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Ketamine psychotherapy for heroin addiction: Immediate effects and two-year follow-up

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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.
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Regular article
Ketamine psychotherapy for heroin addiction: immediate
effects and two-year follow-up
Evgeny Krupitsky, M.D., Ph.D.*, Andrey Burakov, M.D., Tatyana Romanova, M.A.,
Igor Dunaevsky, M.D., Rick Strassman, M.D., Alexander Grinenko, M.D.
St. Petersburg Research Center of Addictions and Psychopharmacology, Novo-Deviatkino 19/1, Leningrad Region 188661, Russia
Received 5 November 2001; received in revised form 29 May 2002; accepted 24 June 2002
Abstract
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. D2002 Elsevier
Science Inc. All rights reserved.
Keywords: Ketamine; Heroin Addiction; Psychotherapy; Psychedelics; Hallucinogens; Treatment
1. Introduction
Evidence suggests that psychedelic psychotherapy is a
promising approach to the treatment of addiction. The
method of drug-assisted psychotherapy utilizes the acute
psychological effects of hallucinogenic, or psychedelic,
drugs to enhance the normal mechanisms of psycho-
therapy, and at times, partakes of less traditional psycho-
therapeutic processes. The results of our recent study
using ketamine psychotherapy (KPT) in the treatment of
detoxified alcoholic patients (Krupitsky & Grinenko,
1997), as well as a recent review of previous studies
carried out in the 1960s and early 1970s (Halpern, 1996),
support this hypothesis. However, not all studies demon-
strated positive outcomes and different methodologies
make it difficult to generalize results across studies
(Grinspoon & Bakalar, 1979). Ketamine, normally used
for general anesthesia, but in smaller doses producing a
profound psychedelic experience (Bowdle et al., 1998), is
a useful drug in this regard.
As an adjunct to the psychotherapeutic treatment of
addiction, ketamine has several advantages over other
psychedelics: it is safe and short acting; it is already an
approved prescription medicine, and it has been shown to be
an effective treatment for alcoholism (Krupitsky & Gri-
nenko, 1997). Also, because of its influence on the NMDA
receptor, it is similar to other NMDA receptor ligands such
as acomprosate and ibogaine (Mash et al., 1998; Sass,
Soyka, Mann, & Zieglgansberger, 1996), and may possess
similar anti-craving properties.
Until now, treatments for a variety of addictions have
included therapy and counseling, Alcoholics Anonymous,
Narcotics Anonymous, different kinds of rehabilitation pro-
grams, drug substitution maintenance programs, and phar-
macotherapy. However, in many cases these methods have
0740-5472/02/$ – see front matter D2002 Elsevier Science Inc. All rights reserved.
PII: S0740-5472(02)00275-1
* Corresponding author. Tel./fax: +7-812-532-7397.
E-mail address: kru@ek3506.spb.edu (E. Krupitsky).
Journal of Substance Abuse Treatment 23 (2002) 273 – 283
relatively high rates of recidivism. There remains a pressing
need for new, more successful treatments.
In the early 1970s, Savage and McCabe (1973) showed
that LSD-assisted psychotherapy had a positive effect on
treatment outcome in heroin-addicted individuals: 25% of
the subjects treated with LSD remained abstinent from
opiates for one year, as opposed to only 5% of the con-
ventional weekly group psychotherapy. By the time their
study was published, human research with these substances
had become extraordinarily difficult due to changes in the
legal status of these drugs, and duplication of their work was
not possible.
Later in the 1980s and 1990s, both animal studies and
anecdotal human reports suggested anti-craving properties
of another psychedelic, ibogaine (‘‘Endabuse’’) (Lotsof,
1995; Mash et al., 1998). However, concerns about ibogaine
toxicity halted further human research with it in the United
States (Binienda, Scallet, Schmued, & Ali, 2001; Glick,
Maisonneuve, & Szumlinski, 2000).
In order to extend our results using KPT for alcoholism,
we now report our findings from a treatment protocol
employing KPT in a group of detoxified intravenous heroin
addicts within a double-blind protocol. Treatment of heroin
addiction in Russia is important for two reasons. There was
an epidemic of heroin addiction in Russia within the last
decade, closely related to an HIV epidemic. In addition, all
opioid agonists (methadone) and even partial agonists/
antagonists (buprenorphine) are legally prohibited in Russia.
The only available medication for heroin addiction in Russia
is naltrexone, with its attendant problem of poor compliance.
2. Materials and methods
2.1. Design
Seventy detoxified heroin-addicted patients were ran-
domly assigned to one of two groups. The subjects of
the high dose group received psychotherapy in combina-
tion with a psychedelic dose of ketamine (2.0 mg/kg im).
The subjects of the low dose group received the same
psychotherapy combined with a sub-psychedelic dose of
ketamine (0.20 mg/kg im). We have found that this dose
induces some pharmacological effects without inducing a
full psychedelic experience, thus acting as an active
placebo condition (see Results section below). Both the
psychotherapist and subject were blind to the dose of
ketamine, and all subjects were treated similarly except
for their dose of ketamine. A clinical evaluator, other
than the psychotherapist providing KPT, performed all of
the subjects’ psychological and clinical evaluations dur-
ing the treatment and follow-up period. This rater was
also blind to the dose of ketamine. The low ketamine
dose group was considered to be an ‘‘active placebo’
which allowed a study to be performed within the
rigorous scientific double-blind design.
2.2. Subjects
All 70 subjects were screened, evaluated and random-
ized in the study. They were recruited from the inpatient
department of the Leningrad Regional Center of Ad-
dictions, an alcohol and drug abuse treatment center with
a 300-bed hospital located in the Leningrad Region,
an administrative territory around the city of St. Peters-
burg. After they completed acute detoxification, informed
consent was obtained from all subjects prior to acceptance
into the study. The study was approved by the Insti-
tutional Review Board at the Leningrad Regional Center
of Addictions. All subjects were treated as inpatients and
discharged from the hospital after they completed KPT.
There were 35 subjects (27 male and 8 female) in the
high dose group and 35 subjects (28 male and 7 female) in
the low dose group. There were no statistically significant
differences between the high dose and low dose groups
with respect to age (High [Mean ± SD] = 23.0 ± 4.4 vs.
Low = 21.6 ± 3.0 years), duration of heroin addiction
(31.7 ± 24.1 vs. 37.4 ± 23.0 months, respectively), and
duration of abstinence from heroin (25.3 ± 14.8 vs. 24.5 ±
10.1 days, respectively).
The subjects participating in the study were mostly
young adults, consistent with the fact that the typical age
of heroin-addicted individuals in Russia is between 17 and
26. In addition, the average duration of addiction is from
three to four years. Many individuals die because of
overdose or become incarcerated within the first few years
of heroin abuse.
2.3. Psychotherapist
Psychotherapy was provided by a psychiatrist spe-
cially trained in KPT. Only one KPT session was
carried out for each subject. The details of KPT
sessions and psychotherapeutic techniques are described
below in Treatment Procedure.
2.4. Patient selection
The following inclusion and exclusion criteria were
employed for patient selection:
2.4.1. Inclusion criteria
ICD-10/DSM-IV criteria of current Heroin Depend-
ence present for at least one year, age between 18 and
30, at least a 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 in St. Petersburg
or Leningrad region, home telephone number at which
the subject could be reached, not currently on pro-
bation, and competency to give informed consent and
otherwise participate.
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283274
2.4.2. Exclusion Criteria
ICD-10/DSM-IV diagnosis of organic mental disorder,
schizophrenic disorder, paranoid disorder, major affective
disorder, or seizure disorder; family history of psychi-
atric disorders listed above; ICD-10/DSM-IV diagnosis
for alcoholism or polydrug dependency; advanced neu-
rological, cardiovascular, renal, or hepatic diseases; preg-
nancy; clinically significant cognitive impairment; active
tuberculosis or current febrile illness; AIDS-defining
illness; significant laboratory abnormality such as severe
anemia, unstable diabetes, or liver function tests three
times above normal; pending legal charges with potential
incarceration; concurrent participation in another research
study; or concurrent treatment in another substance
abuse program.
2.5. Screening evaluation
The screening evaluation included: (1) Formal psy-
chiatric examination; (2) Complete medical examination,
including blood chemistry panel (including hepatic func-
tions), urine analysis, HIV-test, pregnancy test, and
EKG; and (3) Review of previous medical and psychi-
atric records.
2.6. Assessment instruments
In order to provide comparability with our previous
studies of KPT for alcoholism (Krupitsky & Grinenko,
1997), we used the same battery of assessment instru-
ments,. We also used instruments widely used in psycho-
therapy outcome research. Finally, due to the specific
nature of ketamine psychotherapy, instruments were con-
sidered desirable that might indicate changes in the areas
of personality, life values and goals, spiritual development,
and unconscious emotional attitudes.We used specially
adapted Russian versions of the international scales and
questionnaires mentioned below.
2.6.1. Psychiatric symptoms and psychopathology
assessments
ICD-10 Structured Clinical Interview for Psychiatric
Disorders (SIDI)
Zung Self-rating Depression Scale (ZDS) (Zung,
1965) - to assess depression
Spielberger Self-rating State-Trait Anxiety Scale
(SAS) (Spielberger, Anton, & Bedell, 1976) - to
assess state and trait anxiety
Visual Analog Scale of Craving (VASC) - 100 mm
line marked by subjects relative to the intensity of
craving experienced while completing the scale
Scale of Anhedonia Syndrome (SA) (Krupitsky,
Burakov, Romanova, Vostrikov, & Grinenko, 1998) -
to assess the severity of the syndrome of anhedonia.
Many detoxified heroin addicts report that the
termination of withdrawal leads to a syndrome of
anhedonia, which includes affective symptoms
(mostly depression), anxiety, tension, irritability, feel-
ing as if life is dull and empty, passivity, sleep
disturbance, and craving for heroin. SA has affective,
cognitive, and behavioral subscales
Hallucinogenic Rating Scale (HRS) (Strassman,
Qualls, Uhlenhuth, & Kellner, 1994) - to assess acute
subjective responses to a psychoactive drug challenge
2.6.2. Psychological assessments
Minnesota Multiphasic Personality Inventory (MMPI)
(Dahlstrom, Welsh, & Dahlstrom, 1972) - to assess
personality characteristics
Locus of Control Scale (LCS) developed by Rotter
(Phares, 1976) and adapted in Russia by Bazhin,
Golynkina, and Etkind (1993) - to assess the
perception by subjects of their ability to control and
manage different situations in their lives
Color Test of Attitudes (CTA) (Etkind, 1980) - to
assess nonverbal unconscious emotional attitudes.
The methodology of CTA has been described in
detail previously (Krupitsky & Grinenko, 1997)
Purpose-in-Life Test (PLT) (Crumbaugh, 1968), based
on Frankl’s (1978) concept of the individual’s
aspiration for meaning in life (PLT was adapted in
Russia by Leontiev (1992)
Spirituality Changes Scale (SCS) based on the
combination of the Spirituality Self-Assessment
Scale developed by Whitfield (1984), who studied
the importance of spirituality in Alcoholics Anony-
mous; and the Life Changes Inventory developed by
Ring (1984), to estimate psychological changes
produced by near-death experiences. The SCS has
been shown to be sensitive to changes in spirituality
in our studies of KPT in alcoholism (Krupitsky &
Grinenko, 1997)
2.7. Treatment assessment, outcome and follow-up
2.7.1. Assessment schedule
ZDS, SAS, VASC, SA, MMPI, LCS, CTA, and PLT were
administered pre-therapy (baseline) and post-therapy (dur-
ing the week after the ketamine session). SCS and HRS
were administered only post-therapy to assess spiritual
changes and acute subjective effects of the drug treatment.
ZDS, SAS, and VASC were administered also at 1, 3, 6, 12,
18 and 24 months after treatment was completed, in those
subjects abstaining from heroin. Those who relapsed were
unavailable for assessment.
2.7.2. Follow-up data
Psychiatrists who were blind to the dose of ketamine
collected follow-up data on a monthly basis for up to
24 months, if the subject had not relapsed before that.
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283 275
Follow-up data included: Information from the subject
about his/her drug use during the follow-up period; exam-
ination for evidence of injection sites over the subject’s
veins; information from the subject’s relatives and/or
colleagues about his/her drug use; urine drug testing at
1, 3, 6, 12, 18, and 24 months after completion of therapy;
ZDS, SAS, and VASC data at 1, 3, 6, 12, 18, and 24
months. We were unable to follow patients after they
relapsed to heroin due to poor compliance. None of the
subjects received continued care or other treatment for
their addiction or psychiatric problems after their participa-
tion in the KPT study, until they completed participation in
the follow-up study or relapsed.
2.8. Treatment procedure
Witnessed informed consent was obtained from all
patients before inclusion into the study.
Ten hours of psychotherapy were provided before the
ketamine session in order to prepare subjects for the session.
Five hours of psychotherapy were provided after the ket-
amine session to help subjects interpret and integrate their
experiences during the session into everyday life.
An anesthesiologist was present throughout the ketamine
session to respond to any complications. The length of the
ketamine session was about 1.5 2 hr. Only one ketamine
session was carried out for each subject. The subject was
instructed to recline on a couch with eyeshades. Music pre-
selected by psychotherapist was used throughout the keta-
mine session. The psychotherapist provided emotional sup-
port for the subject and carried out psychotherapy during the
session. Psychotherapy was existentially oriented, but also
took into account the subject’s individual and personality
problems (Krupitsky & Grinenko, 1997). Subjects were
discharged from the hospital soon after the KPT (within 3
to 5 days).
2.9. Description of the psychotherapeutic technique
provided
There are three main stages in our method of KPT
(Krupitsky & Grinenko, 1997). The first stage is prepara-
tion. In this stage, preliminary psychotherapy is carried out
with subjects. During these psychotherapeutic sessions it is
explained to the subjects that the relief of their dependence
from heroin will be attempted in an altered state of con-
sciousness. They will have particular experiences that will
help them to realize the negative effects of heroin abuse, and
the positive aspects of life without drugs. We explain that
the ketamine session may induce insights concerning their
personal problems. It could modify their system of values,
their notions of self and the world around them, and
possibly contribute to discovering their purposes in life.
They were told that these processes might positively effect
changes in their personality, facilitating the development of
a life without heroin.
During the ketamine sessions, subjects often experience
an altered state that has been described as the separation of
consciousness from the body and the dissolving of the ego.
Therefore, it is very important to prepare subjects carefully
for such an unusual experience. The therapist pays close
attention to such issues as the subject’s personal motives for
treatment, his goals for his new life without drugs, and his
theory about the cause of his disease and its consequences.
An individually tailored psychotherapeutic set is formed
during this phase of treatment. This psychotherapeutic set
includes the patient’s ideas about his/her personal reasons
for addiction and how KPT might help them. This becomes
the most salient factor influencing the psychological content
of the second stage of the KPT. It is also important to create
an atmosphere of confidence and mutual understanding
between the psychotherapist and patient during this first
stage of KPT.
The second stage of KPT is the ketamine session itself.
With a background of special music (we used mostly
soothing instrumental music intended to promote relaxation
and abreaction), the subject is administered the assigned
dose of ketamine. While under the influence, the subject is
then treated psychotherapeutically. The content of these
psychotherapeutic sessions is based on the data of the
subject’s case history. The session is directed toward the
resolution of their personality problems and the formation
of a stable orientation to a future without drugs. We try to
help our subjects create new meaning and purpose in life
during this session. We clearly direct the subject’s experi-
ences by verbal influences and guiding the musical back-
ground toward the symbolic resolution of the personality
conflicts during the ketamine session. Two physicians, one
a psychotherapist and one an anesthesiologist, conduct this
second stage of KPT, because some complications and side
effects (such as increased blood pressure and depression of
breath) are possible, though very rare. No such complica-
tions occurred in our study. After the session, the subject
rests. The subjects write a detailed self-report of their
experience later that evening.
In the third stage, special psychotherapeutic sessions are
carried out within several days after the KPT session. This
discussion is directed toward helping the subject establish a
connection between their ketamine experience and their
intra- and interpersonal problems, especially those that re-
inforce the subjects desire for a life without drugs. We try
also to assist subjects to integrate the insights from the
ketamine session into everyday life.
2.10. Data management and statistical analysis
All subject-related information was filed under a study
code number for purposes of confidentiality and to maintain
the double-blind design.
The software package ‘‘Statistica’’ (‘‘STATISTICA for
Windows’’, release 5.0 A, StatSoft, Inc., Tulsa, OK, USA)
was used. Independent variables were treatment group (dose
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283276
of ketamine), and time of assessment (pre- and post-therapy,
or during the follow-up; see assessment schedule). Depen-
dent variables were clinical and psychological ratings, and
rate of abstinence and relapse. The rate of abstinence and
relapse was considered the primary outcome variable. The
psychometric data were treated as secondary outcome
variables independent from each other. Data were analyzed
using within subjects repeated measures ANOVA for within
groups comparisons (with an LSD test for post-hoc compar-
isons), and Student’s t-test for between group comparisons.
3. Results
3.1. Components of the ketamine experience
Acute psychological responses to the ketamine experi-
ence were evaluated with the Hallucinogen Rating Scale,
an instrument developed using N,N-dimethyltryptamine
(DMT), as the normative agent (Strassman et al., 1994)
(Table 1). HRS scores provided evidence that patients in the
high dose group had a full psychedelic experience, compar-
able to a psychedelic dose of DMT. HRS scores in the low
dose group suggest that patients experienced some drug
effects, but these fell short of a full psychedelic effect. Differ-
ences between the scores of high and low dose groups were
statistically significant for all HRS scales except Volition.
3.2. Treatment outcome: Follow-up data for 24 months
The follow-up data included information from subjects,
their relatives, and urine drug testing results. Follow-up
data for 24 months are presented in Fig. 1. The rate of
abstinence in the high dose group was significantly higher
than that of the low dose group (Fig. 1), while the
corresponding rate of relapse was lower. The differences
between the high dose and low dose group in rates of both
abstinence and relapse were statistically significant starting
from the first month and then for almost all of the 24
months of follow-up (Fig. 1).
Table 1
Acute effects of two ketamine doses on hallucinogen rating scale subscales
Subscales of Hallucinogenic Rating Scale (HRS)
Dose of ketamine Intensity Somaesthesia Affect Perception Cognition Volition
High Mean 1.84
a,
*** 1.7
a,
*** 2.22
a,
*** 1.74
a,
** 2.31
a,
*** 2.39
SD
b
0.45 0.38 0.45 0.55 0.39 0.74
Low Mean 1.11 0.98 1.43 0.86 1.28 2.05
SD
b
0.54 0.57 0.43 0.57 0.72 0.69
a
Statistical significance of differences between the high dose and low dose group: * - p< .05; ** - p< .01; *** - p< .001.
b
SD- Standard Deviation.
Fig. 1. Rate of abstinence: relapse free proportion. * p< .05; ** p< .01.
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283 277
3.3. Craving for heroin
There were no statistically significant baseline differences
in craving (as well as in all other psychometrics) between
groups. Both doses of ketam ine in KPT sessions signifi cantly
reduced craving for heroin as evaluated by the Visual Analog
Scale of Craving (Table 2). This effect on craving in the high
dose group was significantly greater than in the low dose
group immediately after KPT, as well as at 1 and 3 months
after the ketamine session. Also, craving in the high dose
group was significantly reduced at the two year follow-up,
but only for the first month in the low dose group.
3.4. Syndrome of anhedonia
In both high and low dose groups, KPT significantly
reduced the severity of all three components of the syn-
drome of anhedonia (Fig. 2). While scores for each subscale
show a positive effect for the high dose group, these
differences were not statistically significant.
Table 2
KPT influence on craving, anxiety, and depression
Scales Dose of ketamine Before KPT After KPT 1 month 3 months 6 months 12 months 18 months 24 months
Visual Analog Scale of Craving High Mean 29.24 3.97***
,+++
7.72*
,+++
5.40**
,+++
9.25
++
3.17
+++
0.57
+++
1.71
+++
SD 27.32 5.04 13.25 13.35 15.67 4.52 0.98 4.53
Low Mean 36.34 15.06
+++
20.18
++
28.33 19.75 27.00 12.50 0.00
a
SD 24.88 16.54 22.41 27.93 14.54 24.04 2.12
a
Spielberger State Anxiety Scale High Mean 41.17 35.71
+
35.81
+
36.36 38.00 37.00 33.57 37.14
SD 11.55 8.64 9.69 7.46 9.3 10.75 11.98 9.37
Low Mean 45.11 38.06
++
35.26
+++
37.17
+
35.88
+
28.50
+
25.00
++
31.00
a
SD 11.86 10.62 8.38 7.49 7.83 7.78 2.83 —
a
Spielberger Trait Anxiety Scale High Mean 45.97 42.23
+
39.54
++
38.71
+
37.33
++
37.44
+
38.86 40.86
SD 9.9 9.12 9.21 7.17 5.68 8.45 9.99 7.77
Low Mean 46.69 40.74
++
40.13
++
37.58
++
36.50
++
33.50
+
36.50 34.00
a
SD 8.73 8.35 8.09 7.05 7.50 3.54 4.95 —
a
Zung Depression Scale High Mean 46.20 42.66 39.88
+
39.57
+
40.50 39.44
+
35.00
++
37.66
+
SD 8.96 9.21 9.81 8.10 9.40 10.63 9.45 6.89
Low Mean 49.31 41.71
+++
40.87
+++
38.00
+++
37.50
+++
35.00
+
37.00 30.00
a
SD 9.26 10.28 6.81 9.02 6.41 1.41 1.41 —
a
Notes: 1. Statistical significance of differences between the scores before KPT and later scores:
+
-p< .05;
++
-p< .01;
+++
-p< .001.
2. Statistical significance of differences between the high dose and low dose group: * - p< .05; ** - p< .01; *** - p< .001.
3. SD - Standard Deviation.
4.
a
- There is only one subject in this group.
Fig. 2. KPT influence on the syndrome of anhedonia. + p< .05; ++ p< .01; +++ p< .001.
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283278
3.5. Anxiety
Follow-up revealed that both KPT groups demonstrated
significantly reduced state and trait anxiety compared to
baseline, measured with the Spielberger Anxiety Scale
(Table 2). The level of anxiety was within normal limits
by 3, 6, 12, and 24 months of abstinence in both groups.
There were no significant differences between the high and
low dose groups.
3.6. Depression
Both high and low dose KPT significantly reduced
elevated levels of pre-treatment depression relative to
baseline values, measured by the Zung Depression Scale
(Table 2). There were no significant differences between
the two groups.
3.7. MMPI
Relative to baseline values, high dose KPT produced a
decrease in scores for the following MMPI scales: depres-
sion, conversion hysteria, paranoia, schizophrenia, and the
Taylor scale of anxiety (Fig. 3). The self-sufficiency score
also significantly increased. Low dose KPT decreased
scores of the following scales: hypochondriasis, depression,
conversion hysteria, masculinity-femininity, paranoia, psy-
chasthenia, schizophrenia, sensitivity-repression, and the
Taylor scale of anxiety. The self-sufficiency score also
significantly increased. There were no significant differ-
ences in the MMPI scores between the two groups either
before or after the KPT session.
3.8. Locus of control
The locus of control in heroin addicts, evaluated with
the Locus of Control Scale, became significantly more
‘‘internal’’ after KPT in both groups. In the high dose
group the LCS index had increased from (Mean ± SD)
4.1 ± 1.5 before KPT to 5.2 ± 2.1 after KPT ( p< .01);
in the low dose group corresponding values were 3.8 ±
1.3 before KPT and 4.5 ± 1.4 after it ( p< .01). In
addition, locus of control in the area of failures became
significantly more internal in the high dose group after
KPT compared to baseline: 5.2 ± 1.8 and 4.2 ± 2.0,
respectively ( p< .05).
Fig. 3. MMPI. + p< .05.
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283 279
3.9. Understanding the meaning and purpose of one’s
own life
Ketamine psychotherapy caused a significant increase in
indices measuring understanding the meanings and purposes
in life, as well as self-actualization, and the ability to control
oneself and one’s own life in accordance to those life
purposes. In particular, understanding of the meaning of life
increased in the high dose group from (Mean ± SD) 75.4 ±
21.0 to 99.6 ± 20.4 ( p< .001), while in the low dose group
it increased from 77.5 ± 20.4 to 95.9 ± 19.9 ( p< .001).
Understanding of purposes in life increased from 22.2 ± 8.6
to 30.1 ± 7.6 in the high dose group ( p< .001), and from
23.6 ± 7.1 to 28.5 ± 7.0 in the low dose group ( p< .001).
Self-actualization increased from 16.8 ± 6.8 to 22.9 ± 6.7
(p< .001) in the high dose group, and from 16.1 ± 6.8 to
21.8 ± 6.5 ( p< .01) in the low dose group. There were no
statistically significant differences between groups.
3.10. Spirituality
The Spirituality Changes Scale (SCS) demonstrated a
similar increase in the level of spiritual development after
KPT in both groups of heroin addicts. In particular, the
number of answers showing the increase of spiritual devel-
opment after KPT in the high dose group was (Mean ± SD)
27.2 ± 9.3; in the low dose it was 25 ± 9.6. Changes in
SCS scores in heroin addicts were similar to those induced
by KPT in alcoholics in our previous studies (Krupitsky &
Grinenko, 1997).
3.11. Non-verbal emotional attitudes
The methodology of the Color Test of Attitudes (CTA) has
been described in detail previously (Krupitsky & Grinenko,
1997). According to the CTA data (Table 3), significant
positive changes in the high dose group occurred in patients’
nonverbal/unconscious assessments of seven of nine images:
‘‘Me now’’, ‘‘The ideal image of self’’, ‘‘Me in the future’’,
‘‘My family’’, ‘‘My job’’, ‘‘A man abstaining from drugs’’,
and ‘‘Psychiatrist’’. This means that the patients emotionally
accepted these images and, in turn, incorporated attitudes
towards abstinence connected with them.
Low dose group effects were less than in the high dose
group and involved only four images: ‘‘Me now’’, ‘‘My
family’’, ‘‘My job’’, and ‘‘Psychiatrist’’ (Table 3). Thus,
high dose KPT in heroin addicts produced greater changes
in nonverbal unconscious emotional attitudes of heroin
addicts than did low dose KPT.
3.12. Side effects and complications
There were no complications, such as protracted psychosis
or flashbacks, after KPT. No subject participating in the study
became addicted to ketamine. The only side effect noted in all
subjects was an acute increase in systolic and particularly
diastolic blood pressure of 20 30% during the session.
4. Discussion
This double-blind, active-placebo controlled study dem-
onstrates that ketamine-assisted psychotherapy of heroin
addicts is more effective when a high, psychedelic, dose
of ketamine is administered than when a low, sub-psyche-
delic, dose is administered. However, many of the measured
change variables did not differ significantly between high
and low dose groups. This suggests that the psychotherapy
common to both groups played an important role in the
observed effects.
We confirm that acute psychological effects of ketamine
in a sub-anesthetic doses are psychedelic in nature. For
example, quantitative assessment of these effects in the high
dose group using the Hallucinogen Rating Scale (HRS)
My job Heroin addict A man abstaining from drugs Psychiatrist
Dose of ketamine Before KPT After KPT Before KPT After KPT Before KPT After KPT Before KPT After KPT
High Mean 16.66 12.6
+++
24.00 25.03 14.23 11.66
+
14.86 12.17
+
SD 7.33 6.36 6.96 7.01 6.89 6.71 7.98 7.45
Low Mean 16.46 11.77
++
24.46 26.46 11.74 9.49 13.31 10.03
+
SD 8.33 7.40 9.17 8.14 7.85 7.15 8.82 7.76
Note: 1.See notes for Table 2.
2. The lower the score, the more positive the attitude to the image is.
Table 3
KPT influence on non-verbal emotional attitudes
Attitude to the images of the Color Test of Attitudes (CTA)
Me now The ideal image of self Me in the past Me in the future My family
Dose of ketamine Before KPT After KPT Before KPT After KPT Before KPT After KPT Before KPT After KPT Before KPT After KPT
High Mean 16.11 10.51
+++
15.43 11.43
++
24.97 26.63 15.43 12.4
++
16.51 11.94
++
SD 6.72 5.53 7.02 6.59 5.45 4.77 5.19 6.32 7.65 7.45
Low Mean 14.00 8.00
++
11.09 9.66 24.23 26.60 14.69 11.66 14.69 10.91
+
SD 8.05 5.35 6.48 7.69 7.87 6.85 8.21 8.13 8.86 8.03
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283280
were similar to those induced by a dose of the tryptamine
hallucinogen N,N-dimethyltryptamine described by experi-
enced psychedelic users as fully psychedelic (Strassman,
1996). Average HRS scores in the high dose group are
similar to those obtained by Bowdle and co-authors also
using sub-anesthetic doses of ketamine (Bowdle et al.,
1998). All but one HRS subscale scores differed signifi-
cantly between the high dose and low dose groups. The
single exception was Volition, a subscale with previously
described problems in sensitivity to other experimental
interventions (Strassman, Qualls, & Berg, 1996) (Table 1).
Subjects in the high dose group had a typical psychedelic
experience while patients in the low dose group experienced
something that functions as ketamine-facilitated guided
imagery (Leuner, 1977). However, subjects in the low dose
group were often affected by their experiences and consid-
ered them as useful and therapeutic.
While HRS scores in the low dose group were signifi-
cantly less, they still were substantially higher than those
seen in placebo groups in Strassman’s DMT and Bowdle’s
ketamine studies. Thus, subjects in the low dose group had
experiences of what might be referred to as ‘‘sub-psyche-
delic’’. This could be the effect of set and setting combined
with a relatively low dose of ketamine. Similar effects were
noted in a previous study by Kurland, Savage, Pahnke,
Grof, & Olsson, (1971). They used 500 mcg of LSD as their
high dose, and 50 mcg as their low dose, in treating alcohol-
dependent individuals. It was believed that 50 mcg would be
an active placebo, but they found the frequency of ‘‘peak
experiences’’ to be similar in both groups. This finding may
relate to the important, and often ignored, interplay between
set (state of the research subject), setting (physical and
interpersonal circumstances in which the drug is taken),
and dose of drug (Strassman, 1995).
Nevertheless, above certain dose levels psychedelic
effects are usual; thus set and setting are more likely to
play a role in lower dose conditions (Strassman et al., 1994).
Future studies may therefore demonstrate a greater effect of
ketamine as an adjunct to psychotherapy of addicted
patients using even lower doses of ketamine or placebo.
Ketamine psychotherapy produced no significant adverse
reactions in this study. This is in distinct contrast to reports
from the first phase of psychedelic psychotherapy studies
with other compounds in 1960s (Grinspoon & Bakalar,
1979). This might be because the mechanism underlying
ketamine action (blockade of calcium channel within the
NMDA receptor) is different from that of other psyche-
delics, which are primarily serotonin partial agonists. Also,
excluding patients with co-morbid psychiatric disorders
might have reduced the overall risk of adverse effects.
The rate of abstinence in the high dose group was
significantly greater than that of the low dose group, while
the corresponding rate of relapse was lower (Fig. 1). These
differences emerged at the first month of follow-up and
continued through the subsequent 23 months. The rate of
abstinence in the high dose group also was higher than the
typical rate of abstinence in conventional treatment pro-
grams for heroin addiction in Russia. These programs
usually include only drug counseling, cognitive behavioral
psychotherapy, and limited prescription of naltrexone (all
agonists are legally prohibited in Russia). Almost 50% of
patients in the high dose group and 60% of subjects in the
low dose group relapsed within the first 3 months after KPT.
Thus, repeated sessions carried out within the first few
months after KPT might provide a higher rate of abstinence.
Halpern (1996) in his review of the studies of psychedelic
psychotherapy of addictions came to a similar conclusion.
We are currently testing that hypothesis in an ongoing study.
High dose KPT produced greater and longer-lasting
decrements in drug craving in heroin addicts than did low
dose KPT. Other NMDA receptor antagonists, such as
ibogaine and acamprosate, have a similar influence on
craving (Sass et al., 1996; Mash et al., 1998). A long
lasting anti-depressant effect of a single ketamine halluci-
nogenic experience has also been recently noted by Berman
et al. (2000).
Both groups showed a significant reduction in the
severity of the syndrome of anhedonia, which appears to
be a protracted withdrawal syndrome, and occurred more
quickly than did traditional treatment with selective sero-
tonin reuptake inhibitors (SSRIs) which takes at least 3
weeks. The reduction in the severity of this syndrome
contributes to relapse prevention (Krupitsky et al., 1998).
Also, the severity of all components of the anhedonia
syndrome was reduced, including the cognitive, while
SSRIs influence primarily affective and behavioral compo-
nents (Krupitsky, Burakov, Romanova, Vostrikov, & Gri-
nenko, 1999).
Both groups showed a positive effect on anxiety, depres-
sion, mood, and activity in everyday life. All of those effects
might favor abstinence since high levels of depression and
anxiety may provoke relapse to heroin in heroin addicts
(Nunes et al., 1998).
Both groups’ MMPI scores changed similarly, suggesting
that patients became more confident, more optimistic about
their possibilities and their futures, less anxious, less
depressed and neurotic, and more emotionally open after
treatment. These changes are also similar to those noted in
alcoholics after KPT (Krupitsky & Grinenko, 1997). Of note
is that positive MMPI changes in the low dose group were
similar to those in the high dose group and included even
more scales. However, the scores for the Lie scale signifi-
cantly increased while those for the Validity scale decreased
in the low dose group. This result may mean that low dose
group patients tried to present themselves in a more positive
and socially acceptable way, rather than reflecting deeper
personality effects.
Locus of control data suggest that both groups demon-
strated an increase in patients’ confidence in their ability to
control and manage different situations in their lives. They
felt more responsible for their lives and futures after
treatment. The fact that locus of control in the area of
E. Krupitsky et al. / Journal of Substance Abuse Treatment 23 (2002) 273–283 281
failures became significantly more internal after high dose
KPT suggests that those patients assumed more responsibil-
ity for failures and problems of their lives after treatment.
Purpose in Life Test data revealed that both groups were
better able to understand the meaning of their lives, their life
purposes, and perspective. Both groups demonstrated pos-
itive changes in life values of heroin addicts reflecting the
increased understanding and importance of life values other
than the heroin ‘‘high’’. Relative to Frankl’s approach
(1978), which considers alcoholism and addictions as an
‘‘existential neurosis’’ resulting from loss of meaning of life
(‘‘existential void’’), we believe treatment may have helped
fill this void to some extent.
A psychedelic ketamine experience is to some extent
similar to the near-death experience (NDE) (Jansen, 1997,
2001). And, similar to the NDE, it might be transformative
and induce changes in spiritual development and worldview
(Ring, 1984; Krupitsky and Grinenko, 1997). In addition,
many reports suggest that religious or spiritual conversion is
an important factor in ‘‘spontaneous’’ recovery from drug
abuse. Indeed, Twelve Steps and Alcoholic Anonymous
programs have a distinctly spiritual/religious orientation
(Corrington, 1989; Whitfield, 1984). A therapy that enhan-
ces the likelihood of a conversion or spiritual experience
therefore might have utility in the treatment of substance
abuse. Ketamine-assisted psychotherapy may represent one
method of eliciting spiritual experiences in subjects with
chemical dependence and thus help promote abstinence.
High dose KPT elicited greater effects than low dose
conditions on the non-verbal emotional attitudes measured
with the CTA. These data suggest that high dose KPT
modifies unconscious attitudes related to abstinence. The
CTA data also support the hypothesis that enhancement of
the relationship with the psychiatrist is salutary.
The results of this double-blind, randomized clinical trial
of KPT for heroin addiction showed that high dose (2.0 mg/
kg) ketamine psychedelic psychotherapy elicits a full psy-
chedelic experience in heroin addicts. On the other hand,
low dose KPT (0.20 mg/kg) elicits a ‘‘sub-psychedelic’’
experience which functions as ketamine-facilitated guided
imagery. High dose KPT produced a significantly greater
rate of abstinence in heroin addicts within the first 24
months of follow-up than did low dose KPT. High dose
KPT brought about a greater and longer-lasting reduction in
craving for heroin, as well as greater positive change in
nonverbal unconscious emotional attitudes. Thus, it is
possible that the higher rate of abstinence in the high dose
group was to some extent due to positive effects of ketamine
on craving, similar to other NMDA receptor ligands such as
ibogaine and acamprosate.
Both treatment groups demonstrated changes in depres-
sion, anxiety, anhedonia, and psychological profile assessed
with a battery of verbal tests. These results support the
hypothesis that the effects of psychedelic psychotherapy on
the verbal level do not necessarily lead to high rates of
abstinence from drugs and alcohol (Grinspoon & Bakalar,
1979). These results might also reflect some common
effects of our psychotherapy of heroin addiction provided
to all patients independent of the psychedelic effects of
high-dose ketamine. Future research will explore further
how to utilize these unique psychological effects more
effectively in promoting abstinence. The most pressing need
is to assess whether repeated KPT treatments are more
useful than single sessions.
Acknowledgments
The authors are very grateful to the Multidisciplinary
Association for Psychedelic Studies (MAPS, www.maps.org)
and to the Heffter Research Institute (HRI, www.heffter.org)
for their support of this study.
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... Despite the preliminary nature of the evidence described above, a small number of studies have examined the promising effects of ketamine combined with psychotherapy for treating disorders other than depression, including alcohol, heroin, cocaine, and cannabis abuse [69][70][71][72]. Ketamine was found to have benefits in treating substance addiction and dependence, increasing abstinence rates, reducing relapse rates, and decreasing cravings. ...
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... Krupitsky eventually realized that patients benefited similarly from positive, transcendent experiences while on ketamine and shifted from a model of aversive conditioning to one informed by existential and transpersonal psychology. This model has been described as Ketamine Psychedelic Psychotherapy (KPP) or Ketamine Psychedelic Therapy (KPT), and was used successfully in the treatment of alcohol and opioid use disorders (Krupitsky and Grinenko, 1997;Krupitsky et al., 2002Krupitsky et al., , 2007. Moreover, these studies indicated that ketamine could be combined with psychotherapeutic interventions to produce meaningful and enduring changes in psychological attitudes, concepts of self, and overall functioning. ...
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