This review (2021) investigates the potential of ketamine for alcohol use disorder (AUD). This is partly motivated by the concurrent depression and PTSD that those with AUD suffer from, for which more evidence of ketamine’s effectiveness is known.

Abstract

“Excessive alcohol consumption is involved in 1/10 of deaths of U.S. working-age adults and costs the country around $250,000,000 yearly. While Alcohol Use Disorder (AUD) pathology is complex and involves multiple neurotransmitter systems, changes in synaptic plasticity, hippocampal neurogenesis, and neural connectivity have been implicated in the behavioral characteristics of AUD. Depressed mood and stress are major determinants of relapse in AUD, and there is significant comorbidity between AUD, depression, and stress disorders, suggesting potential for overlap in their treatments. Disulfiram, naltrexone, and acamprosate are current pharmacotherapies for AUD, but these treatments have limitations, highlighting the need for novel therapeutics. Ketamine is a N-methyl-D-Aspartate receptor antagonist, historically used in anesthesia, but also affects other neurotransmitters systems, synaptic plasticity, neurogenesis, and neural connectivity. Currently under investigation for treating AUDs and other Substance Use Disorders (SUDs), ketamine has strong support for efficacy in treating clinical depression, recently receiving FDA approval. Ketamine’s effect in treating depression and stress disorders, such as PTSD, and preliminary evidence for treating SUDs further suggests a role for treating AUDs. This review explores the behavioral and neural evidence for treating AUDs with ketamine and clinical data on ketamine therapy for AUDs and SUDs.“

Authors: Stephen D. Worrell & Thomas J. Gould

Summary

Ketamine is a N-methyl-D-Aspartate receptor antagonist that affects multiple neurotransmitter systems, synaptic plasticity, hippocampal neurogenesis, and neural connectivity, and is currently under investigation for treating Alcohol Use Disorder and other Substance Use Disorders.

1.1. Impacts

Excessive alcohol consumption is implicated in one in ten deaths among working-age adults in the U.S. annually, costs the U.S. $249 billion in 2010 and $223.5 billion in 2006, and necessitates more advanced and effective therapeutics to mitigate the public health concerns related to excessive alcohol consumption and Alcohol Use Disorder.

1.2. Positive and negative reinforcement in AUD and addiction

There are theories about the development of addiction to alcohol and other drugs of abuse that help understand the heterogeneity of addiction. One theory focuses on the role of positive and negative reinforcement in the development of addiction.

The initial positive reinforcement stage of substance abuse evolves into a negative reinforcement stage, characterized by withdrawal symptoms that include negative affect and physiological symptoms. The negative reinforcement stage is critical for the maintenance and propagation of addiction.

A recent study indicated that negative reinforcement was more strongly associated with alcohol dependence than positive reinforcement, and that therapeutic intervention might be particularly beneficial if it could target negative reinforcement.

1.3. Comorbidity of depression and post traumatic stress disorder with AUD

One report found that depressed mood was the strongest determinant for relapse in men treated for AUD. Another report found that comorbidity between AUD and depression was relatively high, and that patients with substance-induced MDD could benefit from a therapeutic that has both anti-addictive and anti-depressive properties.

Similar to depression, stress and related disorders, such as post-traumatic stress disorder, may also be co-morbid with and predict relapse in alcohol use disorder. There may be overlap in underlying causative factors and effective treatment strategies for these diseases.

1.4. Dopaminergic system

The behavioral patterns seen in alcohol use disorder can be traced back to dysregulation of multiple neurobiological systems, including dopamine, norepinephrine, serotonin, opioid, GABA, and glutamate systems. Dopamine signaling in the nucleus accumbens is perhaps the most common neural circuitry associated with addiction. Alcohol can cause positive reinforcing effects in the nucleus accumbens and decrease nucleus accumbens activity in the ventral tegmental-nucleus accumbens pathway, which could lead to lasting behavioral changes associated with addiction.

1.5. Acetylcholinergic system

Alcohol addiction is complicated, and multiple neurotransmitter systems are involved in different symptoms and stages of AUD. Nicotinic acetylcholinergic receptors (nAChRs) may be involved in the rewarding and reinforcing effects of alcohol, and may partially explain the high co-morbidity of alcohol consumption and nicotine/tobacco use.

1.6. Noradrenergic system

Researchers have shown that rats experience increased norepinephrine synthesis and down-regulated alpha-2 adrenergic receptors in response to acute alcohol exposure. Moreover, a noradrenergic alpha-1 receptor antagonist prevented stress-induced reinstatement of alcohol-seeking behavior in rats.

While the alpha-1 adrenergic system may play a role in alcohol withdrawal-related stress and anxiety, prazosin did not significantly reduce alcohol use in patients with AUD.

1.7. Serotonergic system

Serotonin is another neurotransmitter implicated in alcohol use disorder that is also associated with anhedonia and depression. Low levels of serotonin metabolites are seen in type 2 alcoholics and are associated with increased impulsivity, aggression, and earlier onset of use.

The serotonergic system has been shown to interact with other neurotransmitter systems during alcohol consumption, and plays a role in AUD pathology directly and through its interaction with other neurotransmitter systems.

1.8. Opioid system

The opioid system is often associated with morphine and heroin addiction, but alcohol use disorder also involves the opioid system. The -opioid receptor and other systems represent potentially viable therapeutic targets for alcohol use disorder, but existing drugs can be repurposed for AUD treatment.

1.9. GABAergic system

Alcohol’s reinforcing and rewarding effects can be explained by its ability to modulate GABA, the predominant inhibitory neurotransmitter in the central nervous system. The depressant effects of alcohol can also be reinforcing, as decreased GABAA receptor signaling in the amygdala leads to increased fear and anxiety.

1.10. Glutamatergic system

Glutamate is the predominant excitatory neurotransmitter in the central nervous system, and it is also involved in the effects of alcohol. NMDA receptor antagonists are used to treat withdrawal seizures, and ketamine may help regulate glutamate activity during withdrawal and mitigate further alcohol use.

Alcohol effects nearly every neurotransmitter system and interacts with one another to manifest alcohol-induced effects. Glutamatergic signaling is particularly important in AUD and ketamine may help treat AUD by regulating hippocampal neurogenesis and synaptic plasticity through antagonism of glutamatergic signaling.

1.11. Hippocampal neurogenesis

Alcohol alters numerous brain regions, including the hippocampus, which is crucial for learning, depression, and PTSD. Alcohol may also inhibit hippocampal neurogenesis, which could explain the maladaptive learning that supports alcohol craving and seeking. Researchers have shown that binge alcohol administration decreases hippocampal neurogenesis and progenitor cell proliferation in adolescent rhesus monkeys, and that depression is also associated with decreased hippocampal neurogenesis. Ketamine may help treat PTSD and depression by increasing hippocampal neurogenesis.

1.12. Synaptic plasticity

Neuronal synaptic plasticity is altered in AUD, and this alteration can lead to maladaptive memories, cravings, and drug seeking behaviors. Ketamine can reverse these effects and thus treat AUD through mechanisms to be discussed later.

1.13. Current treatments for AUD

Understanding the neurobiological changes seen with addiction is key to finding effective treatment strategies. Pharmacologic treatments for AUD include disulfiram, naltrexone, and acamprosate, which cause adverse physiological symptoms upon consumption of alcohol.

Naltrexone is used in AUD treatment, but can induce mild dysphoria. However, there have been contrasting results regarding the use of naltrexone and ketamine together, with Yoon et al. (2019) finding that the combination helped reduce drinking behavior in those with comorbid depression and AUD.

Acamprosate, an allosteric modulator of NMDA receptors, is the final approved medication for treating AUD. Although studies provide evidence of the effectiveness of acamprosate, this is not universal, and treatment compliance due to adverse reactions is an issue with traditional medical interventions.

2.1. History

Ketamine is a water-soluble aryl-cyclo-alkylamine compound that was discovered in the 1950′ s and was later characterized as “PCP”. It was eventually synthesised into a new compound, Ketalar, which was approved by the FDA in 1962 for use in anesthesia and analgesia.

Ketamine gained notoriety as a multifaceted therapeutic, but also as a recreational drug, leading to a problematic marked uptick in illicit use. A double-blind, placebo-controlled clinical trial was conducted in 2000 to examine the effects of ketamine on patients with major depression.

Researchers found that ketamine hydrochloride (0.5 mg/kg) provided significant improvement in depressive symptoms compared to the control group within 72 h of administration. Furthermore, the antidepressant effects occurred shortly after infusion and lasted for up to one-week post-treatment.

2.2. Mechanisms of action

Ketamine is an NMDA receptor antagonist, but its therapeutic mechanisms of action may be more complex than those of other NMDA receptor antagonists. Moreover, ketamine is already FDA approved to treat TRD, making it highly feasible to repurpose it for AUD treatment.

Ketamine affects several signaling systems, including NMDA receptors, BDNF, calmodulin-dependent protein kinase III, and mTOR. These systems are involved in AUD, and understanding how they contribute to the potential addictive and therapeutic effects remains an important area of research.

Ketamine’s NMDA receptor antagonism effect can modulate several key neural processes that are altered in addiction, depression, and PTSD such as synaptic plasticity, neurogenesis, and neural network connectivity.

Synaptic plasticity is an important neural process that regulates production of synaptic proteins. Ketamine’s NMDA receptor antagonism decreases activation of eukaryotic elongation factor 2 (eEF2), which modulates synaptic plasticity and could account for rapid antidepressant effects and potential AUD treatment efficacy. A sensitized amygdala could contribute to stress disorders and PTSD by overactivating the neural pathways involved in fear and anxiety. Ketamine could reverse this process and reduce stress and depressed mood, which are key determinants for relapse in recovering addicts.

Alcohol consumption can decrease neurogenesis in the hippocampus, which can contribute to maladaptive learning and memories that contribute to addiction, depression, and stress. Ketamine may also increase neurogenesis by decreasing activity of the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1), which is another possible mechanism of action.

Ketamine may help treat alcohol and drug addiction by rewiring neural connectivity. This rewiring may be similar to the rewiring of neural circuits in depression and PTSD.

Resting-state functional connectivity (rsFC) is an assessment using functional MRI (fMRI) to determine basal-level connections between brain regions without any stimuli. It has been found to be implicated in addiction. Ketamine may help those suffering from alcohol abuse disorder by disrupting problematic neural connections that contribute to continued alcohol use. Ketamine may also affect characterized functional networks that are implicated in addiction, depression, and PTSD.

Functional networks in the brain are involved in reward response, emotion, cognition, and inhibition. Modulation of these networks through brain stimulation techniques can reduce addictive and depressive symptoms in patients. Ketamine has been shown to induce changes in neural networks that correlate with clinical effects, such as decreased negative clinical behaviors and decreased SN activity. This may explain how ketamine is able to help those suffering from PTSD.

2.3. Clinical trials of ketamine therapy

Ketamine has been used to treat depression and PTSD, as well as substance use disorders. It is beyond the scope of this review to summarize all therapeutic studies of ketamine. Ketamine is well-established to treat PTSD, and has been shown to reduce depressive symptoms and alcohol use in combat veterans. It has also been shown to be effective in treating generalized anxiety disorder and social anxiety disorder.

We searched ClinicalTrials.gov and PubMed databases for clinical trials related to ketamine therapy for alcohol-related disorders and substance use disorders. We identified four complete and ongoing trials.

We conducted a search of ketamine therapy for alcohol dependence and depression, cocaine-related disorders, marijuana abuse, and opioid-related disorders. Out of the 11 results, only five were complete and involved therapeutic intervention of ketamine for SUDs.

To find additional trials regarding ketamine therapy for alcohol-related disorders, we searched the PubMed database and excluded articles unrelated to ketamine therapy for alcohol-related disorders. One additional completed study was found and included.

Ketamine has been shown to increase likelihood of abstinence, extend time until relapse, and reduce heavy drinking days in those with alcohol use disorder, and reduce maladaptive reward memories in those with comorbid alcohol use disorder and depression.

Ketamine increased motivation to quit cocaine use and reduced cue-induced cocaine craving, and increased non-reactivity, indicative of coping with stress without engaging in problematic behavior, in studies comparing ketamine to benzodiazepines and mindfulness-based relapse prevention. Ketamine has similar efficacy when treating cannabis use disorder as it does for opioid withdrawal. The drug may be used broadly as an anti-addictive pharmacotherapy.

The first ongoing trial evaluating ketamine for treating AUDs is NCT04084860 led by Elias Dakwar, MD. It will involve 120 participants with AUD and no comorbid psychiatric conditions and will compare ketamine to benzodiazepine infusions. A randomized controlled trial will evaluate ketamine + psychotherapy for severe AUD and comorbid depressive symptoms. The study will compare ketamine + relapse prevention cognitive behavioral therapy to saline + relapse prevention CBT and simple alcohol education.

An open-label, randomized controlled trial led by Dale Terasaki, MD will compare ketamine to naltrexone for preventing hospital admissions in those with severe AUD and will monitor participants for 30 days.

Other ongoing trials are investigating ketamine specifically for treating AUD and comorbid depression. One trial will evaluate intranasal ketamine for the rapid treatment of suicidal ideation, and another trial will evaluate intravenous ketamine + 2 intramuscular naltrexone for the treatment of comorbid AUD and depression. This triple-blind, crossover trial of 20 participants with a major depressive episode and alcohol dependence is the final identified clinical trial for ketamine therapy for AUD and comorbid depression.

Ketamine can be safely delivered through intravenous, intranasal, subcutaneous, sublingual, intramuscular, oral and transdermal administration. The most common dosage for AUD is 0.5 mg/kg, and for TRD and PTSD, 0.5 mg/kg is most frequently given.

The FDA-approved ketamine-based TRD medication comes as an intranasal spray, which contrasts with nearly all studies of ketamine for AUD, which use intravenous administration. Further research is needed to compare the efficacy and safety of different dosages and delivery routes of ketamine used for AUD.

Initial clinical trials show promise for ketamine as treatment for AUD. The drug is already approved for depression and shows promise for treating PTSD and SUDs.

2.4. Preclinical studies and sex-specific effects

Preclinical studies have also investigated ketamine therapy for AUD and alcohol-related disorders, and have found encouraging therapeutic benefit of ketamine for mitigating alcohol consumption and withdrawal.

In one study, ketamine reduced alcohol intake in rats and mice, and in another study, ketamine reduced binge-like drinking behavior. Female mice showed a greater sensitivity to ketamine treatment, as measured by their lower relative alcohol intake.

In contrast to the Rezvani et al. (2017) and Crowley et al. (2019) studies showing sex-specific effects in females, one study found that ketamine decreased alcohol consumption in male rats that self-administered high levels of alcohol, but increased alcohol consumption in female rats that showed low levels of alcohol self-administration.

A recent review outlines many key differences between males and females in terms of alcohol use disorder development, maintenance, and treatments, including higher rates of co-morbid mood and anxiety disorders, and more likely to consume alcohol when experiencing negative emotion.

There are important biological differences between males and females that may explain sex-specific differences in alcohol consumption, its effects, and AUDs. These differences include sex hormones, pharmacodynamics and pharmacokinetics, and a different metabolism of drugs between males and females.

2.5. Biomarkers

To develop ketamine as a potential therapy for AUD, it is important to identify biomarkers related to clinical efficacy and potential risks. A family history of alcoholism may be a useful biomarker to analyze when treating AUDs with ketamine.

Researchers have found that BDNF levels are higher in those who respond to ketamine, and that genetic polymorphisms in the BDNF gene can predict the anti-depressive effects of ketamine. These findings suggest BDNF and related genetic factors may prove useful as a biomarker for AUD treatment with ketamine.

Neuroimaging techniques such as rsFC, MEG, proton magnetic resonance spectroscopy, and EEG may be used to identify patients who could benefit from ketamine therapy for AUD.

EEG monitors electrical impulses in the brain and may be used to monitor synaptic plasticity, a process important in AUD pathology and ketamine therapy. Alterations in synaptic plasticity may help identify patients who clinically respond better to ketamine therapy.

Some allelic variants of GRIN2B, also known as NMDA receptor 2B, have been associated with chronic ketamine abuse. These allelic variants may represent useful genetic markers of ketamine abuse. A study investigated genetic polymorphisms among chronic ketamine users, and found that the G allele at SNP rs6490121 and the T allele at SNP rs41279104 of the NOS1 gene were significantly more frequent in chronic ketamine users, relative to control subjects.

2.6. Addiction liability

While ketamine has potential therapeutic value in treating AUD, it is also a substance of abuse and can produce serious psychological and physiological effects. Further studies should be conducted to identify additional genetic polymorphisms that help predict and prevent ketamine abuse and addiction.

Conclusion

AUDs are complex disorders that involve many factors such as positive reinforcement, negative reinforcement, and a shared pathophysiology with clinical depression and stress disorders, such as PTSD. Ketamine has shown efficacy in treating AUDs and may be effective in treating some forms of AUD.

Ketamine is a short-acting anesthetic that has NMDA receptor antagonist properties. It is able to ameliorate or counter several of the neural changes seen with chronic alcohol administration, but the abuse potential of ketamine should be considered.