Ketamine Treatment for Alcohol Use Disorders Not Just Depression Anymore?

Alcohol use and alcohol use disorders have increased during the COVID pandemic, and deaths related to alcohol also increased. An estimated 88,0005 people (approximately 62,000 men and 26,000 women die from alcohol-related causes annually, making alcohol the third leading preventable cause of death in the United States. The first is tobacco, and the second is poor diet and physical inactivity. More than 6 percent of adults in the U.S. have an alcohol use disorder, about 1 in 12 men and 1 in 25 women. An additional 623,000 people between 12 and 17 have alcohol use disorders[i]. As a result, about 88,000 people die of alcohol-related causes yearly in the United States. In addition, 85.6 percent of people ages 18 and older reported drinking alcohol at some point in their lifetime,[ii] 69.5 percent drank in the past year, and 54.9 drank in the past month[iii]. Therefore, binge drinking is a diagnosis and target for intervention. When treatment, compared to people who did not binge drink, people who drank alcohol at twice the gender-specific binge drinking thresholds are 70 times more likely to have an alcohol-related emergency department (E.D.) visit. The more alcohol is consumed, the more problems, making the volume of drinking or dose an essential target for intervention and treatment. High-intensity drinking is defined as consuming alcohol at levels that are two or more times the gender-specific binge drinking thresholds. For example, when alcohol is consumed at three times the gender-specific dose thresholds, they are 93 times more likely to have an alcohol-related E.D. visit. Drinking too much is an important target for intervention and treatment. The number and rate of alcohol-related deaths increased approximately 25% between 2019 and 2020, the first year of the COVID-19 pandemic[iv].

Alcohol use, alcohol use disorders and alcohol-related deaths are increasing in the United States, and we know new treatments are needed. Renewed interest in psychedelic medicine, from mescaline[v] to psilocybin[vi] to ibogaine, has emerged because addictions have been challenging to treat and nearly impossible to cure. For example, while at least 14.5 million Americans live with alcohol use disorder, only about 7% receive lasting benefits from currently available treatments. Binge drinking, too much, or other pathological drinking leading to alcoholism is a complex set of behaviors mediated by neurobiological underpinnings. We have treatments for detoxification from alcohol dependence and relapse, reducing FDA-approved pharmacotherapies. Generally, these pharmaceuticals have been better than placebo but limited in long-term disease-changing efficacy. Partially this may be because these medications have specific targets that are tangential to the disease of alcoholism. They target the binge/intoxication phase (naltrexone) and preoccupation/anticipation/craving phase (naltrexone and acamprosate) or punish use  (Antabuse ) but do not change tolerance or reward thresholds or loss of control. Treatment programs offer social & positive reinforcement, sponsors, and camaraderie with 12 Step A.A. treatments. These behavioral treatments have been very effective when linked to positive reinforcement as they are in the treatment of impaired health professionals[vii]. However, even successful treatment of AUD or SUD often results in depression, negative affect, and anhedonia. These appear most disabling during protracted abstinence and appear to involve dopaminergic dysfunction. TMS, ketamine, and other treatments for depression and anhedonia may benefit these patients.

Naltrexone and injectable naltrexone (Vivitrol)[viii] are wonder drugs. Still, they are not taken regularly or for long enough periods to interrupt the natural history of the disease and cause prolonged remissions. No treatment re-sets the brain and returns it, and the brain reward threshold to be used or abuse or dependence functionality. Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are life-shortening, chronic and relapsing diseases that are generally refractory to the current treatments. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple abused substances. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist, which is effective in treating severe depression and, more recently, in treating SUDs.[ix]

Carlos Zarate, MD at the NIH, studying ketamine in depression, identified a family history of alcoholism[x] as a marker that predicted responders to ketamine for depression. More recent studies sponsored by NIDA and NIAAA at Columbia University have looked at ketamine as a treatment for alcohol and other substance use disorders[xi]. In one of these studies, a single ketamine infusion was found to improve measures of cocaine use disorders[xii] . A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing the risk of relapse. More recently, they showed the same positive outcomes in alcohol drinking in persons with alcohol dependence engaged in motivational enhancement therapy[xiii]. It is unclear how long-lasting these effects are and where ketamine would fit the treatment algorithm for alcohol use and other substance use disorders. More extensive studies and replication by other Groups will help settle these and other questions.

New research[xiv] suggests that low doses of ketamine, combined with psychological therapy, can help people with severe alcohol use disorder (AUD) stay sober longer. Researchers from the University of Exeter in the United Kingdom[xv] say their clinical trial is the first to examine whether a low dose of ketamine — a drug used as an anesthetic in humans and animals — prevents relapse when used with therapy. In addition, researchers have explored the use of the drug ketamine to treat depression and other conditions. In the study, researchers examined 96 people with previous alcohol use issues who weren’t using alcohol at the time. Researchers reported the group was more than 2.5 times more likely to remain completely abstinent at the trial’s end than participants on placebo.

Now, experts say ketamine may help people with high-intensity drinking and alcohol use disorder. In a clinical trial, researchers said participants who were given ketamine and psychological therapy stayed sober longer than other groups. Researchers reported that the participants with ketamine combined with therapy stayed entirely straight for 162 of 180 days in the ensuing six months. The 87 percent abstinence was “significantly higher than any of the other groups,” researchers said. There was not a comparison trial to other forms of treatment such as naltrexone or acamprosate. Ketamine offers the most significant promise in cocaine, cannabis, methamphetamine, and opioid use disorders[xvi].

Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. A recent double-blind placebo-controlled phase 2 clinical study [xvii]  of ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at a 6-month follow-up. In this Ninety-six patient study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up, with the most significant reduction in the ketamine plus therapy group compared with the saline plus education. This study demonstrated that three infusions of ketamine treatment were well tolerated in patients with alcohol use disorder and were associated with more days of abstinence from alcohol at a 6-month follow-up. These data support the earlier study of Dakwar and colleagues at Columbia university[xviii]  Ketamine significantly increased the likelihood of abstinence, delayed the time to relapse, and reduced the probability of heavy drinking days compared with midazolam. These original clinical studies suggest that an analysis of ketamine and its effects should be done before assuming ipso facto that the treatment will not work. Ketamine appears to have significant impacts across diagnostic categories from depression to SUD[xix]s. More research and care are necessary to mitigate the risks of ketamine abuse and diversion[xx].

Studies, for example, of PTSD have not demonstrated beneficial effects for ketamine compared with placebo in combat and other veterans [xxi] On the other hand. In contrast, treatments for cannabis use disorders have been elusive while CUDs are increasing. A small study by the Columbia University group on ketamine [xxii] showed decreased cannabis use after ketamine infusions. Similar findings were demonstrated in a 55-patient study of cocaine use disorders at Columbia University. Fifty-five cocaine-dependent individuals were randomly assigned to receive a 40-minute infusion of ketamine (0.5 mg/kg) or midazolam (the control condition) during a 5-day inpatient stay. They also initiated a 5-week course of mindfulness-based relapse prevention. Cocaine use was assessed through self-report and urine toxicology. The primary outcomes were end-of-study abstinence and time to relapse (defined as first use or dropout). 48.2% of individuals in the ketamine group-maintained abstinence over the trial, compared with 10.7% in the midazolam group. A single ketamine infusion improved a range of important treatment outcomes in cocaine-dependent adults engaged in mindfulness-based behavioral modification, including promoting abstinence, diminishing craving, and reducing the risk of relapse[xxiii]. Additional studies are necessary for AUD and other SUDs before ketamine infusions are widely adopted.

References

[i] https://www.niaaa.nih.gov/sites/default/files/AlcoholFactsAndStats.pdf

[ii]https://www.samhsa.gov/data/sites/default/files/reports/rpt29394/NSDUHDetailedTabs2019/NSDUHDetTabsSect2pe2019.htm#tab2-17b

[iii] https://www.niaaa.nih.gov/sites/default/files/AlcoholFactsAndStats.pdf

[iv] White AM, Castle IP, Powell PA, Hingson RW, Koob GF. Alcohol-Related Deaths During the COVID-19 Pandemic. JAMA. 2022;327(17):1704–1706. doi:10.1001/jama.2022.4308

[v] https://www.forbes.com/sites/louismetzgeriv/2022/04/26/mental-health-startup-journey-colab-aims-to-develop-mescaline-as-an-fda-approved-treatment-for-alcohol-use-disorder/?sh=17e5a6cf3f3a

[vi] Chi T, Gold JA. A review of emerging therapeutic potential of psychedelic drugs in the treatment of psychiatric illnesses. J Neurol Sci. 2020 Apr 15;411:116715. doi: 10.1016/j.jns.2020.116715. Epub 2020 Jan 31. PMID: 32044687.

[vii] DuPont RL, McLellan AT, White WL, Merlo LJ, Gold MS. Setting the standard for recovery: Physicians’ Health Programs. J Subst Abuse Treat. 2009 Mar;36(2):159-71. doi: 10.1016/j.jsat.2008.01.004. PMID: 19161896.

[viii] Srivastava AB, Gold MS. Naltrexone: A History and Future Directions. Cerebrum. 2018 Sep 1;2018:cer-13-18. PMID: 30746025; PMCID: PMC6353110.

[ix] Jones JL, Mateus CF, Malcolm RJ, Brady KT, Back SE. Efficacy of Ketamine in the Treatment of Substance Use Disorders: A Systematic Review. Front Psychiatry. 2018 Jul 24;9:277. doi: 10.3389/fpsyt.2018.00277. PMID: 30140240; PMCID: PMC6094990.

[x] Niciu MJ, Luckenbaugh DA, Ionescu DF, Guevara S, Machado-Vieira R, Richards EM, Brutsche NE, Nolan NM, Zarate CA Jr. Clinical predictors of ketamine response in treatment-resistant major depression. J Clin Psychiatry. 2014 May;75(5):e417-23. doi: 10.4088/JCP.13m08698. PMID: 24922494; PMCID: PMC4310499.

[xi] Dakwar E, Levin F, Hart CL, Basaraba C, Choi J, Pavlicova M, Nunes EV. A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial. Am J Psychiatry. 2020 Feb 1;177(2):125-133. doi: 10.1176/appi.ajp.2019.19070684. Epub 2019 Dec 2. PMID: 31786934.

[xii] Dakwar E, Nunes EV, Hart CL, Foltin RW, Mathew SJ, Carpenter KM, Choi CJJ, Basaraba CN, Pavlicova M, Levin FR. A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial. Am J Psychiatry. 2019 Nov 1;176(11):923-930. doi: 10.1176/appi.ajp.2019.18101123. Epub 2019 Jun 24. PMID: 31230464.

[xiii] Dakwar E, Levin F, Hart CL, Basaraba C, Choi J, Pavlicova M, Nunes EV. A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial. Am J Psychiatry. 2020 Feb 1;177(2):125-133. doi: 10.1176/appi.ajp.2019.19070684. Epub 2019 Dec 2. PMID: 31786934.

[xiv] Adjunctive Ketamine With Relapse Prevention–Based Psychological Therapy in the Treatment of Alcohol Use Disorder

Meryem Grabski, Amy McAndrew, Will Lawn, Beth Marsh, Laura Raymen, Tobias Stevens, Lorna Hardy, Fiona Warren, Michael Bloomfield, Anya Borissova, Emily Maschauer, Rupert Broomby, Robert Price, Rachel Coathup, David Gilhooly, Edward Palmer, Richard Gordon-Williams, Robert Hill, Jen Harris, O. Merve Mollaahmetoglu, H. Valerie Curran, Brigitta Brandner, Anne Lingford-Hughes, and Celia J.A. Morgan

American Journal of Psychiatry 2022 179:2, 152-162

[xv] https://www.healthline.com/health-news/ketamine-and-psychological-therapy-may-help-people-with-severe-alcohol-use-disorder

[xvi] Walsh, Z., Mollaahmetoglu, O., Rootman, J., Golsof, S., Keeler, J., Marsh, B., . . . Morgan, C. (2022). Ketamine for the treatment of mental health and substance use disorders: Comprehensive systematic review. BJPsych Open, 8(1), E19. doi:10.1192/bjo.2021.1061

[xvii] Meryem Grabski, Amy McAndrew, Will Lawn, Beth Marsh, Laura Raymen, Tobias Stevens, Lorna Hardy, Fiona Warren, Michael Bloomfield, Anya Borissova, Emily Maschauer, Rupert Broomby, Robert Price, Rachel Coathup, David Gilhooly, Edward Palmer, Richard Gordon-Williams, Robert Hill, Jen Harris, O. Merve Mollaahmetoglu, H. Valerie Curran, Brigitta Brandner, Anne Lingford-Hughes, and Celia J.A. Morgan

American Journal of Psychiatry 2022 179:2, 152-162

[xviii] Elias Dakwar, Frances Levin, Carl L. Hart, Cale Basaraba, Jean Choi, Martina Pavlicova, and Edward V. Nunes

A Single Ketamine Infusion Combined With Motivational Enhancement Therapy for Alcohol Use Disorder: A Randomized Midazolam-Controlled Pilot Trial. American Journal of Psychiatry 2020 177:2, 125-133

[xix] Sepulveda Ramos C, Thornburg M, Long K, et al. (March 30, 2022) The Therapeutic Effects of Ketamine in Mental Health Disorders: A Narrative Review. Cureus 14(3): e23647. DOI 10.7759/cureus.23647

[xx] Sassano-Higgins S, Baron D, Juarez G, Esmaili N, Gold M. A REVIEW OF KETAMINE ABUSE AND DIVERSION. Depress Anxiety. 2016 Aug;33(8):718-27. doi: 10.1002/da.22536. Epub 2016 Jun 22. PMID: 27328618.

[xxi] Abdallah CG, Roache JD, Gueorguieva R, Averill LA, Young-McCaughan S, Shiroma PR, Purohit P, Brundige A, Murff W, Ahn KH, Sherif MA, Baltutis EJ, Ranganathan M, D’Souza D, Martini B, Southwick SM, Petrakis IL, Burson RR, Guthmiller KB, López-Roca AL, Lautenschlager KA, McCallin JP 3rd, Hoch MB, Timchenko A, Souza SE, Bryant CE, Mintz J, Litz BT, Williamson DE, Keane TM, Peterson AL, Krystal JH. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology. 2022 Jul;47(8):1574-1581. doi: 10.1038/s41386-022-01266-9. Epub 2022 Jan 19. Erratum in: Neuropsychopharmacology. 2022 May 11;: PMID: 35046508; PMCID: PMC8767037.

[xxii] Azhari N, Hu H, O’Malley KY, Blocker ME, Levin FR, Dakwar E. Ketamine-facilitated behavioral treatment for cannabis use disorder: A proof of concept study. Am J Drug Alcohol Abuse. 2021 Jan 2;47(1):92-97. doi: 10.1080/00952990.2020.1808982. Epub 2020 Nov 11. PMID: 33175580.

[xxiii] Dakwar E, Nunes EV, Hart CL, Foltin RW, Mathew SJ, Carpenter KM, Choi CJJ, Basaraba CN, Pavlicova M, Levin FR. A Single Ketamine Infusion Combined With Mindfulness-Based Behavioral Modification to Treat Cocaine Dependence: A Randomized Clinical Trial. Am J Psychiatry. 2019 Nov 1;176(11):923-930. doi: 10.1176/appi.ajp.2019.18101123. Epub 2019 Jun 24. PMID: 31230464.