CATIE News

10 October 2019 

Can intravenous ketamine and mindfulness therapy break cocaine dependency?

  • Scientists conducted a randomized study of ketamine and mindfulness
  • Results appear promising as some people were able to stop using cocaine
  • More research lies ahead to uncover ketamine’s potential in addiction medicine

Previous research has shown links between cocaine use and heightened risk for HIV or hepatitis C infection. Harm reduction strategies help to reduce this risk, and some researchers have investigated ways to assist people who wish to reduce or stop their cocaine use. There is no approved treatment for cocaine dependency, but the anesthetic ketamine has shown potential in preliminary clinical trials.

About ketamine

Over the past 20 years, accumulating research has shown that the drug ketamine can relieve feelings of depression in some people. An intravenous formulation of ketamine has been in use in Canada and other high-income countries for many years, first as a veterinary anaesthetic and later for anaesthesia in humans. Some psychiatrists have successfully treated people suffering from depression with intravenous ketamine, although this use of intravenous ketamine has not been approved by regulatory authorities. Powdered ketamine has been used as a club or party drug (commonly called “K” or “Special K”). This use of ketamine has the potential to lead to dependency in some people.

In March 2019, the U.S. Food and Drug Administration (FDA) approved a closely related form of ketamine (esketamine), formulated as a nasal spray. This spray is meant to be used as part of combination treatment for depression that is resistant to standard treatment.

Now, scientists in the U.S. think that intravenous ketamine has the potential to successfully treat cocaine dependency in some people.

In a randomized clinical trial with 55 participants, scientists found that a combination of a single infusion of ketamine combined with mindfulness-based exercises helped to significantly reduce dependence on cocaine in some people.

These results should be considered very promising but preliminary. Additional research is needed in clinical trials that are larger, longer and of a different design than the present study. Later in this CATIE News bulletin, we will explain some of the issues that future clinical trials of ketamine might explore.

Study details

Scientists enrolled people who wanted to quit using cocaine but were unable to because of dependence. Participants were hospitalized for five consecutive days in a research unit of a psychiatric hospital. On the first day, they began mindfulness-based relapse prevention (more about this later) and continued this every day for five consecutive days. On the second day, participants were randomly assigned to receive one of the following, given intravenously over 40 minutes:

  • ketamine at a dose of 0.5 mg/kg
  • the sedative midazolam at a dose of 0.025 mg/kg

Prior to the intravenous infusion, to help disguise which study drug would be administered, scientists told participants that they would receive one of the following drugs/substances:

  • amantadine
  • buspirone
  • D-cycloserine
  • ketamine
  • memantine
  • midazolam
  • saline

Another reason for disguising which drug would be administered was to reduce what the scientists called “expectancy effects.”

At the end of the fifth week, researchers provided participants with referrals to doctors who specialize in addiction medicine. Finally, six months after the study began, study staff telephoned participants to conduct interviews.

About mindfulness in general

According to Canadian psychologist Scott Bishop, PhD, mindfulness-based therapy was “adapted from traditional mindfulness meditation practices” originating from Buddhism. It was originally developed to help prevent relapse in people who had recovered from depression by reducing psychological distress.

In mindfulness-based therapy, Dr. Bishop says, therapists teach participants to become more aware of “thoughts and feelings and to change their relationship with them. Mindfulness allows the participants to step back from thoughts and feelings during stressful situations rather than engaging in anxious worry or other negative thinking patterns that might otherwise escalate a cycle of stress reactivity and contribute to heightened emotional distress.”

During mindfulness-based therapy, participants learn a variety of meditation practices, including seated and walking meditations, a body scan that is done lying down and yoga. Many practices begin with focusing attention on breathing. As their attention wanders, participants are encouraged to accept and acknowledge their thoughts and feelings and redirect their attention back to their breathing. As the course progresses, participants develop a more direct exploration of difficult sensations, feelings and thoughts.

Typically, mindfulness-based therapy consists of eight to 10 weekly sessions, during which participants are guided through a meditation practice. Participants are taught about the effects of stress and emotions on their mind and body and how to handle stressful situations using mindfulness. They also practice meditating at home each day using recordings that help guide them. There is more than an hour of practice and homework each day.

According to Dr. Bishop, mindfulness-based therapy “involves a reflective, warm, accepting and contemplative approach to situations, open-mindedness and a tendency towards curious introspection.”

Mindfulness and other issues in the present study

Scientists in the present study adapted traditional mindfulness techniques that have been developed to reduce the risk of relapse among people who have tried to previously break their dependency on substances. This adapted form of mindfulness is called mindfulness-based relapse prevention (MBRP). Used by itself, scientists have found MBRP to have “modest efficacy” in people with substance use disorders. Four sessions of MBRP were given on days two and five of the study.

Participants returned to the study site twice weekly, for additional sessions of MBRP (which were given once a week) and for giving blood and urine samples and undergoing assessment by study physicians.

The basic profile of participants at the start of the study was as follows:

  • age – 47 years
  • 74% men, 26% women
  • cocaine was used in the following ways: smoked (freebased) – 64%; inhaled as a powder – 24%; taken in both forms – 13% (note that numbers do not total 100% due to rounding)
  • co-existing issues: post-traumatic stress disorder – 14%; alcohol use disorder – 22%
  • most participants seemed to have a modest degree of depressive illness

Although not mentioned by the scientists, it is unlikely that any participants had chronic viral infections such as hepatitis C virus or HIV.

Results

Participants who received ketamine (hereafter called the ketamine group) were subsequently less likely to use cocaine. Furthermore, during the final two weeks of the study, when technicians were collecting urine samples from participants to assess their use of cocaine, 48% of people in the ketamine group vs. 11% in the midazolam group did not use cocaine.

The scientists found that people in the ketamine group had a 53% reduced risk of relapse (dropping out of the study or using cocaine) and a 58% reduced craving for cocaine compared to people in the midazolam group. Furthermore, the reduction in cocaine craving (assessed by validated questionnaire) appeared to be sustained among some people in the ketamine group.

All of these differences between the ketamine and midazolam groups were statistically significant; that is, not likely due to chance alone.

Safety

According to the scientists, both study drugs were well tolerated. Ketamine was associated with well-known side effects—confusion and auditory and visual hallucinations. However, the scientists stated that these side effects resolved “within 30 minutes after infusion.” Systolic blood pressure increased by 20 points after ketamine infusion, but this also subsequently resolved.

The scientists stated that midazolam caused “mild sedation lasting no longer than 12 hours.” They noted that neither study drug was associated with any of the following: “persistent psychiatric disturbances, clinical worsening, increased drug use, or emergence of new drug misuse (ketamine, opioids or benzodiazepines), as assessed by self-report, urine toxicology, and psychiatric assessment.”

Telephone interviews

Six months after the study began, participants disclosed the following: 44% of the ketamine group and no one in the midazolam group had stopped using cocaine. Unlike the first five weeks of the study, no urine analysis was done to confirm non-use of cocaine.

Bear in mind

In this well-designed exploratory study, scientists found that a single infusion of ketamine accompanied by MBRP resulted in a significant proportion of participants stopping their cocaine use. However, it is important to note that it did not help everyone.

Based on the study’s design (there was no group of participants who did not receive MBRP), it is not clear if MBRP is necessary to help people stop using cocaine. It is possible that ketamine alone or a combination of ketamine and another psychological approach could have been as effective.

The present study was imperfect—it was relatively small, most participants were men and everyone was under intense medical surveillance during the first five days. Furthermore, participants did not have serious mental illnesses, such as severe depression, bipolar disorder or schizophrenia. However, it is likely that scientists and people with substance dependency will be interested in further research with ketamine. Perhaps this interest will lead to the development of a research agenda for studying ketamine.

For the future

Future studies of ketamine’s potential for relieving substance dependency should take at least the following issues into account:

  • enroll many people
  • monitor participants for several years to find out more about the long-term effectiveness and safety of ketamine when used to treat addiction
  • enroll at least these populations: women, people with chronic viral infections such as hepatitis B or C viruses and/or HIV, people with severe mental health conditions
  • include community research sites in addition to hospital-based ones
  • compare the effects of different formulations, doses and schedules of ketamine
  • explore the potential of ketamine in cases of dependency with substances other than cocaine

Much work by scientists lies ahead if they are to learn about ketamine’s potential in addiction medicine. Scientists will have to design clinical trials, write lengthy grant proposals and have their grants compete against other grants for limited research funds. Even if money is secured, they will have to hire staff and screen hundreds, if not thousands, of potential volunteers for future studies. All of this effort will mean that the full potential of ketamine will not be known for many years.

—Sean R. Hosein

REFERENCES:

  1. Dakwar E, Nunes EV, Hart CL, et al. A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: A randomized clinical trial. American Journal of Psychiatry. 2019; in press.
  2. Carey B. Fast-acting depression drug, newly approved, could help millions. The New York Times. 5 March 2019. Available at: https://www.nytimes.com/2019/03/05/health/depression-treatment-ketamine-fda.html
  3. Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000 Feb 15;47(4):351-4.
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  11. Singh JB, Fedgchin M, Daly E, et al. Intravenous esketamine in adult treatment-resistant depression: A double-blind, double-randomization, placebo-controlled study. Biological Psychiatry. 2016 Sep 15;80(6):424-431.
  12. Tang WK, Lau CG, Ungvari GS, et al. Recovery of cognitive functioning following abstinence from ketamine. Addictive Behaviors. 2019 Aug 7;99:106081.
  13. Yang SS, Jang MY, Lee KH, et al. Sexual and bladder dysfunction in male ketamine abusers: A large-scale questionnaire study. PLoS One. 2018 Nov 28;13(11):e0207927.
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  15. Wang LJ, Chen CK, et al. Cognitive profile of ketamine-dependent patients compared with methamphetamine-dependent patients and healthy controls. Psychopharmacology (Berl). 2018 Jul;235(7):2113-2121.

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