Ketamine for the treatment of addiction: Evidence and potential mechanisms

This review (2018) looks at the studies done with ketamine for the treatment of addiction. The results are promising and various mechanisms underlie these effects. Both effects at the neurological (neurogenesis, neuroplasticity, and more) and psychological (mystical experience, reconsolidation of drug-related memories) are discussed.

Abstract

“Ketamine is a dissociative anaesthetic drug which acts on the central nervous system chiefly through antagonism of the n-methyl-d-aspartate (NMDA) receptor. Recently, ketamine has attracted attention as a rapid-acting anti-depressant but other studies have also reported its efficacy in reducing problematic alcohol and drug use. This review explores the preclinical and clinical research into ketamine’s ability to treat addiction. Despite methodological limitations and the relative infancy of the field, results thus far are promising. Ketamine has been shown to effectively prolong abstinence from alcohol and heroin in detoxified alcoholics and heroin dependent individuals, respectively. Moreover, ketamine reduced craving for and self-administration of cocaine in non-treatment seeking cocaine users. However, further randomised controlled trials are urgently needed to confirm ketamine’s efficacy. Possible mechanisms by which ketamine may work within addiction include: enhancement of neuroplasticity and neurogenesis, disruption of relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy. Identifying the mechanisms by which ketamine exerts its therapeutic effects in addiction, from the many possible candidates, is crucial for advancing this treatment and may have broader implications understanding other psychedelic therapies. In conclusion, ketamine shows great promise as a treatment for various addictions, but well-controlled research is urgently needed.”

Authors: I. Ivan Ezquerra-Romano, Will Lawn, Evgeny M. Krupitsky & Celia J. A. Morgan

Summary

Abstract

Ketamine is a dissociative anaesthetic drug that acts on the central nervous system and may be effective in treating addiction. It may do this by enhancing neuroplasticity, disrupting relevant functional neural networks, treating depressive symptoms, blocking reconsolidation of drug-related memories, provoking mystical experiences and enhancing psychological therapy efficacy.

Introduction

Despite decades of research into the causes of and treatment for addiction, it continues to be a global problem. Alcohol use disorder affects 5% of the world’s adult population and 2.9% of people in the US are dependent on an illicit substance.

Ketamine may be used as a treatment for addiction, and it has the potential to improve abstinence, treat unresponsive patients, and deal with substance use disorders with no effective pharmacological treatments.

Ketamine: from anaesthesia to addiction

Ketamine is a chemical class of drugs known as arylcyclohexylamines, which were developed by Parke-Davies to find a safe and reliable anaesthetic. It is used in many clinical settings, including veterinary settings, and has been determined by World Health Organisation as an essential medicine.

Ketamine is normally administered intravenously, where it induces dissociation, sedation and analgesia, and at sub-anaesthetic doses, it can also produce psychedelic experiences. These effects are usually considered adverse, but recreational users find some of them appealing.

Ketamine induces psychosis-like effects in rats and healthy humans, which have been used as a model of schizophrenia for neuroimaging research and pharmacological research.

Researchers have defined four specific stages of ketamine-induced non-ordinary states of consciousness as a function of drug dose. These include an empathogenic experience, an out-of-body experience, an ego-dissolving transcendental experience, and a near death experience.

Ketamine’s use in clinical settings and study in the scientific community increased, as did its recreational use. Its abuse liability has led many countries to make ketamine a controlled substance.

Pharmacology and applications

Ketamine is a wide ranging pleiotropic molecule that affects a variety of receptors and cellular processes. It rapidly crosses the blood-brain barrier and exerts its effects on the CNS within 5 minutes after injection.

Ketamine is a racemate of the two enantiomers: S-ketamine and R-ketamine. S-ketamine has greater affinity for NMDA receptors, but R-ketamine shows more potency and longer-lasting anti-depressant effects in animal models.

Ketamine is an effective analgesic which impedes ‘wind-up’, a type of neuroplasticity, in the dorsal horn of the spinal cord. It is used to treat chronic pain syndromes such as fibromyalgia, burns, neuropathic pain, post-herpetic neuralgia and migraine.

A double-blind, placebo-controlled study reported that ketamine had rapid antidepressant effects, and more research replicated these results in the following years. This stimulated a great deal of psychiatric research into ketamine.

Preclinical evidence in addiction

Preclinical research on the anti-addictive properties of ketamine is somewhat sparse, however one study found that ketamine reduced alcohol intake in rats without affecting motor activity or water consumption.

Addiction is characterised by disruptions in learning and memory. Ketamine administration disrupted reconsolidation of morphine-induced conditioned place preference in rats, and this effect was maintained after a priming injection of morphine.

Clinical studies of ketamine in the treatment of addiction

The earliest recorded use of ketamine in the treatment of addiction was by Salvador Roquet, but it was not investigated scientifically until decades later. Krupitsky and Grinenko (1997) published a review of 10 years of previous research.

The KPT procedure consisted of three stages: a preliminary psychotherapy session, a ketamine session and a group psychotherapy session. The ketamine session helped patients realise the negative aspects of alcohol dependence and see the positive sides of sobriety.

Krupitsky & Grinenko’s 1997 report found that 66% of patients who underwent ketamine-prolonged therapy (KPT) did not relapse during a year, compared with 24% of those who underwent treatment as usual. However, this study lacked two critical features of modern-day, gold-standard clinical trials: randomization and blinding.

In a further study, 70 detoxified heroin-dependent patients were randomized into two KPT groups, and the experimental group received 2.0 mg/kg i.m. of ketamine. The higher dose of ketamine resulted in a greater rate of abstinence, and a greater and longer-lasting reduction in craving for heroin.

Krupitsky’s lab compared the impact of a single vs three KPT sessions on heroin dependent individuals. The results indicated that three KPT sessions were more effective than one KPT session, and that repeated doses of ketamine were more effective than a pharmacological placebo.

In the US, another psychiatrist has successfully conducted KPT since 1994, treating individuals with drug addiction, food addiction, and other psychological disorders.

In 2014, 8 cocaine dependent males received 3 infusions of ketamine, separated by 48 hours. The higher dose of ketamine led to greater mystical-type effects, which were found to mediate motivation to quit cocaine.

The same research group administered ketamine to 20 non-depressed, cocaine-dependent participants to evaluate cocaine self-administration, cocaine craving, and cue-induced reactivity. Ketamine significantly reduced cocaine self-administration, craving, and reactivity, and some participants remained abstinent for the entire 2-week follow-up.

Ketamine’s potential mechanisms of action in addiction

Plasticity, neurogenesis and synaptogenesis

Neural plasticity is the reorganisation of brain circuitry by forming new synapses. Addiction is associated with diminished glutamatergic synaptic transmission and reduced plasticity.

Ketamine induces synaptogenesis by stimulating protein synthesis and the insertion of AMPA receptors, and this is the mechanism by which ketamine can reverse the glutamatergic changes associated with depression and addiction.

However, subsequent work casts doubt upon this possible mechanism, as the effects of (2R,6R)-HNK on mice in the forced-swim and learned helplessness tests are independent of differences in mTOR levels.

Neurogenesis refers to the birth of new neurons in the brain. It has been suggested that the loss of neurogenesis in addiction may contribute to self-administration and the vulnerability of relapsing.

The reduction of BDNF serum levels in addiction is supported in humans by the reduction of neurogenesis. Therefore, increasing or stabilising BDNF levels could help to treat addiction.

Ketamine increases peripheral plasma levels of the neuroplasticity marker BDNF in depressed people who respond to treatment, and this increase is robustly correlated with the drug’s antidepressant effects. However, one study in human patients with depression failed to show an increase in BDNF plasma levels 4 hours after ketamine infusion.

Disruption of functional networks

Ketamine, despite acting in a pharmacologically different way to classic serotonergic psychedelics, shares similar psychological effects with these psychedelics. This may explain how ketamine exerts its anti-addictive effects.

Two landmark studies examined psychedelic experiences using fMRI (LSD and psilocybin). They found that the brain connectivity was dispersed and that functional networks were disrupted, with the decrease of connectivity maximal in functional hubs such as the thalamus, putamen and high-level association cortices.

Ketamine has been shown to decrease connectivity between and within resting-state consciousness networks, and psilocybin has been shown to increase neuronal activity in prefrontal cortical areas, anterior cingulate cortex and insula. This increase in activity may help to normalise the corticolimbic system connectivity, which is disrupted in addiction.

Psychedelics have shown promising results in treating various addictions, and the way they modulate functional networks and produce subjective effects may well be important in ketamine’s therapeutic value for both addiction and depression.

In 2000, a clinical trial with four subjects diagnosed with depression compared ketamine to saline injection. The results showed moderate evidence for a greater reduction in scores after ketamine infusion compared to saline, lasting for 3 days after infusion.

A systematic review and meta-analysis of seven randomised, double-blind, placebo-controlled trials found that ketamine was effective in the treatment of major depressive disorder.

Ketamine has shown a 65-70% response rate in treating depression within 24 hours, and its effects last for approximately a week. Furthermore, ketamine reduces suicidal ideation for several days after the infusion.

Depression and addiction’s co-expression is almost ubiquitous. Ketamine, a drug that rapidly and reliably alleviates depression symptoms, may be effective in enhancing abstinence in those experiencing addiction, because it takes some time to reduce depressive symptoms.

Many individuals take drugs and drink alcohol to escape negative affective states, and stress is a well-established risk factor for drug addiction. Therefore, reducing negative affective states may help addicts to reduce their drug intake.

Depression predisposes and predicts future relapse to different drugs, and ketamine can help prevent relapse in the vulnerable period post-detoxification in alcohol dependence, and other drug addictions.

Reconsolidation

After initial acquisition, memories are thought to be stored in a stabilised state. However, after reactivation, these memories are rendered transiently unstable and labile, before they then restabilise.

Researchers have demonstrated that memories can be vulnerable to manipulation and disruption during reconsolidation. This makes non-pharmacological and drug therapies that aim at weakening drug-cue memories of interest.

Preclinical studies have shown that ketamine can disrupt maladaptive appetitive memories. A meta-analysis of preclinical studies found that NMDAR antagonists can be used to target reward memory reconsolidation, but memantine produces none of the psychological effects that ketamine produces.

Mystical experiences and psychedelic effects

The subjective psychedelic experience has been shown to be psychologically beneficial in long-term studies, including helping patients undergo a cathartic process, improve relationships with the world and other people, and enhance self-awareness and personal growth.

Ketamine therapy increased motivation to quit by improving spirituality, self-concept, emotional attitudes to other people and positive changes in life values and purposes. Moreover, ketamine’s mystical experiences were positively dose-dependent and may help to rapidly shift patients’ mindsets towards the integration and acceptance of a sober lifestyle.

The degree of network dissolution in LSD and psilocybin is correlated with the intensity of the psychedelic experience, and ketamine may be useful in treating addiction.

Ketamine’s psychedelic effects have been considered as adverse side-effects in the majority of the literature, but the studies presented in this review suggest that these subjective effects have an important impact in the treatment of addicts.

Enhancing psychological therapy

Ketamine may enhance the efficacy of psychological therapies, by providing a unique mental state that facilitates and enriches therapeutic experiences. This may help people who are addicted to alcohol remain abstinent, by improving their ability to embrace new therapeutic content.

Evaluating ketamine as a treatment for addiction

Ketamine treatment increased one-year abstinence rates in alcoholics from 24% in the control group to 66% in the ketamine group, and reduced cocaine self-administration by 67% relative to baseline in non-treatment seeking cocaine users. However, there is a surprising lack of preclinical research investigating whether ketamine can disrupt addictive drug use in animals.

There are few randomised controlled trials which specifically test the efficacy of ketamine on reducing relapse in treatment-seeking addicted individuals. These trials must be conducted so that experimental data and less controlled data can be confirmed in high quality clinical trials.

Ketamine’s use as a recreational drug may have hampered its seemingly counterintuitive clinical application in addiction, however, no complications were observed in any of the studies on addiction discussed above.

Ketamine is a clear advantage over competing treatments for addiction, as it does not require daily administration. However, intranasal administration seems to be the optimal method of administration, and is currently being studied.

Conclusions

Ketamine is a promising drug for treating addiction. More high quality clinical research is urgently needed to confirm that ketamine can help reduce relapse in people who have recently stopped using drugs.

Notes

This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health‘

Highlight from the authors/publisher:

• “Preliminary evidence suggests that ketamine may be effective in addiction
• Potential interacting mechanisms are enhancing neurogenesis and psychological therapies
• Ketamine may reduce depressive symptoms in a risky window for addiction relapse”