Insights on Ketamine Treatment for Depression Co-Morbid with Alcohol Use Disorder

Hello All, 

I recently got inspired to write this post after discussing with one of my patients the progress they’ve made over the course of their esketamine treatments. Though it was not intended for the esketamine to help with remission from a substance use disorder, a patient mentioned to me that they were going on over 4 months of complete sobriety from alcohol use as they have been receiving the esketamine treatments. The patient felt that since starting esketamine, it was becoming easier to resist the compulsion to drink. Prior to the treatment the patient had been engaging in daily binge drinking. I was intrigued by this outcome and it made me want to delve into the literature further to see what else has been noted on this topic. 

To describe the status quo, there have not been very many major innovations in the treatment of substance use disorders in the last few years, particularly for alcohol use disorder. There are only 3 FDA approved treatments for alcohol use, specifically naltrexone, disulfiram, and acamprosate. The most recently approved was injectable naltrexone in 2006, or 20 years ago. These existing treatments, while helpful, still leave something to be desired in that many people either cannot tolerate these medicines due to side effects, do not consistently take them, or do not achieve the best outcome of abstinence and remission.

Per a systematic review and meta-analysis published in the Journal of the American Medical Association in November 2023, while there was a benefit to oral naltrexone, it showed only a 7% reduction in the risk of returning to drinking compared to placebo. When looking at a large dataset of multiple clinical trials, injectable naltrexone did not show a statistically significant reduction in return to drinking or heavy drinking, but showed an estimated reduction of 5 fewer heavy drinking days in a 30 day period of treatment. While statistically significant, the clinical impact of this intervention seems quite limited. A significant number of the clinical trials also tested the medication in combination with psychosocial treatments which are not always accessible to many individuals suffering from substance use disorder and so it is harder to determine how much of the improvement was from the psychosocial interventions versus the medication.

I find the lack of innovation in this area unfortunate due to the significant impact of Alcohol Use Disorders, which cost the United States approximately $249 billion annually in healthcare costs, lost productivity, unemployment and disability, criminal justice costs, and property damages such as car accidents, fires, and social services. More importantly, alcohol consumption raises the risk for all the major causes of death such as dementia, trauma, cancer, cardiovascular and cerebrovascular disease, gastrointestinal issues such as cirrhosis, diabetes, mood disorders, suicide, and many other chronic illnesses. Alcohol directly causes approximately 178,000 deaths annually in the United States and this number has increased significantly in the last 10 years. Among adults aged 15-49 years old, alcohol is the leading risk factor for death and disability globally.

In the past few years, data is emerging on the potential for ketamine to reduce compulsive substance use while also treating co-morbid mood disorders, which in my opinion represents a unique and possible major breakthrough in the state of SUD treatment. Below, I will summarize a few of the most well known studies that have been informing some of our treatment protocols at Piedmont Interventional Psychiatry. 

1. The KARE Trial 

The "Ketamine for Reduction of Alcoholic Relapse" (KARE) trial is a double blinded and placebo controlled study which is the gold standard of evidence based medicine. It focused on the synergy between low-dose ketamine and Relapse Prevention-Based Therapy. What they found in the treatment group was: Increased Abstinence: The most striking finding was that participants who received ketamine combined with therapy had a significantly higher rate of abstinence at 12 and 24 weeks after treatment.   Reduced Heavy Drinking: The study found a significant reduction in the number of "heavy drinking days" compared to those receiving standard care.

 Improved Mood & Wellbeing: While primarily focused on abstinence during treatment and relapse, the study noted that the treatment was well-tolerated and supported overall psychological resilience with significantly reduced depression scores in the treatment arm, making patients more receptive to the coping strategies taught in therapy.

Source: Grabski M, McAndrew A, Lawn W, et al. Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder. Am J Psychiatry. 2022;179(2):152-162. doi:10.1176/appi.ajp.2021.21030277

2. Combining Ketamine with Alcohol Use Disorder treatment shows promise in synergistically treating Depression and Reducing Drinking

An open label study at the VA in Connecticut showed that participants had improvements in depression ranging from 57-92% after just 4 treatments. Additionally, 80% of participants reported reduction in cravings and consumption of alcohol as measured by the “Obsessive Compulsive Drinking Scale”. All the participants in the study were also prescribed injectable Naltrexone (Vivitrol) for alcohol use 1 week prior to ketamine infusions and had an excellent response to both treatments. In this smaller open label study, 100% of participants responded after 4 treatments. The authors recommend further randomized clinical trial data with larger sample sizes before coming to a definitive conclusion regarding the effect of combining these treatments. 

Source: Yoon G, Petrakis IL, Krystal JH. Association of Combined Naltrexone and Ketamine With Depressive Symptoms in a Case series of Patients With Depression and Alcohol Use Disorder. JAMA Psychiatry. 2019;76(3):337–338. doi:10.1001/jamapsychiatry.2018.3990

3. Disruption of Maladaptive Reward Memories Leading to Reduced Relapse

I enjoyed reading this study because it helped me understand better one of the fundamental reasons why relapse is so common in substance use disorders. This study explored using ketamine to rewire the brain's associations between alcohol and activating the brain’s reward pathway.  What they found in the treatment group was;

 * Reduced Cravings: By administering ketamine after "reactivating" an alcohol-related memory, the researchers were able to disrupt the reward memory. This led to a significant and rapid decrease in the urge to drink.

 * Decreased Consumption: Following a single dose of ketamine, patients significantly reduced their weekly alcohol consumption and the number of drinking days over a 9-month period.

 * Positive Biological Change: This study showed that ketamine doesn't act as a substitute to drinking the way some detoxification and anxiety medications do; instead it can potentially weaken the biological "hooks" that trigger a craving when a person sees alcohol. The study describes how ketamine facilitates “memory reconsolidation” which helps the patient to diminish the maladaptive memories and lead to more objective thinking about their drinking.

Source: Das RK, Gale G, Walsh K, et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nat Commun. 2019;10(1):5187. Published 2019 Nov 26. doi:10.1038/s41467-019-13162-w

4. Ketamine with Psychotherapy Leading to Improved Meaning

Dr. Evgeny Krupitsky’s pioneering work in Russia focused on "Ketamine Psychotherapy" (KPT), in which the medication is used to facilitate a deep psychological breakthrough.

In Krupitsky’s broader clinical research (including his opioid use study and related substance use studies), ketamine was found to produce a 65-70% abstinence rate at one year, compared to only 24% in the control group receiving conventional treatment.

Also, KPT was shown to significantly reduce anxiety and depression. Patients reported a greater "meaning of life" and improved emotional stability, which acted as a protective barrier against the emotional triggers of relapse.

Source: Krupitsky EM, Grinenko AY. Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. J Psychoactive Drugs. 1997;29(2):165-183. doi:10.1080/02791072.1997.10400185

5. Ketamine Infusion + Motivational Enhancement therapy Improved Abstinence and Heavy Drinking

Dr. Dakwar and his colleagues published this randomized controlled trial  with an active control (midazolam) which suggested that a ketamine infusion increased the likelihood of abstinence, delayed the time to relapse, and reduced the likelihood of heavy drinking days.  Approximately 82% of the participants receiving ketamine did not have any heavy drinking days during the study versus 59% in the group receiving motivational enhancement therapy and the midazolam infusion. There were no dropouts in the study in the group that received ketamine, whereas 6 patients in the control group dropped out of treatment. One of the limitations of the study was that the initial time period following the patients was 21 days. However, they reached out to patients 6 months after treatment to inquire whether they remained abstinent. Only 47.5% of the patients answered the post-study survey, but of those 75% of those treated with ketamine remained abstinent compared to 27% in the placebo group.

Source: Dakwar E, Levin F, Hart CL, et al. A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial. Am J Psychiatry. 2020;177(2):125-133. doi:10.1176/appi.ajp.2019.19070684

Summary:

Findings across these studies suggest that ketamine in conjunction with psychotherapy and other interventions has significant potential in the treatment of substance use disorders. The evidence base for treating depression is already well established. Ketamine works via its multiple positive effects on brain function including boosting neuroplasticity to facilitate reductions in depression and anxiety which when inadequately treated can contribute to self-medicating behaviors with substances. Ketamine also works by causing positive adaptations in the reward center of the brain, reversing the harm caused by addictive substances. The treatment in that way has the potential to address one of the root causes of relapse. These same adaptations also help with anhedonia or the inability to feel pleasure and enjoyment in depression. Ketamine also facilitates psychotherapy by allowing a reworking of the memories surrounding the individual’s substance use so that they can think more clearly about the issue, experience reduced cravings, and not have the uncontrolled association of a reward from alcohol related cues.

Note: We always counsel our patients to cease any substance use prior to ketamine or esketamine treatment as most illicit drugs and regular alcohol consumption can interfere with the efficacy of the treatments for depression and increase the risk of negative or unintended side effects and complications. As ketamine does have some risk for abuse and dependence when not used as prescribed by your physician, and safe monitoring is essential during treatment, we currently only provide in clinic ketamine treatments. We do not offer acute detoxification as this is typically done at the hospital level but our providers can refer you to the appropriate facility for that.

Finally- We offer a Discount on Your Potential Treatment Plan

We currently have a special offer to those who want to purchase a package of ketamine treatments. Our hope is to make this treatment accessible and cost-effective, but foremost to offer the treatment safely, with the appropriate medical screenings and monitoring, and for the right indications. I believe that ketamine treatment comes out to be far more cost effective than other treatment options such as specialized psychotherapy, residential rehabilitation and intensive outpatient programs, repeated hospitalizations and emergency room visits, and many other such treatments. Unfortunately the current standard of care is not effective for many people and so other options really should be considered to enhance patient outcomes for this disorder.

Reach out to us now if you want further details and are interested in starting a treatment plan that could help result in remission from depression, post-traumatic stress, and alcohol use simultaneously!