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Single Versus Repeated Sessions of Ketamine-Assisted Psychotherapy for People with Heroin Dependence

  • V.M.Bekhterev National Medical Reserach Center for Psychiatry and Neurology

Abstract and Figures

A prior study found that one ketamine-assisted psychotherapy session was significantly more effective than active placebo in promoting abstinence (Krupitsky et al. 2002). In this study of the efficacy of single versus repeated sessions of ketamine-assisted psychotherapy in promoting abstinence in people with heroin dependence, 59 detoxified inpatients with heroin dependence received a ketamine-assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and were then randomized into two treatment groups. Participants in the first group received two addiction counseling sessions followed by two KPT sessions, with sessions scheduled on a monthly interval (multiple KPT group). Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year follow-up, survival analysis demonstrated a significantly higher rate of abstinence in the multiple KPT group. Thirteen out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to 6 out of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. It was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.
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Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 13 Volume 39 (1), March 2007
Single Versus Repeated Sessions of
Ketamine-Assisted Psychotherapy for
People with Heroin Dependence
Evgeny M. Krupitsky, M.D., Ph.D.*; Andrei M. Burakov, M.D., Ph.D.**;
Igor V. Dunaevsky, M.D., Ph.D.***; Tatyana N. Romanova, M.S.****;
Tatyana Y. Slavina, M.D., Ph.D.***** & Alexander Y. Grinenko M.D., Ph.D.******
Abstract A prior study found that one ketamine-assisted psychotherapy session was signicantly
more effective than active placebo in promoting abstinence (Krupitsky et al. 2002). In this study of the
efcacy of single versus repeated sessions of ketamine-assisted psychotherapy in promoting abstinence
in people with heroin dependence, 59 detoxied inpatients with heroin dependence received a ketamine-
assisted psychotherapy (KPT) session prior to their discharge from an addiction treatment hospital, and
were then randomized into two treatment groups. Participants in the rst group received two addiction
counseling sessions followed by two KPT sessions, with sessions scheduled on a monthly interval
(multiple KPT group). Participants in the second group received two addiction counseling sessions
on a monthly interval, but no additional ketamine therapy sessions (single KPT group). At one-year
follow-up, survival analysis demonstrated a signicantly higher rate of abstinence in the multiple KPT
group. Thirteen out of 26 subjects (50%) in the multiple KPT group remained abstinent, compared to
6 out of 27 subjects (22.2%) in the single KPT group (p < 0.05). No differences between groups were
found in depression, anxiety, craving for heroin, or their understanding of the meaning of their lives. It
was concluded that three sessions of ketamine-assisted psychotherapy are more effective than a single
session for the treatment of heroin addiction.
Keywords—hallucinogens, heroin addiction, ketamine, psychedelics, psychotherapy, treatment
†This study was supported by the Multidisciplinary Association for
Psychedelic Studies (MAPS), Sarasota, Florida, USA and by the Heffter
Research Institute, Santa Fe, New Mexico, USA. The authors are also very
thankful to Rick Doblin, Lisa Jerome, Valerie Mojeiko, and Dr. George
Greer for assistance in editing the manuscript, and to Tatyana Volskaya,
M.A., for data management.
*Chief of the Research Laboratory, St. Petersburg Regional Center of
Addictions and Psychopharmacology, St. Petersburg State Pavlov Medical
University, St. Petersburg, Russia.
**Psychiatrist, St. Petersburg Regional Center of Addictions and
Psychopharmacology, St. Petersburg State Pavlov Medical University, St.
Petersburg, Russia.
***Anesthesiologist, St. Petersburg Regional Center of Addictions
and Psychopharmacology, St. Petersburg State Pavlov Medical University,
St. Petersburg, Russia.
****Clinical Psychologist, St. Petersburg Regional Center of
Addictions and Psychopharmacology, St. Petersburg State Pavlov Medical
University, St. Petersburg, Russia.
*****Psychiatrist and Medical Director, St. Petersburg Regional
Center of Addictions and Psychopharmacology, St. Petersburg State Pavlov
Medical University, St. Petersburg, Russia.
******Director, St. Petersburg Regional Center of Addictions and
Psychopharmacology, St. Petersburg State Pavlov Medical University, St.
Petersburg, Russia.
Please address correspondence and reprint requests to Evgeny M.
Krupitsky, M.D., Ph.D., St. Petersburg Regional Center of Addictions and
Psychopharmacology, Novo-Deviatkino 19/1, Leningrad Region 188661,
Russia. Email:
Psychedelic-assisted psychotherapy utilizes the acute
psychological effects of psychedelic, or hallucinogenic,
drugs to enhance the normal mechanisms of psychotherapy.
Many studies carried out in the 1950s and 1960s suggested
that psychedelic-assisted psychotherapy might be an efcient
treatment for alcoholism and addictions (Grinspoon &
Bakalar 1979). However, it is difcult to generalize across
these studies because of differences in methodology. After
they were scheduled in 1970, the use of psychedelic drugs
in research was strictly limited, signicantly curtailing
Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 14 Volume 39 (1), March 2007
the development of studies employing more sophisticated
methods. However, data collected in the 1950s and 1960s
provide some important insights about treatment effects of
psychedelic psychotherapy, which have been summarized
in Halpern’s (1996) comprehensive review.
One of the insights gained from previous research
concerns the transient psychotherapeutic and psychologi-
cal effects of psychedelic psychotherapy. The effects of
psychedelic psychotherapy are often very pronounced
within several days or weeks after a treatment session, but
then these effects quickly decline (Halpern 1996). This
phenomenon was termed a “psychedelic afterglow.” Pahnke
and colleagues (1970) described an afterglow as a positive
post-hallucinogen state occurring in subjects after they have
a transcendent psychedelic peak experience:
If a psychedelic-peak experience has been achieved and sta-
bilized during the session, a clinical picture which we have
termed the psychedelic afterglow can be observed in the days
after the session. Mood is elevated and energetic; there is a
relative freedom from concerns of the past and from guilt and
anxiety, and the disposition and capacity to enter into close
interpersonal relationships is enhanced. These psychedelic
feelings generally persist for from two weeks to a month and
then gradually fade into vivid memories that hopefully will
still inuence attitude and behavior. During this immediate
postdrug period, there is a unique opportunity for effective
psychotherapeutic work on strained family or other interper-
sonal relationships.
Ketamine is a drug used for anesthesia that acts as an
NMDA receptor antagonist. Sub-anesthetic doses produce
profound transformative experiences that share many ele-
ments with some near-death experiences (Jansen 2001).
Previous studies have found that this experience often causes
important insights about the self and the world, and can help
people accept a new meaning of life, new values and new
purpose in life related to abstinence from drugs and alcohol
(Krupitsky et al. 2002; Krupitsky & Grinenko 1997).
Recent studies that employed a single-session ketamine
psychotherapy (KPT) paradigm for alcohol and heroin-de-
pendent patients have demonstrated that KPT is an effective
treatment in promoting abstinence in alcoholics (Krupitsky
& Grinenko 1997) and heroin addicts (Krupitsky et al. 2002).
However, these studies did not clarify whether the effect of
a single KPT session might be further enhanced by repeated
The major aim of this study was to compare the efcacy
of a single session of ketamine-assisted psychotherapy with
a multiple (three session) KPT regime in people with heroin
dependence. The authors sought to determine whether the
repeated sessions of KPT carried out over one-month inter-
vals would improve the efcacy of a single KPT session, as
reected in objective measures of treatment outcome, such
as abstinence from heroin on follow-up. In other words,
could the efcacy of KPT in treating heroin dependence be
increased by administering multiple KPT sessions and thus
stabilizing the afterglow?
After detoxication, 59 heroin-dependent participants
were assigned to one of two groups on a random selection ba-
sis. The randomization was done after the rst KPT session,
but prior to the second session of KPT or counseling.
The participants in the multiple KPT group received
three KPT sessions with a psychedelic (hallucinogenic)
dose of ketamine (2.0 mg/kg i.m.), with one-month intervals
between sessions. They received their rst KPT session as
inpatients after detoxication, just before being discharged
from a psychiatric hospital. They came to the same hospi-
tal one and two months later for the second and third KPT
sessions as outpatients. An individual addiction counseling
session was conducted every time before the repeated (sec-
ond and third) KPT sessions.
The participants in the single KPT group received
only one KPT session with the same dose of ketamine and
the same psychotherapeutic technique and environment as
participants in the multiple KPT group. They received the
KPT session as inpatients after detoxication, prior to being
discharged from the psychiatric hospital. After one and two
months, the same psychotherapist who carried out the KPT
conducted an individual addiction counseling session at the
psychiatric hospital.
All participants were treated alike and were given the
same preparation for KPT. The KPT sessions, regardless
of their number, were given under uniform circumstances
at the same psychiatric hospital. Clinical evaluators blind
to whether participants had received one or three KPT ses-
sions performed psychological and clinical evaluations on
all participants during treatment and follow-up periods.
Out of 73 heroin-dependent patients screened, 59 of
them (mean age M ± SD = 22.6 ± 3.9 years, duration of
heroin abuse 38.8± 30.4 months, 49 males and 10 females)
met inclusion criteria and were included in the study. Par-
ticipants were recruited from the inpatient department of
the Leningrad Regional Center of Addictions, a 300-bed
hospital for treating patients with alcoholism and chemi-
cal dependencies who are living in the Leningrad Region.
Informed consent was obtained from all participants prior
to acceptance into the study. The study was approved by the
Human Experimentation Ethical Committee at St. Petersburg
Pavlov State Medical University.
A psychotherapist specially trained by the investiga-
tor in conducting KPT provided psychotherapy to study
Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 15 Volume 39 (1), March 2007
participants. All KPT and addiction counseling sessions for
participants in both single and multiple KPT groups were
done by the same psychotherapist.
Participant Selection
The following exclusion and inclusion criteria were
employed for participant selection:
•Inclusion criteria: ICD-10/DSM-IV criteria of current
heroin dependence present for at least one year; age
between 18 and 35; at least high school education;
abstinence from heroin and other substances of abuse
for at least two weeks; not currently on psychotropic
medication; at least one relative willing to assist in
follow-up and provide outcome data; stable address
within St. Petersburg or nearest district of Leningrad
Region; participant has a home telephone number at
which he/she can be reached; not currently on proba-
tion; and competency to give informed consent and
otherwise participate.
•Exclusion criteria: ICD-10/DSM-IV criteria of organic
mental disorder, schizophrenic disorder, paranoid
disorder, major affective disorder, or seizure disorder;
ICD-10/DSM-IV criteria for alcoholism or polydrug
dependency; advanced neurological, cardiovascular,
renal, or hepatic diseases; pregnancy; family history of
psychiatric disorders listed above; clinically signicant
cognitive impairment; active tuberculosis or current
febrile illness; AIDS; signicant laboratory abnormal-
ity such as severe anemia, unstable diabetes, or liver
function tests more than three times above normal;
pending legal charges with potential impending incar-
ceration; concurrent participation in another treatment
study; or concurrent treatment in another substance
abuse program.
Participant’s Evaluation
The participant’s evaluation included a formal psychi-
atric and clinical examination and a battery of psychiatric
and psychological scales.
Formal psychiatric and clinical examination included a
standard medical examination, with blood chemistry panel
(including hepatic functions), urine analysis, pregnancy
test, electrocardiogram, and review of previous medical and
psychiatric records.
The psychological assessment consisted of two parts,
psychiatric assessments and psychological assessments.
Psychiatric symptoms were assessed with Zung Self-Rated
Depression Scale (ZDS; Zung 1965), Spielberger Self-Rated
State-Trait Anxiety Scale (SAS; Spielberger et al. 1976),
and the Visual Analog Scale of Craving for Heroin (VASC;
Krystal et al. 1998). Psychological assessment consisted of
the Purpose-in-Life Test (PLT; Crumbaugh 1968) based on
Frankl’s (1978) concept of people’s aspiration for the mean-
ing of life, intended to assess the participant’s understanding
of the meaning of his/her life. All international rating scales
mentioned above had been specially adapted and validated
in Russia before the study.
Treatment Assessment, Outcome and Follow-Up
During the treatment phase, the investigators performed
urine drug testing before the rst KPT session in both groups,
before each successive KPT and counseling session in the
multiple KPT group, and before each addiction counseling
session in the single KPT group. The ZDS, SAS, VASC, and
PLT were administered before and after the rst KPT session
in both groups, before and after the second and third KPT
and addiction counseling sessions in the multiple KPT group,
and before and after each of the two addiction counseling
sessions in the single KPT group.
One month after the nal treatment, and then at three-
month intervals for the remainder of the year, participants
completed a follow-up interview in person with a research
assistant. Each participant underwent a physical examina-
tion to determine the presence or absence of traces (marks)
of injections on his or her veins, and a urine sample was
collected for drug testing. Information from the physical
examination was used to determine whether a participant
had abstained from heroin. Abstinent participants completed
the ZDS, SAS, VASC, and PLT during this examination.
In addition, psychiatrists blind to condition collected
follow-up data on a monthly basis for up to 12 months after
the end of the treatment phase (the last session). During
monthly telephone interviews, the psychiatrists collected
self-reported information from the participant about his/her
drug use during the follow-up period, using the Time Line
Follow Back technique (Sobell & Sobell 1992). Information
from the participant’s relatives about the participant’s drug
use was collected in the same manner.
Treatment Procedure
Before the rst ketamine session, participants received
ve hours of psychotherapy focused on the participants’
addictions to prepare them for the ketamine session, and
they received ve hours of psychotherapy after the rst
ketamine session to help them to interpret their experience
during the ketamine session and integrate it into everyday
life. One hour of addiction counseling was provided before
the second and third KPT sessions to prepare participants
to explore issues related to their chemical dependence
during those sessions. After the second and third KPT ses-
sions, participants in the multiple KPT group received an
additional hour of psychotherapy after each session to help
them integrate their experience during these sessions.
An anesthesiologist was available throughout all ket-
amine sessions to treat any possible complications. Ketamine
was injected intramuscularly at the dose of 2 mg/kg. The
length of a ketamine session was between 1.5 and two hours.
The participant was instructed to recline on a couch with eye-
shades. The participant listened to a preselected program of
music throughout the session. The psychotherapist provided
Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 16 Volume 39 (1), March 2007
emotional support for the participant and carried out psycho-
therapy during the ketamine session. The psychotherapy was
existentially-oriented, focusing on assisting the participant
to consider and formulate a purposeful or meaningful life,
but also took into account the participant’s individuality,
and his or her specic personality problems. This therapy
aimed to establish a strong personal motivation for a sober
life without drugs.
The ketamine experience is similar to some near-death
experiences (Jansen 2001), and it may produce a positive
shift in the participant’s understanding of the meaning
of life, life purposes, and spiritual development through
mechanisms similar to those seen with near-death experi-
ences (Krupitsky et al. 2002; Krupitsky & Grinenko 1997).
The major goal of the psychotherapy provided before, dur-
ing, and after KPT sessions was to assist the participant in
reaching this positive shift. The details of KPT technique
and psychotherapeutic intervention have been described in
previous publications (Krupitsky et al. 2002; Krupitsky &
Grinenko 1997).
Ketamine produces diverse experiences ranging from
spiritual rapture to fear and even horror, sometimes all in
the same person and during the same session. People have
reported experiencing violent or rapid travel through tunnels
or corridors, derealization, extreme depersonalization asso-
ciated with intense fear or euphoria, and feeling connected
to God or a higher power. The transformative experiences
often began with extreme fear, including fear of the world
ending or apocalypse, and often ended in an experience of
rebirth associated with oceanic, or positively experienced,
ego loss and boundlessness. All of these experiences were
emotionally intense and compelling. Many people reported
great difculty in expressing their experiences in words. It
should be noted that despite these common themes, the pa-
tient almost always experienced individually specic themes
that reected the individual’s case history and personality
problems in symbolic form.
After the rst KPT session, all participants received
an addiction counseling session at their second and third
monthly scheduled appointments. These sessions included
manualized addiction counseling procedures used in Rus-
sia, which include elements of cognitive-behavioral therapy
and a motivational enhancement approach. Participants in
the multiple KPT group also received brief instructions
preparing them for additional KPT during these addiction
counseling sessions.
Data Management and Statistical Analysis
Data management and analysis were performed with
SPSS 11.0 statistical software package. The rate of absti-
nence was considered the primary outcome variable. The
psychometric data were treated as secondary outcome
variables, with each scale considered independent of other
scores. Survival analysis (Kaplan-Meier survival function)
was employed to assess differences in the rate of abstinence
between the single and multiple KPT groups.
Kaplan-Meier Survival Analysis
P < 0.01
Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 17 Volume 39 (1), March 2007
MANOVA within-subjects repeated measures of analy-
sis design with Tukey test for post-hoc comparisons were
employed to assess the effect of single versus repeated KPT
and counseling sessions and changes in psychometrics over
the treatment and follow-up periods. Independent variables
were participant’s condition (single or multiple KPT) and
follow-up time point, and dependent variables were ZDA,
SAS, VASC, and PLT scores.
Retention in Treatment and Abstinence Rate
Six out of 59 participants enrolled in the study (mean
age M ± SD = 23.0 ± 5.5 years, duration of heroin abuse
48.3 ± 48.0 months, ve males and one female) relapsed
and dropped out of treatment within the rst month after the
initial KPT session. Prior to the second session, the 53 re-
maining participants were randomized into the two treatment
groups. Twenty-six participants (mean age M ± SD = 22.4
± 4.1 years, duration of heroin abuse 36.5 ± 27.6 months,
21 males and ve females) were assigned to the multiple
KPT group and received two more KPT sessions, includ-
ing addiction counseling sessions before KPT, separated by
one-month intervals. Twenty-seven participants (mean age
M ± SD = 22.7 ± 3.5 years, duration of heroin abuse 38.9 ±
29.2 months, 23 males and four females) were assigned to
the single KPT group and received two addiction counseling
sessions separated by one-month intervals. There were no
statistically signicant differences between these groups in
the mean age, duration of heroin addiction, and gender.
In the multiple KPT group, four out of 26 participants
(15.4%) relapsed and dropped out of treatment after the
second KPT session but prior to the third. In the single KPT
group, seven out of 27 participants (25.9%) relapsed and
dropped out of treatment after the rst counseling session.
The difference in the retention in treatment phase between
the two groups was not statistically signicant.
However, Kaplan-Meier survival analysis revealed sta-
tistically-signicant differences in the follow-up abstinence
rate between groups: the abstinence rate was signicantly
greater in the multiple KPT group throughout the year of the
follow-up (Figure 1). At the end of the one-year follow-up,
13 out of 26 participants (50%) in the multiple KPT group
remained abstinent compared to six out of 27 participants
(22.2%) in the single KPT group (p < 0.05).
Symptom intensity for all measures administered
(depression, state and trait anxiety, and craving for heroin)
were signicantly reduced after the rst KPT session in both
groups, and then gradually decreased further in both groups
in those participants who did not relapse and who showed
up for scheduled appointments. There were no signicant
differences in these scores between the single and multiple
KPT groups (see Table 1). Those who relapsed were
unavailable for psychometric evaluation. The understand-
ing of the meaning of life measured by the PLT improved
in both groups in a similar manner (Table 1), and there were
no statistical differences between the two groups.
Side Effects
There were no complications, such as protracted psy-
chosis or ashbacks, after KPT. No participant taking part in
the study became addicted to ketamine. The only side effect
noted in all participants was an acute increase in systolic and
particularly diastolic blood pressure of 20% to 30% during
the ketamine psychotherapy session.
Results of this study showed that a three session KPT
program is more effective in promoting abstinence from
heroin addiction than a single KPT session followed by two
counseling sessions. The rate of abstinence was signicantly
higher in the three KPT session group throughout a year of
follow-up. At the end of one year, the rate of abstinence
in the multiple KPT sessions group (50%) was more than
twice as high as in the single KPT session group (22.2%).
Furthermore, if we include the six participants who relapsed
after a single KPT session but prior to condition assignment
into the single KPT group, it lowers the rate of abstinence at
12 months to 18.2%, lending further support to the conten-
tion that a single KPT session does not provide the same
benets as multiple KPT sessions. These results correspond
very well with the observations made in clinical studies
with psychedelics carried out in the 1950s and 1960s that
provided the rationale for the multiple session approach
used in this study. In particular, Halpern (1996) noted that,
“the longer follow-up, the less improvement was observed
across the single dose studies.” In the review of Grinspoon
and Bakalar (1979), the authors wrote that “Some controlled
studies show an improvement lasting from several weeks
to several months . . . The obvious recourse of supplemen-
tary treatments every once in a while has been suggested
but never taken seriously possibly because everyone is
mesmerized by the vision of a quasi-miraculous single-
shot cure . . .”
This study does not compare ketamine-assisted therapy
with placebo, raising issues of separating effects resulting
from ketamine-assisted therapy versus those arising from
psychotherapy or from placebo effect. However, a previ-
ous investigation we conducted has addressed this issue,
nding that high-dose ketamine produced a greater rate of
abstinence from heroin than psychotherapy conducted with
active placebo (Krupitsky et al. 2002). Building on these
ndings, we chose to examine whether multiple (three)
psychotherapy sessions could produce greater benets than
a single session.
It is interesting to note that the 22.2% rate of abstinence
after one year in the single KPT session group in this study
Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 18 Volume 39 (1), March 2007
Psychometric data
Psychometrics by Time Points (M±SE)
Symptom Group 1st Session 2nd Session 3rd Session Follow-ups
Before After Before After Before After 1st Month 3rd Month 6th Month 9th Month 12th Month
Depression 1st 41.2± 36.9± 36.6± 37.5± 35.6± 34.5± 35.1± 34.3± 36.7± 37.4± 34.3±
1.5 1.4 1.3 1.6 1.5 1.4 1.4 1.4 1.7 1.8 1.4
2nd 44.7± 39.9± 40.8± 38.0± 35.8± 35.0± 35.4± 36.8± 34.5± 37.9± 30.6±
2.0 1.8 2.0 1.6 1.3 1.3 1.6 1.3 1.2 1.3 0.7
State anxiety 1st 43.8± 38.4± 38.9± 37.0± 34.6± 33.4± 33.0± 32.6± 34.8± 33.7± 30.6±
1.9 2.2 2.2 1.7 1.7 1.3 1.6 1.7 2.1 1.9 1.8
2nd 42.7± 39.9± 39.6± 38.4± 35.3± 33.3± 33.0± 32.5± 31.1± 32.4± 28.1±
1.5 1.8 1.6 1.8 1.0 1.3 1.7 1.3 1.4 1.4 0.6
Trait anxiety 1st 42.0± 34.4± 33.8± 32.0± 33.2± 29.9± 30.4± 26.9± 31.6± 29.6± 25.8±
2.0 2.3 1.9 1.8 2.4 1.6 1.7 1.1 2.0 1.4 1.3
2nd 41.5± 33.3± 36.4± 34.3± 31.15± 29.2± 30.5± 29.6± 26.4± 23.6± 24.7±
1.9 1.6 2.0 1.9 1.5 1.3 1.9 1.1 1.6 0.8 0.5
Craving for heroin 1st 20.1± 9.6± 11.9± 6.07± 7.1± 5.4± 6.09± 2.6± 5.3± 3.2± 0.3±
4.7 3.6 3.5 2.7 3.1 3.0 2.6 1.0 2.1 1.7 0.2
2nd 22.8± 4.6± 8.9± 7.3± 4.7± 3.3± 7.2± 3.7± 3.9± 1.9± 0.0±
5.4 1.6 3.3 2.8 1.5 1.1 2.9 1.4 1.3 0.5 0.0
Understanding 1st 92.0± 106.5± 108.8± 110.3± 112.8± 113.8± 115.2± 115.2± 114.9± 115.7± 119.6±
the meaning 3.6 3.6 3.2 2.9 3.1 2.6 3.7 3.3 2.8 3.8 3.4
of life 2nd 90.3± 101.6± 103.0± 103.3± 113.6± 113.5± 114.9± 115.1± 120.5± 119.8± 124±
3.6 3.6 3.7 4.1 2.8 2.7 3.4 3.2 2.3 2.7 0.8
Notes: First group — multiple KPT, second group — single KPT. MANOVA results: All the psychometrics signicantly improved over the time points. No signicant
differences in either one psychometric were found between the rst and the second group.
Krupitsky et al. Ketamine Psychotherapy for Heroin Dependence
Journal of Psychoactive Drugs 19 Volume 39 (1), March 2007
was similar to the one year abstinence rate of 24% after a
single KPT session in a previous study of KPT for heroin
addiction (Krupitsky et al. 2002), in which a single KPT
session was compared to a single active placebo session (a
low, nonpsychedelic dose of ketamine). Due to the close
similarities in rate of one year abstinence in the single KPT
groups in this current study and in the previous study, it
seems likely that the groups are well-matched. This supports
the assumption that, were a placebo group to have been
added to this current study, the rate of one year abstinence
would have been somewhat similar to that in the earlier
study, or 6%. It is also notable that the rate of abstinence
for single KPT participants was similar to the rate of reten-
tion in treatment for people receiving the opioid antagonist
naltrexone (Krupitsky et al. 2004), and the rate of abstinence
in the multiple KPT was even higher than after naltrexone
treatment. These ndings suggest that multiple sessions of
KPT hold promise as a treatment for people with heroin
dependence, and that multiple sessions are better than a
single session of KPT, despite lack of signicant differences
between the two groups in self-reported depression, anxiety
or cravings for heroin.
The lack of signicant differences between single and
multiple KPT groups on other outcome measures, includ-
ing those for depression, anxiety, life purpose and heroin
craving, suggests that increased rates of abstinence in the
multiple KPT group is at least partly due to factors not mea-
sured in this study. This effect could be related to a specic
shift in the participant’s mind and his or her attitude to life
that was described by Pahnke and colleagues (1970) as an
“afterglow,” and for which we do not yet have a rating scale
to measure. In the future, we may employ measures more li-
able to capture this shift or change in attitude or life view.
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... There are a number of potential reasons for that, including our eligibility criteria. Some KAP or Ketamine Psychedelic Therapy (KPT) studies were not published in the last 10 years (Krupitsky and Grinenko 1997;Krupitsky et al. 2007), did not focus on unipolar depression (Ragnhildstveit et al. 2021;Robison et al. 2022) or did not have a clinical trial design (Joneborg et al. 2022). These studies usually focus on set and setting, psychotherapeutic support and other psychosocial aspects which were scarce in the research reviewed in this article. ...
... In these forms of psychotherapy it is standard to have the presence of at least one skilled therapist to support and mediate powerful therapeutic experiences helping patients to deal with challenging experiences (Dore et al. 2019). Psychotherapeutic support is offered to the patients before, after and during the ketamine session (Krupitsky et al. 2007). Like other psychedelic therapies, in the sessions, the researchers use music in the experimental setting. ...
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.
... In a double-blind, non-placebo-controlled clinical trial, intramuscular (i.m.) administration of ketamine (0.2 vs 2 mg/kg) in heroin abstinent individuals induced a dose-dependent enhancement of abstinence rates and longer-lasting decrease in heroin craving, with higher doses of ketamine being more effective 15 . The same authors also compared the effectiveness of a single vs three consecutive ketamine sessions (2 mg/kg, i.m.) to maintain abstinence in detoxified heroin dependent patients, showing that repeated administration of ketamine was superior in prolonging abstinence compared with the single administration group 16 . ...
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Opioid addiction is a pressing public health concern marked by frequent relapse during periods of abstinence, perpetuated by negative affective states and anhedonia-driven behaviors. In addition to the current epidemic that was declared in the U.S.A., opioid-related deaths are increasing in other countries around the world. Classical antidepressants, or the currently prescribed opioid substitution pharmacotherapies have limited efficacy to reverse maladaptive behavioral responses, negative affect or prevent relapse in opioid abstinent individuals. Here, by establishing and using novel mouse models for the study of opioid addiction, we demonstrate, for the first time, the therapeutic potential of ketamine's metabolite, (2R,6R)-hydroxynorketamine (HNK). In particular, our studies showcase (2R,6R)-HNK's ability to reverse conditioning to sub-effective doses of morphine in stress-susceptible mice, prevent conditioned-place aversion and mitigate acute somatic withdrawal symptoms in opioid-dependent animals. In addition, we show that this metabolite reverses anhedonia, anxiety-like behaviors, cognitive impairment, and general stress susceptibility associated with protracted opioid withdrawal, thereby presenting a promising therapeutic avenue for opioid relapse prevention. Our results strongly suggest that (2R,6R)-HNK, potentially by augmenting downstream brain-derived neurotrophic factor (BDNF) and GluN2A N-methyl-D-aspartate receptor signaling, effectively reverses maladaptive behavioral responses typical of protracted opioid abstinence. Furthermore, it facilitates the extinction of opioid conditioning and prevents stress-induced reinstatement of opioid-seeking behaviors. Our findings highlight how (2R,6R)-HNK, through an enhancement of synaptic plasticity in mood-regulating brain areas, has the potential to be an effective, next-generation pharmacotherapy for opioid use disorders by addressing emotional disturbances associated with protracted abstinence.
... Classic psychedelics have garnered considerable research interest for addiction treatment historically (Krebs & Johansen, 2012;Mangini, 1998;Savage & McCabe, 1973) as well as in recent years (Johnson, 2022). Some evidence also suggests that non-classic psychedelics (involving primary mechanisms of action other than 5-HT2AR agonism; including ibogaine, ketamine, and MDMA) may be possible options for treating SUDs (Dakwar et al., 2019;Ezquerra-Romano et al., 2018;Krupitsky et al., 2007;Krupitsky & Grinenko, 1997;Mash et al., 2018;Schenberg et al., 2014;Sessa et al., 2021). ...
Substance use disorders (SUDs) have an enormous impact on public health. With classic psychedelic-assisted therapies showing initial promise in treating multiple SUDs, it is possible that these treatments will become legally available options for patients with SUDs in the future. This article highlights how classic psychedelic-assisted therapies might be integrated into current clinical practice. We first describe contemporary evidence-based treatments for SUDs and highlight how classic psychedelic-assisted therapies might fit within each treatment. We suggest that classic psychedelic-assisted therapies can be integrated into most mainstream evidence-based SUD treatments that are currently used in clinical settings, indicating broad compatibility of classic psychedelis with contemporary SUD treatment paradigms.
... Thus, extending its therapeutic effects on treatment resistant depression, ketamine has garnered attention as a potential treatment for PTSD as well. This development is important because ketamine's therapeutic effects are ultra-rapid and in preliminary studies it has shown therapeutic effects in suicidality and substance abuse (opioids, alcohol, cocaine) as well [21]. ...
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Post-traumatic stress disorder (PTSD) affects ~ 6% of adolescents and adults in the US. Increased N-methyl-D-aspartate (NMDA) receptor activation leads to heightened intrusive memories and is associated with an increased risk of developing PTSD. Ketamine is an NMDA antagonist with ultra-rapid therapeutic action for treatment-resistant depression and suicide. In this meta-analysis, we assessed the effect of subanesthetic ketamine infusion on PTSD severity. Six databases were investigated according to PRISMA guidelines with quality assessments according to the NIH Quality Assessment tool. Eligible criteria included: 1) Randomized Control Trial (RCT) or cohort study 2) Used a single or multiple ketamine infusion(s) 3) Studies using another treatment for PTSD to which (2) is added 4) PTSD symptoms are measured at pre-infusion baseline and up to at least 40 minutes after infusion using a valid PTSD symptom measurement scale 5) Study included ≥ 5 patients. The primary outcome was the first measured value of PTSD symptoms after treatment completion. Meta-analysis using a random effects model was performed on pre-to-post changes in PTSD severity within ketamine treated patients and to compare ketamine to control outcomes. The search retrieved 526 articles. Nine articles met inclusion criteria: 5 RCTs and 4 cohort studies. Meta-analysis revealed that ketamine infusion reduced PTSD symptom severity (pre-post ketamine: standardized mean difference pre-to-post: 3.07, 95% confidence interval 1.54–4.60, P < 0.01). These results support ketamine infusions as an effective treatment modality for PTSD symptoms. Ketamine-assisted psychotherapy is shown to enhance ketamine effect and aid in prolonging remission. Further research is needed to provide effective and long-lasting PTSD treatment.
... In a follow-up study, Krupitsky et al. (2007a) evaluated the efficacy of single vs. repeated sessions of ketamine-assisted psychotherapy in increasing abstinence from heroin. Participants were randomized to one or three sessions of ketamine given at one-month intervals. ...
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A rapid review synthesizing published research on the possible therapeutic applications of psychedelics.
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The United States is entering its fourth decade of the opioid epidemic with no clear end in sight. At the center of the epidemic is an increase in opioid use disorder (OUD), a complex condition encompassing physical addiction, psychological comorbidities, and socioeconomic and legal travails associated with the misuse and abuse of opioids. Existing behavioral and medication-assisted therapies show limited efficacy as they are hampered by lack of access, strict regimens, and failure to fully address the non-pharmacological aspects of the disease. A growing body of research has indicated the potential of hallucinogens to efficaciously and expeditiously treat addictions, including OUD, by a novel combination of pharmacology, neuroplasticity, and psychological mechanisms. Nonetheless, research into these compounds has been hindered due to legal, social, and safety concerns. This review will examine the preclinical and clinical evidence that psychoplastogens, such as ibogaine, ketamine, and classic psychedelics, may offer a unique, holistic alternative for the treatment of OUD while acknowledging that further research is needed to establish long-term efficacy along with proper safety and ethical guidelines.
The opioid crisis remains a major public health concern, causing significant morbidity and mortality worldwide. Pain is frequently observed among individuals with opioid use disorder (OUD), and the current opioid agonist therapies (OAT) have limited efficacy in addressing the pain needs of this population. we reviewed the most promising non-opioid analgesic therapies for opioid-dependent individuals synthesizing data from randomized controlled trials in the Medline database from December 2022 to March 2023. Ketamine, gabapentin, serotonergic antidepressants, and GABAergic drugs were found to be the most extensively studied non-opioid analgesics with positive results. Additionally, we explored the potential of cannabinoids, glial activation inhibitors, psychedelics, cholecystokinin antagonists, alpha-2 adrenergic agonists, and cholinergic drugs. Methodological improvements are required to advance the development of novel analgesic strategies and establish their safety profile for opioid-dependent populations. we highlight the need for greater integration of experimental pain methods and abuse liability assessments, more granular assessments of prior opioid exposure, greater uniformity of pain types within study samples, and a particular focus on individuals with OUD receiving OAT. Finally, future research should investigate pharmacokinetic interactions between OAT and various non-opioid analgesics and perform reverse translation basic experiments, particularly with methadone and buprenorphine, which remain the standard OUD treatment.
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Ketamine is a prescription drug used for general anesthesia. In subanesthetic doses, it induces profound psychedelic experiences and hallucinations. The subanesthetic effect of ketamine was the hypothesized therapeutic mechanism in the authors' use of ketamine-assisted psychotherapy for alcoholism. The results of a controlled clinical trial demonstrated a considerable increase in efficacy of the authors' standard alcoholism treatment when supplemented by ketamine psychedelic therapy (KPT). Total abstinence for more than one year was observed in 73 out of 111 (65.8%) alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p < 0.01). The authors' studies of the underlying psychological mechanisms of KPT have indicated that ketamine-assisted psychedelic therapy of alcoholic patients induces a harmonization of the Minnesota Multiphasic Personality Inventory (MMPI) personality profile, positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes to various aspects of self and other people, positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development. Most importantly, these psychological changes were shown to favor a sober lifestyle. The data from biochemical investigations showed that pharmacological action of KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, i.e., those neurochemical systems which are involved in the pathogenesis of alcohol dependence. The data from EEG computer-assisted analysis demonstrated that ketamine increases theta activity in cerebrocortical regions of alcoholic patients. This is evidence of the reinforcement of limbic cortex interaction during KPT session.
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Seventy detoxified heroin-addicted patients were randomly assigned to one of two groups receiving ketamine psychotherapy (KPT) involving two different doses of ketamine. The patients of the experimental group received existentially oriented psychotherapy in combination with a hallucinogenic ("psychedelic") dose of ketamine (2.0 mg/kg im). The patients of the control group received the same psychotherapy combined with a low, non-hallucinogenic (non-psychedelic), dose of ketamine (0.2 mg/kg im). Both the psychotherapist and patient were blind to the dose of ketamine. The therapy included preparation for the ketamine session, the ketamine session itself, and the post session psychotherapy aimed to help patients to integrate insights from their ketamine session into everyday life. The results of this double blind randomized clinical trial of KPT for heroin addiction showed that high dose (2.0 mg/kg) KPT elicits a full psychedelic experience in heroin addicts as assessed quantitatively by the Hallucinogen Rating Scale. On the other hand, low dose KPT (0.2 mg/kg) elicits "sub-psychedelic" experiences and functions as ketamine-facilitated guided imagery. High dose KPT produced a significantly greater rate of abstinence in heroin addicts within the first two years of follow-up, a greater and longer-lasting reduction in craving for heroin, as well as greater positive change in nonverbal unconscious emotional attitudes than did low dose KPT.
Research into treating drug dependence with hallucinogens, although promising, ended with questions still unanswered because of varying, in some cases skeptical, methodology and insufficient adherence to a double-blind, placebo-controlled design. Interest is again emerging, especially with the recent patenting in the United States of ibogaine for its apparent anti-craving properties. A review of the literature shows that these properties may be present across the entire family of hallucinogens. Potential efficacy may be tied to their agonism and antagonism at specific serotonin receptor sites. After the administration of a hallucinogen, there is a positive “afterglow” lasting weeks to months which might be extended through repeated dosing. Ibogaine and LSD both have lengthy periods of action, making their application unwieldy. However, tryptamines, such as N,N-Dimethyltryptamine (DMT), are so short-acting that they could easily be administered in an office setting. With numerous hallucinogens yet to be tested, a hallucinogen might well be discovered with superior anti-craving properties and non-deleterious side-effect profile.
This study evaluated the dose-related ethanol-like subjective effects of the N-methyl-D-aspartate (NMDA) glutamate receptor antagonist ketamine hydrochloride in recently detoxified alcoholics. Twenty male inpatients meeting DSM-III-R criteria for alcohol dependence and who had not consumed alcohol for 10 to 27 days prior to the study completed 3 test days that involved the intravenous infusion of ketamine hydrochloride (0.1 mg/kg or 0.5 mg/kg) or saline solution under randomized double-blind conditions. Ethanol-like subjective effects were assessed using the Sensation Scale; the Biphasic Alcohol Effects Scale; visual analog scales to measure "high" and degree of similarity to ethanol, cocaine, and marijuana; a scale assessing the number of standard alcohol drinks producing similar subjective effects; and visual analog scales measuring ethanol craving. Ketamine produced dose-related ethanol-like effects on each scale measuring its similarity to ethanol. Its effects were more similar to the sedative or descending limb effects of ethanol than to the stimulant or ascending limb effects. Ketamine effects also were more like ethanol than marijuana or cocaine. Ethanol-like effects were more prominent at the higher ketamine dose, a dose rated as similar to greater levels of ethanol intoxication. However, ketamine did not increase craving for ethanol. The production of ethanol-like subjective effects by ketamine supports the potential clinical importance of NMDA receptor antagonism among the mechanisms underlying the subjective effects of ethanol in humans.
SINCE the initial publications on the development and validation of the Self-Rating Depression Scale (SDS),1,2 there has been continued interest in it. Diversity in the application of this tool is evidenced by its use in the programs of suicide prevention centers, alcoholism clinics, child guidance and adult psychiatric clinics, health and welfare agencies, and by various research groups, including the Veterans Administration Cooperative Studies in Psychiatry and the Early Clinical Drug Evaluation Unit of the Psychopharmacology Research Branch, National Institute of Mental Health. In a series of studies exploring social structure and mental illness, Redlich et al3-6 reported highly significant relationships between social class position and aspects of psychiatric disorders, such as prevalence of psychiatric patients, types of psychiatric disorders, and choice of treatment modalities. If these relationships exist as such, is there a significant correlation between social status and results