Efficacy of Ketamine in the Treatment of Substance Use Disorders : A Systematic Review
Jennifer L. Jones, Camilo F. Mateus, Robert J. Malcolm, Kathleen T. Brad and Sudie E. Back
Frontiers in Psychiatry, 2018, 1-10.
doi : 10.3389/fpsyt.2018.00277
Background : Despite advances in behavioral and pharmacotherapy interventions, substance use disorders (SUDs) are frequently refractory to treatment. Glutamatergic dysregulation has received increasing attention as one common neuropathology across multiple substances of abuse. Ketamine is a potent N-methyl-D-aspartate (NMDA) glutamatergic receptor antagonist which has been found to be effective in the treatment of severe depression. Here we review the literature on the efficacy of ketamine in the treatment of SUDs.
Methods : A systematic review of the PubMed, Scopus, and ClinicalTrials.gov databases was undertaken to identify completed and ongoing human studies of the effectiveness of ketamine in the treatment of SUDs between January 1997 and January 2018.
Results and conclusion : Seven completed studies were identified. Two studies focused on alcohol use disorder, two focused on cocaine use disorder, and three focused on opioid use disorder. Both cocaine studies found improvements in craving, motivation, and decreased cocaine use rates, although studies were limited by small sample sizes, a homogeneous population and short follow-up. Studies of alcohol and opioid use disorders found improvement in abstinence rates in the ketamine group, with significant between-group effects noted for up to two years following a single infusion, although these were not placebo-controlled trials. These results suggest that ketamine may facilitate abstinence across multiple substances of abuse and warrants broader investigation in addiction treatment. We conclude with an overview of the six ongoing studies of ketamine in the treatment of alcohol, cocaine, cannabis, and opioid use disorders and discuss future directions in this emerging area of research.
Keywords : ketamine, substance use disorders, addiction, glutamate, abstinence
Alcohol and illicit drug use is an escalating and complex global public health burden. In 2010, the global prevalence of alcohol and illicit drug use disorders were 9.6 and 10.9% respectively (1). Mortality rates have risen to epidemic proportions in some countries due to increasing prevalence of opioid use. For example, the United States, which accounts for 25%of global overdose mortality, has experienced an 88% increase in opioid overdose deaths each year from 2013 to 2016 (2, 3). Substance use disorders (SUDs) include cognitive, behavioral, and physiological symptoms.
Hallmark signs of SUDs include impaired control, cravings, social impairment, risky use, and withdrawal symptoms. Withdrawal from heavy, prolonged alcohol use can result in life-threatening seizures and autonomic instability in addition to hallucinations, severe agitation, and anxiety. Physiologic response to opioid withdrawal can also be severe, and includes nausea, emesis, diarrhea, myalgias, intractable lacrimation and rhinorrhea, fevers, dysphoria and insomnia. Fear of these withdrawal symptoms is frequently cited as a barrier to treatment and reason for relapse (4).
Despite the high prevalence and substantial societal burden of SUDs, effective pharmacotherapy options are limited. FDA-approved medications for alcohol use disorder include naltrexone (an opioid receptor antagonist) and acamprosate (a GABA-agonist) which have been shown in meta-analyses to modestly reduce rates of return to heavy drinking (5), and disulfiram and nalmefene (approved in the European Union although not FDA-approved in the U.S.) have shown overall Hedge’s g effect sizes of 0.58 and 0.33, respectively (6, 7). Treatment options for opioid dependence include full opioid agonists (methadone), partial agonists (buprenorphine) and antagonists (naltrexone). For cannabis and stimulant use disorders, there are no FDA-approved treatments (8). With limited treatment options, a myriad of non-FDA approved medications (e.g., gabapentin, clonidine, bupropion) are tried as standalone pharmacotherapies and in conjunction with behavioral interventions.
Glutamatergic dysregulation in the prefrontal cortex and mesolimbic regions (including the amygdala and the nucleus accumbens) has been implicated in addiction pathology across multiple substances of abuse (9). Similarly, depression has been shown to have aberrant glutamate signaling (10–12). Ketamine is a potent, non-competitive NMDA receptor antagonist which has been widely used in conjunction with general anesthesia following FDA approval in the U.S. in 1970. More recently, ketamine has been shown in two meta-analyses to induce ultra-rapid remission of severe depression and suicidal ideation using sub-anesthetic dosages (13–15). This anti-depressant effect is hypothesized to result from improved prefrontal cortex glutamate homeostasis (16). These changes ultimately produce synaptic improvements such as structurally increased spine density at synaptic proteins (17). These effects may improve ability to learn new behaviors (18) and may be beneficial in the treatment of SUDs. Our overall objective is to provide a review of the recent literature on the efficacy of ketamine in the treatment of SUDs.
A comprehensive search in the PubMed/MEDLINE, Scopus and clinicaltrials.gov databases from 1 January 1996 to 1 January 2018 was conducted. PubMed was searched using the following MESH search terms: “Substance-Related Disorders” and “Ketamine/therapeutic use.” The Scopus database was searched using the term “ketamine” in conjunction with the following title keywords: “cocaine,” “alcohol,” “cannabis,” “marijuana,” “amphetamine,” “methamphetamine,” “tobacco,” “nicotine,” “heroin,” and “opi.” Results from both databases were filtered to include only human studies with full text articles available in English. Case reports were excluded. “Ketamine” was the term used in the clinicaltrial.gov database search of active studies. The inclusion criteria were as follows: studies must have evaluated the efficacy of ketamine (with or without a behavioral intervention) in humans for the treatment of a SUD or the treatment of withdrawal symptoms from a substance of abuse. See Figure 1 for detailed study methodology characteristics.