suicidality and ketamine, and for the extraction of model-derived mechanistic parameters that can be used to identify patient subgroups and personalized treatment approaches. Future computational studies on ketamine's mechanism of action should optimize task design and modeling approaches to ensure parameter reliability, and external factors such as set and setting, as well as psychedelic-assisted therapy should be evaluated for their additional therapeutic value.
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In recent years, the scientific study of meditation and psychedelic drugs has seen remarkable developments. The increased focus on meditation in cognitive neuroscience has led to a cross-cultural classification of standard meditation styles validated by functional and structural neuroanatomical data. Meanwhile, the renaissance of psychedelic research has shed light on the neurophysiology of altered states of consciousness induced by classical psychedelics, such as psilocybin and LSD, whose effects are mainly mediated by agonism of serotonin receptors. Few attempts have been made at bridging these two domains of inquiry, despite intriguing evidence of overlap between the phenomenology and neurophysiology of meditation practice and psychedelic states. In particular, many contemplative traditions explicitly aim at dissolving the sense of self by eliciting altered states of consciousness through meditation, while classical psychedelics are known to produce significant disruptions of self-consciousness, a phenomenon known as drug-induced ego dissolution. In this article, we discuss available evidence regarding convergences and differences between phenomenological and neurophysiological data on meditation practice and psychedelic drug-induced states, with a particular emphasis on alterations of self-experience. While both meditation and psychedelics may disrupt self-consciousness and underlying neural processes, we emphasize that neither meditation nor psychedelic states can be conceived as simple, uniform categories. Moreover, we suggest that there are important phenomenological differences even between conscious states described as experiences of self-loss. As a result, we propose that self-consciousness may be best construed as a multidimensional construct, and that “self-loss,” far from being an unequivocal phenomenon, can take several forms. Indeed, various aspects of self-consciousness, including narrative aspects linked to autobiographical memory, self-related thoughts and mental time travel, and embodied aspects rooted in multisensory processes, may be differently affected by psychedelics and meditation practices. Finally, we consider long-term outcomes of experiences of self-loss induced by meditation and psychedelics on individual traits and prosocial behavior. We call for caution regarding the problematic conflation of temporary states of self-loss with “selflessness” as a behavioral or social trait, although there is preliminary evidence that correlations between short-term experiences of self-loss and long-term trait alterations may exist.
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Objective: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects. Method: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1. Results: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis. Conclusions: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.
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Psychedelic drugs are making waves as modern trials support their therapeutic potential and various media continue to pique public interest. In this opinion piece, we draw attention to a long-recognised component of the psychedelic treatment model, namely ‘set’ and ‘setting’ – subsumed here under the umbrella term ‘context’. We highlight: (a) the pharmacological mechanisms of classic psychedelics (5-HT2A receptor agonism and associated plasticity) that we believe render their effects exceptionally sensitive to context, (b) a study design for testing assumptions regarding positive interactions between psychedelics and context, and (c) new findings from our group regarding contextual determinants of the quality of a psychedelic experience and how acute experience predicts subsequent long-term mental health outcomes. We hope that this article can: (a) inform on good practice in psychedelic research, (b) provide a roadmap for optimising treatment models, and (c) help tackle unhelpful stigma still surrounding these compounds, while developing an evidence base for long-held assumptions about the critical importance of context in relation to psychedelic use that can help minimise harms and maximise potential benefits.
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Aims: The experience of a compromised sense of “self”, termed ego-dissolution, is a key feature of the psychedelic experience. This study aimed to validate the Ego-Dissolution Inventory (EDI), a new 8-item self-report scale designed to measure ego-dissolution. Additionally, we aimed to investigate the specificity of the relationship between psychedelics and ego-dissolution. Method: Sixteen items relating to altered ego-consciousness were included in an internet questionnaire; eight relating to the experience of ego-dissolution (comprising the EDI), and eight relating to the antithetical experience of increased self-assuredness, termed ego-inflation. Items were rated using a visual analog scale. Participants answered the questionnaire for experiences with classical psychedelic drugs, cocaine and/or alcohol. They also answered the seven questions from the Mystical Experiences Questionnaire (MEQ) relating to the experience of unity with one’s surroundings. Results: Six hundred and ninety-one participants completed the questionnaire, providing data for 1828 drug experiences (1043 psychedelics, 377 cocaine, 408 alcohol). Exploratory factor analysis demonstrated that the eight EDI items loaded exclusively onto a single common factor, which was orthogonal to a second factor comprised of the items relating to ego-inflation (rho = −0.110), demonstrating discriminant validity. The EDI correlated strongly with the MEQ-derived measure of unitive experience (rho = 0.735), demonstrating convergent validity. EDI internal consistency was excellent (Cronbach’s alpha 0.93). Three analyses confirmed the specificity of ego-dissolution for experiences occasioned by psychedelic drugs. Firstly, EDI score correlated with drug-dose for psychedelic drugs (rho = 0.371), but not for cocaine (rho = 0.115) or alcohol (rho = −0.055). Secondly, the linear regression line relating the subjective intensity of the experience to ego-dissolution was significantly steeper for psychedelics (unstandardized regression coefficient = 0.701) compared with cocaine (0.135) or alcohol (0.144). Ego-inflation, by contrast, was specifically associated with cocaine experiences. Finally, a binary Support Vector Machine classifier identified experiences occasioned by psychedelic drugs vs. cocaine or alcohol with over 85% accuracy using ratings of ego-dissolution and ego-inflation alone. Conclusion: Our results demonstrate the psychometric structure, internal consistency and construct validity of the EDI. Moreover, we demonstrate the close relationship between ego-dissolution and the psychedelic experience. The EDI will facilitate the study of the neuronal correlates of ego-dissolution, which is relevant for psychedelic-assisted psychotherapy and our understanding of psychosis.
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Ketamine, via intravenous infusions, has emerged as a novel therapy for treatment-resistant depression, given rapid onset and demonstrable efficacy in both unipolar and bipolar depression. Duration of benefit, on the order of days, varies between these subtypes, but appears longer in unipolar depression. A unique property is reduction in suicidality although data are more limited. Strategies to extend duration, via multiple doses, maintenance treatment, or subsequent augmenting medications have yielded mixed results. There is a relative paucity of data regarding alternate methods of administration such as intramuscular, intranasal, and oral routes, though preliminary results are promising. Adverse effects most reliably incl ude dissociative and sympathomimetic effects, both transient and mild, and suggest good tolerability. Ketamine's unique effects may represent an opportunity for a paradigm shift in the pharmacologic treatment of depression.
Τhe Food and Drug Administration (FDA) approval of the use of S-ketamine in the form of nasal spray for the treatment of treatment-resistant depression, launched a new category of therapeutic agents in psychiatry. A well-known class of substances, psychedelics, are introduced with a 30-year delay in the treatment of mental disorders. Intravenous ketamine infusion has been studied in the treatment of depression since the 1990s. Here we present the current protocol for the treatment of ketamine infusion in patients with treatment-resistant depression and related clinical information.
Pharmacotherapy is often used to target symptoms of posttraumatic stress disorder (PTSD), but does not provide definitive treatment, and side effects of daily medication are often problematic. Trauma-focused psychotherapies are more likely than drug treatment to achieve PTSD remission, but have high dropout rates and ineffective for a large percentage of patients. Therefore, research into drugs that might increase the effectiveness of psychotherapy is a logical avenue of investigation. The most promising drug studied as a catalyst to psychotherapy for PTSD thus far is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as the recreational drug “Ecstasy.” MDMA stimulates the release of hormones and neurochemicals that affect key brain areas for emotion and memory processing. A series of recently completed phase 2 clinical trials of MDMA-assisted psychotherapy for treatment of PTSD show favorable safety outcomes and large effect sizes that warrant expansion into multi-site phase 3 trials, set to commence in 2018. The nonprofit sponsor of the MDMA drug development program, the Multidisciplinary Association for Psychedelic Studies (MAPS), is supporting these trials to explore whether MDMA, administered on only a few occasions, can increase the effectiveness of psychotherapy. Brain imaging techniques and animal models of fear extinction are elucidating neural mechanisms underlying the robust effects of MDMA on psychological processing; however, much remains to be learned about the complexities of MDMA effects as well as the complexities of PTSD itself.
This book brings together an international group of clinicians and researchers from a broad swath of inter-related disciplines to offer the most up-to-date information about clinical and preclinical research into ketamine and second-generation “ketamine-like” fast-acting antidepressants. Currently available antidepressant medications act through monoaminergic systems, are ineffective for many individuals suffering from depression, and are associated with a delayed onset of peak efficacy of several months. The unexpected emergence of ketamine, an anesthetic N-methyl-D-aspartate (NMDA) receptor antagonist, as a rapid-acting antidepressant has reinvigorated CNS drug discovery research and catalyzed investigation in patient populations historically ignored in antidepressant drug development programs, particularly treatment-resistant patients and those with suicidality. Recent industry and academic research efforts have coalesced to explore NMDA receptor and glutamatergic molecular targets that lack ketamine’s psychotomimetic side effects and abuse liability but retain its rapid onset of efficacy. However, many fundamental questions remain regarding the neurobiological mechanisms underlying ketamine’s rapid antidepressant effects and the puzzling persistence of benefits observed in some patients following a single dose. This book examines how insights from these studies are forging new conceptual models of the neurobiology of stress-related affective, anxiety, and addictive disorders and the nature of treatment resistance. It also discusses how ketamine’s rapid antidepressant effects provide a scientific platform to facilitate innovation in clinical trial designs pertaining to patient selection, choice of control group, outcome measures, and dose-optimization. This book brings together data and insights from this rapidly expanding and extraordinarily promising field of study. Readers will be able to extract integrated themes and useful insights from the material contained in these diverse chapters and appreciate the paradigm-shifting contributions of ketamine to modern psychiatry and clinical neuroscience research. © Springer International Publishing Switzerland (outside the USA) 2016.
4-phosphorloxy-N,N-dimethyltryptamine (psilocybin) and methylenedioxymethamfetamine (MDMA), best known for their illegal use as psychedelic drugs, are showing promise as therapeutics in a resurgence of clinical research during the past 10 years. Psilocybin is being tested for alcoholism, smoking cessation, and in patients with advanced cancer with anxiety. MDMA is showing encouraging results as a treatment for refractory post-traumatic stress disorder, social anxiety in autistic adults, and anxiety associated with a life-threatening illness. Both drugs are studied as adjuncts or catalysts to psychotherapy, rather than as stand-alone drug treatments. This model of drug-assisted psychotherapy is a possible alternative to existing pharmacological and psychological treatments in psychiatry. Further research is needed to fully assess the potential of these compounds in the management of these common disorders that are difficult to treat with existing methods.
Treatments such as ketamine psychotherapy face substantial financial and regulatory obstacles to dissemination into widespread use. Newly patented medications are able to generate enough capital to pay for studies required for FDA approval, personnel to apply for coverage on insurance plans, and marketing to establish a successful launch. Ketamine is an older drug with considerable evidence of efficacy for treatment resistant depression, and almost 50 years of data concerning safety as an anesthetic agent. However, it can no longer be patented, so there is no incentive for pharmaceutical companies to help get it into widespread use. In this paper we discuss some of the complex issues surrounding use of ketamine in the outpatient setting and share information and practice pearls that have been gathered through communication with other practitioners and through direct experience with over 1000 treatments involving 120 patients in the last eight years. The safety and appropriateness of intramuscular ketamine treatment in the outpatient psychiatric office is discussed. We hope to help proponents of effective mental health interventions navigate the actual and potential challenges involved in safe application of this treatment option outside of hospital-based programs.