Ketamine-Assisted Therapy for Substance-Use Disorders
A dissociative anaesthetic, ketamine primarily affects the central nervous system by antagonistically binding to the n-methyl-d-aspartate (NMDA) receptor. Ketamine has recently gained popularity as a fast-acting anti-depressant, but other studies have shown that it is also effective for lowering problematic alcohol and drug usage. The preclinical and clinical evidence on ketamine’s capacity to treat addiction is examined in this review. Results so far are encouraging despite methodological restrictions and the relative youth of the discipline.
In detoxified alcoholics and heroin addicts, ketamine has been proven to successfully prolong abstinence from alcohol and heroin, respectively. Additionally, in cocaine users who were not seeking treatment, ketamine decreased cravings for and self-administration of cocaine. To establish ketamine’s effectiveness, however, additional randomised controlled trials are urgently required. Possible ways that ketamine may influence 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
The symptoms of addiction include cravings, compulsive drug use, and negative subjective experiences during periods of abstinence. Addiction is a chronic, recurring condition. Addiction remains a major global issue and a significant economic burden because to its effects on productivity, health-care expenditures, and criminality despite decades of research into its origins and treatments.
- An estimated 5% of adults worldwide have an alcohol use disorder. 2.9% of Americans are dependent on an illegal substance. Drug overdose is also the main factor in accidental deaths in the US, with opioids (such as heroin and prescription opioids) being the most common. At a year after the start of treatment, relapse rates for current medicines range between 40% and 80%. Additionally, there are currently no effective pharmaceutical treatments for either amphetamine use disorder or cannabis use disorder.
To promote abstinence, treat patients who are not responding, and handle substance use disorders for whom there are no effective pharmacological treatments, innovative pharmacological approaches are urgently needed. In this review, we examine ketamine’s potential for usage as an addiction treatment as well as its potential processes.
- Methadone for heroin dependence, for example, acts as a substitute for the drug of abuse. Other pharmacological treatments for drug addiction can also be used to support abstinence (e.g., acamprosate for alcohol dependence).
While its use as an anaesthetic in hospital settings and scientific research expanded, so did its use for recreational purposes. Recreational use was uncommon in Europe until the ‘rave culture’ of the 1990s. Ketamine has been classified as a prohibited substance in many nations due to its potential for abuse as a recreational drug. The WHO advises against worldwide regulation of ketamine due to its relevance in medicine, particularly in developing countries, whereas China requests it. There is an ongoing international dispute about the best legislation to enact for this substance.
Mechanisms of Action on Addiction: Ketamine
The reorganisation of the brain’s cellular and structural makeup is referred to as neural plasticity. Since new synapses between neurons must form in order for change to occur in brain circuitry, synaptogenesis is a key mechanism for plasticity. The process of synaptogenesis involves the surface expression of AMPARs and upregulation of other synaptic proteins. Addiction is hypothesised to be related to impaired glutamatergic synaptic transmission and decreased plasticity.
- Rapid Anti-Depressant Effects
We now provide a quick overview of the research on ketamine and depression because addiction and depression are commonly comorbid and because ketamine’s use in psychiatry has altered significantly as an anti-depressant. The first clinical trial using ketamine as a therapy for depression appeared in 2000. In a randomised, double-blind design, 0.5 mg/kg of ketamine was intravenously delivered to four participants with a diagnosis of depression. In three participants with the same diagnosis, the outcomes were contrasted with the injection of saline solutions. In contrast to saline, there was some evidence that scores on the Hamilton Rating Scale for Depression (HAM-D) decreased more following ketamine infusion.
The reduction happened quickly and persisted three days following the infusion, outlasting the ketamine’s subjective effects. This finding and the antidepressant benefits seen in animal models of depression motivated researchers in the field to carry out more investigations in humans, despite the small sample size and the restricted follow-up. Since then, more than 30 studies have looked at the antidepressant benefits of ketamine in individuals with serious depressive and bipolar illnesses that are resistant to treatment.
- Seven randomised, double-blind, placebo-controlled trials evaluating the effectiveness of ketamine in the treatment of major depressive disorder were analysed in a recent systematic review and meta-analysis (MDD). Ketamine was only given intravenously in one study; it was given intramuscularly in the others.
In comparison to saline or midazolam, ketamine was linked to higher rates of clinical remission and clinical response at 24 hours, 3 days, and 7 days (used as an active placebo, in order to produce transient subjective effects). There were brief psychotomimetic effects with ketamine, but no major side effects, permanent psychosis, or emotional shifts. In comparison to individuals who received a placebo after 24 hours, patients treated with ketamine had considerably lower depression levels.
- Ketamine has demonstrated a 65-70% response rate in the treatment of depression within 24 hours, in contrast to the standard monoaminergic antidepressants’ 47% response rate after weeks or months. Furthermore, ketamine’s antidepressant effects are virtually immediate and persist for about a week, in contrast to the weeks it takes for traditional antidepressants to work, the need for daily administration, and the fact that the majority of them don’t have enduring benefits. Additionally, research has repeatedly demonstrated that there is a considerable decrease in suicide ideation following a ketamine infusion, which also lasts for several days.
Nearly everyone experiences depression and addiction together. Alcohol, opiate, cannabis, and cocaine use problems are associated with significantly greater incidence of depression than the general population. High levels of anxiety and sadness may also make someone more likely to relapse on heroin, alcohol, cannabis, or cocaine.
- Therefore, a substance (such as ketamine) that may quickly and consistently relieve the symptoms of depression in people who are addicted should be useful in promoting abstinence. It’s significant to note that traditional antidepressants do not decrease drinking, and depressive symptoms continue to be a major cause of relapses. It’s possible that traditional antidepressants don’t work as well in preventing recurrence because depression symptoms don’t go away right away.
The rapid onset of antidepressant activity and high response rate of ketamine as a pharmaceutical treatment for depression are its new merits. Given the crucial role depression plays in addiction, ketamine’s potential utility as a treatment for addiction is backed up by strong evidence that it has immediate antidepressant effects.
Efficacy of Ketamine-Assisted Therapy
Research demonstrating significant treatment effect sizes, particularly in comparison to other treatments, supports the potential of ketamine in the treatment of addiction.
- Ketamine treatment improved one-year abstinence rates in alcoholics from 24% in the control group to 66% in the ketamine group in recently detoxified alcoholics, and also decreased cocaine self-administration by 67% in cocaine users who were not seeking treatment.
These findings unmistakably show significant effects of ketamine administration (both with and without therapy) on drug and alcohol use, effects that are 2�3 times more potent than those of currently available pharmacotherapies.
The recreational use of ketamine may have limited its seemingly illogical clinical usage in addiction treatment. In contrast, none of the aforementioned research on addiction found any consequences. Furthermore, evidence from long-term studies indicates that ketamine addiction and other side effects such ulcerative cystitis require daily and high doses of use. Ketamine’s cognitive effects have been found to vanish entirely in healthy participants 3 days after a single administration. Therefore, the risks of employing ketamine as an addiction treatment in carefully chosen patients are minimal.
The fact that ketamine does not require daily administration makes it a clear winner among addiction treatments. Ketamine doses are isolated and are only administered for a short duration. This would potentially lead to greater medication adherence and be less stigmatising for individuals who are addicted than the obligation to take daily medicine.
However, the majority of trials to far have injected ketamine. A straightforward and affordable route of administration would be required if ketamine was to be used in non-specialized facilities and as a prescription medication. The best way of administration appears to be intranasal.
K & Psychotherapy
While ketamine’s neurobiological and subjective psychological effects may be significant in its effects on addiction disorders, its capacity to increase the effectiveness of psychological therapies is probably going to play a bigger part. A distinct mental state that enables and enriches therapeutic experiences may be provided by ketamine during and after acute drug effects. This may increase treatment efficacy and lengthen its benefits.
Additionally, it is thought that neurogenesis and synaptogenesis are important for learning new knowledge. Due to increases in synaptogenesis and neurogenesis following ketamine infusions, learning of relapse-reducing techniques, such as those utilised in relapse-prevention based cognitive behavioural therapy, may therefore be improved (CBT). In fact, the notion that synaptogenesis and neurogenesis complement psychological therapies is emerging as a novel strategy for the treatment of mental illnesses.
The injection of ketamine, which can cause a “psychedelic” experience, has the potential to broaden patients’ perspectives and increase their openness to the ideas provided in therapy as well as their ability to absorb new therapeutic information. Experiments with and without active therapy circumstances have been developed by researchers to ascertain whether therapy augmentation is a mechanism for ketamine-induced transformation. To research this process and aid persons who are alcohol dependent but are sober in staying abstinent, one current study combines two elements (drug: ketamine/placebo and therapy: CBT/placebo therapy).
The medication ketamine shows promise in the treatment of addiction. According to research, ketamine can help heroin and alcohol addicts abstain from using, as well as curb cravings for and self-administration of cocaine. To confirm that ketamine can aid in lowering relapse in persons who have just stopped taking drugs, however, more high-quality clinical research in humans is urgently required because of the limitations of these trials.
Furthermore, different ketamine and therapy combinations should be looked into. Preclinical and experimental studies must also establish the processes underlie its possibly effective effects. Ketamine is a fascinating hallucinogenic and a substance that is recognised by the medical community; if earlier studies are confirmed, ketamine is likely to emerge as one of the most interesting therapy options for addiction.
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