KETAMINE ASSISTED PSYCHOTHERAPY (KPT) OF HEROIN DEPENDENCE: IMMEDIATE EFFECTS AND TWENTY FOUR MONTHS FOLLOW-UP Krupitsky E.M., Burakov A.M., Romanova T.N., Dunaevsky I.V., Strassman R.J. St.Petersburg State Pavlov Medical University, St. Petersburg V.M. Bekhterev Research Psychoneurological Institute

INTRODUCTION

Many studies conducted in 1950’s and 1960’s suggest that hallucinogen assisted psychedelic psychotherapy may offer an effective treatment for alcoholism and addictions. However, different and not a rigorous scientific methodologies make it difficult to generalize across studies.

Ketamine has several advantages over other psychedelics as an adjunct to psychotherapy:

•Safe•Short acting•Not scheduled as other psychedelics•Allowed for general anesthesia•In our previous studies it has been shown to be an effective treatment for alcoholism

New approaches to treatment of heroin addiction in Russia are particularly important because of:

•Epidemic of heroin addiction since mid-1990s•All agonists (methadone, LAAM) and partialagonists-antagonists (buprenorphine) are prohibited by the law•HIV epidemic among heroin addicts

Seventy detoxified heroin addicts were randomly assigned to one of two groups:The patients of the experimental group received

psychotherapy in combination with a “psychedelic” dose of ketamine (2.0 mg/kg i.m.)

The patients of the control group received the same psychotherapy combined with a very low, non-psychedelic (non-hallucinogenic), dose of ketamine (0.20 mg/kg i.m.)

Both the psychotherapist and subject were blind to the dose of ketamine

Study design

Inclusion criteria: ICD-10/DSM-IV criteria of current Heroin Dependence,

present for at least one year Age between 18 and 30 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 districts of

Leningrad Region Home telephone number at which the patient can be reached Not currently on probation Willingness and ability to give informed consent and otherwise

participate

Exclusion criteria:

ICD-10/DSM-IV criteria of organic mental disorders,schizophrenic disorders, paranoid disorders, major affectivedisorders, and seizure disorders

ICD-10/DSM-IV criteria for alcoholism and polydrugdependency

Advanced neurological, cardiovascular, renal, and hepaticdiseases

Pregnancy Family history of psychiatric disorders listed above 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 >3X above normal Pending legal charges with potential impending incarceration Concurrent participation in another treatment study Concurrent treatment in another substance abuse program

Assessments. Psychiatric symptoms:Psychiatric symptoms and psychopathology were assessed with: ICD-10 Structured Clinical Interview for Psychiatric Disorders

(CIDI) Zung Self-rated Depression Scale (ZDS) - to assess depression Spielberger Self-rated State-Trait Anxiety Scale (SAS) - 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 et al., 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, feeling like life is dull and empty, passivity, sleep disturbance, and craving for heroin. SA has affective, cognitive, and behavioral subscales

Hallucinogen Rating Scale (HRS) (Strassman et al., 1994) - to assess acute subjective responses to a psychoactive drug challenge

Psychological Assessments: Minnesota Multiphasic Personality Inventory (MMPI)) - to assess

personality characteristics Locus of Control Scale (LCS) developed by Rotter - to assess the ability

of the subjects to control and manage different situations in their lives Color Test of Attitudes (CTA) - to assess nonverbal unconscious

emotional attitudes Purpose-in-Life Test (PLT) based on Frankl’s concept of the individual’s

aspiration for meaning in life Spirituality Changes Scale (SCS) based on the combination of the

Spirituality Self-Assessment Scale developed by Whitfield, who studied the importance of spirituality in Alcoholics Anonymous, and the Life Changes Inventory developed by Ring 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

Treatment Assessment, Outcome and Follow-up:

Assessment Schedule: - ZDS, SAS, VASC, SA, MMPI, LCS, CTA, QTLV,

PLT, and PHAMS were administered pre-therapy (baseline) and post-therapy (during 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 of the follow-up in those subjects abstaining from heroin (those who relapsed were unavailable for assessment).

Treatment Assessment, Outcome and Follow-up:

Follow-up Data: Psychiatrists who were blind to ketamine dose collected follow-up data on a monthly basis for up to 24 months (if the subject had not relapsed before that). Follow-up data included: - Information from the subject about his/her drug use during the follow-up period; - Examination 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 a poor compliance.

Treatment Procedure: There are three main stages in our method of KPT. The first stage is preparation. There were 10 hours of psychotherapy provided before the ketamine session in order to prepare subjects for the session. The second stage of KPT is the ketamine session itself. An anesthesiologist was present throughout the ketamine session to respond to any complications which are very rare but still possible. The length of the ketamine session was about 1.5 - 2 hours. Only one ketamine session was carried out for each subject. The subject was instructed to recline on a couch with eyeshades. Pre-selected music was used throughout the ketamine session. The psychotherapist provided emotional support for the subject and carried out psychotherapy during the session. Psychotherapy was existentially oriented, but also took into account the subject’s individuality and personality problems. Subjects were discharged from the hospital soon after the KPT(within three-five days). In the third stage, special psychotherapeutic sessions are carried out within several days after the KPT session. There were 5 hours of psychotherapy provided after the ketamine session to help subjects interpret and integrate their experiences during the session into everyday life.

Data Management and Statistical Analysis: Statistical analysis (using ANOVA, LSD test for post hoc comparisons, and a Student t-test for dependent and independent samples) was performed to assess treatment effects and outcome within both the high dose and low dose groups as well as statistical significance of differences between the high dose and low dose groups. The software package SPSS and “Statistica” were used. Independent variables were treatment (dose of ketamine), and time of assessment (pre- and post therapy, or during the follow-up). Dependent variables were clinical and psychological ratings, and rate of abstinence and relapse.

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Intensity Somaesthesia Affect Perception Cognition Volition

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Low dose

Characteristics of ketamine experience with HRS

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Twelve months follow-up data: Abstinence

85,781,4

54,351,4

42,937,2

31,428,6

31,4 31,425,7 25,7

5,78,5

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28,628,6

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Abstinence: Low dose ketamine group

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Twenty four months follow-up data: AbstinenceAbstinence: High ketamine dose

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Twelve months follow-up data: Relapse

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48,654,3

57,260 60 60

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65,7 65,7

77,2 77,280

82,885,7 85,7

88,691,4

65,765,7

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Relapse: High ketamine dose

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Twenty four months follow-up data: Relapse

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Visual Analog Scale of Craving for Heroin

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Zung Depression Scale

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State-Trait Anxiety Scale

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State Anxiety (high ketamine dose)State Anxiety (low ketamine dose)

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State-Trait Anxiety Scale

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Trait Anxiety (high ketamine dose)Trait Anxiety (low ketamine dose)

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Affective subscale

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KPT influence on the syndrome of anhedonia

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High doseBefore KPTHigh doseAfter KPT

KPT influence on the Minnesota Multiphasic Personality Inventory

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KPT influence on the Minnesota

Multiphasic Personality Inventory

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LC in thearea of

achievements

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LC in thearea of family

life

LC in the area ofprofessionalrelationships

LC in the area ofinterpersonalrelationships

LC in the area of healthand disease

Before KPT (highdose)After KPT (highdose)Before KPT (lowdose)After KPT (lowdose)

KPT influence on the locus of control (LC) in the personality

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Index of theunderstanding

of the meaningof life Understanding

of purposes inlife

Meaning of theprocess of life

Self-actualization

Locus ofcontrol of self

Locus ofcontrol of life

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KPT influence on the purposes in life

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spirituality

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spirituality

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KPT influence on spirituality

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Me now

The idealimage of self

Me in thepast

Me in thefuture

My family

My job

Heroinaddict A man

abstaining from drugs

Psychiatrist

Before KPT (highdose)After KPT (highdose)Before KPT (lowdose)After KPT (lowdose)

KPT influence on non-verbal emotional attitudes

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Side effects and complications:

There were no complications such as protractedpsychosis or flashbacks, after KPT.

No subject participating in the study becameaddicted to ketamine.

The only side effect noted in all subjects was anincrease in both systolic and diastolic blood pressureof 20-30% during the session.

CONCLUSION

The results of this double-blind randomized clinical trial ofKPT for heroin addiction showed that:

High dose (2.0 mg/kg) ketamine psychedelic psychotherapy(KPT) elicits a profound, full psychedelic experience inheroin addicts. On the other hand, low dose KPT (0.2mg/kg) elicits “sub-psychedelic” experiences which arevery similar to ketamine-facilitated guided imagery.

High dose KPT produced a significantly greater rate ofabstinence in heroin addicts within twenty four months offollow-up than did low dose KPT.

High dose KPT brought about more a greater, and longer-lasting reduction in craving for heroin, as well as greaterpositive change in nonverbal unconscious emotionalattitudes.

KETAMINE ASSISTED PSYCHOTHERAPY (KPT) OF HEROIN DEPENDENCE: MULTIPLE VS. SINGLE KPT Krupitsky E.M., Burakov A.M., Romanova T.N., Dunaevsky I.V. St.Petersburg State Pavlov Medical University, St. Petersburg V.M. Bekhterev Research Psychoneurological Institute

Psychedelic afterglow

One of the insights gained from previous research with psychedelics concerns the transient psychotherapeutic and psychological 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. This phenomenon was termed a “psychedelic afterglow.”

Previous KPT study:

About 50% of patients in a high ketamine dose group and 60% of patients in a low dose group relapsed within the first 3 months.

Hypothesis:

Could the efficacy of KPT in treating heroin dependence be increased by administering multiple KPT sessions and thus stabilizing the afterglow?

Study design: 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:

1. 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).

2. Participants in the second group received two addiction counseling sessions on a monthly interval, but no additional ketamine therapy sessions (single KPT group).

Study design II: 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 sessions performed psychological and clinical evaluations on all participants during treatment and follow-up periods.

Drop out: Six out of 59 participants enrolled in the study relapsed

and dropped out of treatment within the first month after the initial KPT session. Prior to the second session, the 53 remaining participants were randomized into the two treatment groups:

Twenty-six participants were assigned to the multiple KPT group and received two more KPT sessions, including addiction counseling sessions before KPT, separated by one-month intervals.

Twenty-seven participants were assigned to the single KPT group and received two addiction counseling sessions separated by one-month intervals. There were no statistically significant differences between these groups in the mean age, duration of heroin addiction, and gender.

Retention in Treatment: 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 first counseling session.

The difference in the retention in treatment phase between the two groups was not statistically significant.

Kaplan-Meier Survival Analysis

P<0.01

Months

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Kaplan-Meier Survival Analysis

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Survival Functions

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Rate of Abstinence: 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).

Depression

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Multiple KPT session Single KPT sessionZung score

State anxiety

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Trait anxiety

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Craving

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Understanding the meaning of life

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Conclusion

Three sessions of ketamine-assisted psychotherapy are more effective than a single session for the treatment of heroin addiction.

What does all of that mean?

Should we take a courage to bridge the gap between psychedelic psychotherapy and main stream?

Even though we can not do that right now…

We should start to go this way…

Think more about that…

Balance all the arguments…

Be very careful with every tiny detail…

THE FUTURE ?THE FUTURE ?

Some men Some men see things as see things as they are, and they are, and say “why?”say “why?”

I dream of I dream of things that things that have never have never been, and been, and say “why say “why

not?”not?”

Robert F KennedyRobert F Kennedy

ACKNOWLEDGEMENT Authors are very much thankful and grateful to the Multidisciplianry Association for Psychedelic Studies (MAPS) as well as to Heffter Research Institute for the support of these studies which otherwise would not be possible.