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.
Introduction
Addiction is a chronic relapsing disorder that is characterised by cravings, habitual drug seeking and unpleasant subjective experiences during abstinence. Despite decades of research into the causes of and treatment for addiction, it continues to be a global problem and is a huge economic burden due to its impact on productivity, health-care costs, and crime. Around 5% of the world’s adult population experience alcohol use disorder. In the U.S., 2.9% of people are dependent on an illicit substance. Furthermore, the leading cause of accidental deaths in the US is drug overdose, with opioids (heroin and prescription opioids) as the most prevalent.
Relapse rates for current therapies range between 40% and 80% at one-year post-treatment initiation. Additionally, both stimulant and cannabis use disorder have no convincing pharmacological treatments to date. Existing pharmacological treatments for drug addiction can act as a substitute for the drug of abuse (e.g., methadone for heroin dependence) or can enhance abstinence via other means (e.g., acamprosate for alcohol dependence). However, novel pharmacological treatments are urgently needed to improve abstinence, treat unresponsive patients and deal with substance use disorders with no effective pharmacological treatments. In this review, we explore the potential of ketamine to be used as a treatment for addiction and its possible mechanisms.
While its application in clinical settings as an anaesthetic and its study in the scientific community increased, so did its recreational use. In Europe, recreational use was rare until the 1990s when it appeared during the “rave culture”. Its abuse liability as a recreational drug has led many countries to make ketamine a controlled substance. There is an on-going international debate regarding the optimal legislation for this drug, with China requesting that ketamine be internationally controlled and the WHO recommending against this, due to its importance in medicine, especially in developing countries.
Ketamine Potential Mechanisms of Action in Addiction
Neural plasticity is defined as the cellular and structural reorganisation of the brain. Synaptogenesis is a crucial mechanism for plasticity, since for change to happen within brain circuitry new synapses between neurons must be formed. Surface expression of AMPARs and upregulation of other synaptic proteins are involved in the process of synaptogenesis. Diminished glutamatergic synaptic transmission and reduced plasticity are thought to be associated with addiction.
Rapid Anti-Depressant Effects
Given addiction is highly comorbid with depression and ketamine’s role within psychiatry changed dramatically when it was discovered to be an anti-depressant, we now briefly describe the research concerning ketamine and depression. In 2000, the first clinical trial hinted at the potential of ketamine as a treatment for depression. Four subjects diagnosed with depression were intravenously administered 0.5?mg/kg of ketamine in a randomised, double-blind design. The results were compared to the injection of saline solutions in 3 subjects with an equivalent diagnosis. Comparison on the Hamilton Rating Scale for Depression (HAM-D) showed moderate evidence for a greater reduction in scores after ketamine infusion compared to saline. The reduction was rapid and outlasted the subjective effects of ketamine, lasting for 3 days after infusion. Despite the small sample size and the limited follow-up, this result and anti-depressant effects observed in animal models of depression encouraged researchers in the field to perform more studies in humans. Since then, over 30 studies have examined the anti-depressants effects of ketamine in patients with treatment-resistant major depressive and bipolar disorders.
A recent systematic review and meta-analysis assessed the results of seven randomised, double-blind, placebo-controlled trials that evaluated the efficacy of ketamine in the treatment of major depressive disorder (MDD). One of the trials administered ketamine intranasally, whereas the rest provided intravenous infusions of the drug. Ketamine was associated with higher rates of clinical remission and clinical response at 24?hours, 3 and 7 days compared to saline or midazolam (used as an active placebo, in order to produce transient subjective effects). Ketamine produced short-lived psychotomimetic effects, but there were no serious complications, persistent psychosis or affective switches. After 24?h, depression scores were significantly reduced for patients treated with ketamine compared to placebo treated patients.
Ketamine has shown a 65-70% response rate in treating depression within 24?hours, which contrasts with the 47% response rate of conventional monoaminergic antidepressants after weeks or months. Furthermore, ketamine’s antidepressant actions are almost immediate and last for approximately a week, whereas conventional anti-depressive medications take weeks to have an effect, are given daily and most of them fail to exert long-lasting effects. Furthermore, studies have consistently shown that after a ketamine infusion there is a significant reduction in suicidal ideation which also lasts for several days.
Depression and addiction’s co-expression are almost ubiquitous. People with alcohol, opioids, cannabis, and cocaine use disorders show notably higher rates of depression than the average of the general population. Furthermore, high levels of depression and anxiety may predispose relapse to heroin, alcohol, cannabis, and cocaine. Hence, a drug, which can rapidly and reliably alleviate depression symptoms (i.e., ketamine), in those experiencing addiction, should be effective in enhancing abstinence. Importantly, conventional anti-depressants do not reduce drinking, and depressive symptoms remain a main trigger of relapses. It may be that conventional anti-depressants fail to reduce relapse because they take some time to reduce depressive symptoms.
The novel benefits of ketamine as a pharmacological treatment for depression is its high response rate and its rapid onset of antidepressant action. Given the important role depression plays in addiction, the robust evidence that ketamine produces rapid antidepressant effects provides substantial support for its potential use to treat addiction.
Evaluating Ketamine as a Treatment for Addictions
The promise of ketamine in the treatment of addiction is supported by research with large treatment effect sizes, especially in comparison to existing treatments. In recently detoxified alcoholics, ketamine treatment increased one-year abstinence rates in alcoholics from 24% in the control to 66% in the ketamine group and reduced cocaine self-administration by 67% relative to baseline in non-treatment seeking cocaine users. These results clearly demonstrate profound effects of ketamine administration (with and without therapy) on drug and alcohol use, of an order of magnitude which is 2 or 3 times more effective than existing pharmacotherapies.
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. Furthermore, evidence from longitudinal studies suggests that ketamine must be taken daily and heavily to develop addiction and other complications such as ulcerative cystitis. In healthy volunteers, the cognitive effects of ketamine have been shown to completely dissipate 3 days after a single exposure. Therefore, the dangers of using ketamine as a treatment for addiction, in properly selected patients is low.
A clear advantage of using ketamine over competing treatments for addiction is that daily administration of the drug is not needed. Ketamine doses are isolated and given for a limited time-period only. This is likely to be less stigmatizing than the requirement to take daily medication for patients struggling with addiction and would hopefully increase medication adherence. However, most studies to date have administered ketamine via injections. If ketamine was to be applicable in non-specialised units and as prescription drug, a simple and cost-effective method of administration would be needed. Intranasal administration seems the optimal method of administration. In fact, in 2014, a small sample size (n = 20) showed significantly greater improvement of depressive symptoms after 24h of intranasal ketamine administration compared to placebo. There are currently further trials studying intranasal administration of (S)-ketamine for the treatment of depression.
Enhancing Psychotherapy
Whilst the neurobiological and subjective psychological effects of ketamine may be important in its effects in addictive disorders, ketamine’s ability to enhance the efficacy of psychological therapies is likely to play an additional role. Speculatively, ketamine can provide a unique mental state during and after acute drug effects that facilitates and enriches therapeutic experiences, which in turn may improve efficacy and lengthen treatment effects.
Furthermore, synaptogenesis and neurogenesis are putatively critical in learning new information. The uptake of psychological therapy may therefore be facilitated after ketamine infusions due increases in synaptogenesis and neurogenesis, and thus improved learning of relapse-reducing strategies, such as those used in relapse-prevention based cognitive behavioural therapy (CBT). In fact, the idea that neurogenesis and synaptogenesis work synergistically with psychological therapies is becoming recognised as a new approach in the treatment of mental disorders. Theoretically, the administration of ketamine (which can produce a psychedelic experience) may open people’s minds so they are more able to embrace what is presented during therapy as well as enhancing the uptake of new therapeutic content. To determine whether enhancement of therapy is a mechanism for ketamine-induced change, researchers have designed experiments with and without active therapy conditions. One current study includes two factors (Drug: ketamine/placebo and Therapy: CBT/placebo therapy) to explore this mechanism, with the aim of helping alcohol dependent people who are sober remain abstinent.
Conclusion
Ketamine is a promising drug for treating addiction. Research studies have shown that ketamine can promote abstinence in alcohol dependence and heroin dependence and reduce craving and self-administration of cocaine. However, these studies have limitations and more high-quality clinical research in humans is urgently needed to confirm that ketamine can help reduce relapse in people who have recently stopped using drugs. Furthermore, preclinical, and experimental research must clarify which mechanisms underpin its potentially efficacious effects, and different combinations of ketamine and therapy should be examined. Ketamine is both a fascinating psychedelic and a medically accepted drug; if previous studies are replicated, ketamine is destined to become one of the most exciting directions in the treatment of addiction.
