Ketamine for the Treatment of Mental Health and Substance Use Disorders: A Comprehensive Systematic Review, 2022
Zach Walsh*, Ozden Merve Mollaahmetoglu*, Joseph Rootman, Shannon Golsof, Johanna Keeler, Beth Marsh, David J. Nutt, and Celia J. A. Morgan
Sources of data:
https://www.cambridge.org/core/journals/bjpsych-open/article/ketamine-for-the- treatment-of-mental-health-and-substance-use-disorders-comprehensive-systematic-review/36E261BFA62CDA6459B88F7777415FDA
www.awaknlifesciences.com/prof-david-nutt
Introduction
The potential of ketamine in the treatment of psychiatric disorders was first recognized in the 1970s and has been the focus of scientific research since the 1990s. Its use in experimental and off-label studies in the context of mental health has been increasing throughout North America and Europe since that time.
In recent years, interest in this substance has emerged in psychiatry following reports of its fast-acting antidepressant effects.
Over the past two decades, ketamine has been developed for the treatment of a wide range of mental health conditions in addition to depression.
It has been established that psychoactive drugs, including ketamine, work best in synergy with psychotherapy, and support for the preparation and integration of dosing is recognized as an essential component of psychedelic-assisted psychotherapy (P.A.P.).
The increasingly prominent KAP (Ketamine-Assisted Psychotherapy) model also strongly emphasizes the role of both therapeutic support and the setting and context (framework) in enhancing and prolonging the effects of ketamine.
Approaches to ketamine psychotherapy that involve active therapeutic support, such as KAP, enhance the subjective psychoactive effects of ketamine administration to maximize therapeutic benefit.
MDD (Major Depressive Disorder, unipolar)
We identified 24 systematic reviews of the antidepressant effect of ketamine in the treatment of unipolar depression and/or MDD. All systematic review or meta-analysis articles showed a rapid onset of the antidepressant effect of ketamine among patients with MDD.
Repeated administrations of ketamine—up to six doses—produce a more prolonged antidepressant effect during follow-up two weeks after the last dose, compared with a single administration, and a longer time to relapse or recurrence.
Studies on non-intravenous routes of administration suggest an antidepressant effect comparable to that of intravenous administration.
Ketamine has been shown to be effective both in trials limited to patients with treatment-resistant depression (i.e., those who did not respond to previous antidepressant trials) and in trials that included patients who had responded to previous treatments. Similarly, the effect of ketamine was observed in patients currently taking other antidepressants, as well as in those who were not taking any medication or who had completed a washout period.
BPD (bipolar disorder)
We identified 17 systematic reviews of the antidepressant effect of ketamine in the treatment of bipolar disorder, nine of which included meta-analyses.
As with unipolar depression, reviews have found that ketamine has a rapid but short-lived antidepressant effect in patients with bipolar disorder.
The main concern with ketamine treatment for bipolar disorder is the risk of inducing mania. Although manic symptoms in patients with bipolar disorder increased immediately after the ketamine infusion, these symptoms tend to resolve within one or two hours. In a meta-analysis, it was reported that treatment-emergent mania was not observed to be statistically significantly more prevalent in the active ketamine intervention group compared with the placebo group.
Suicidal Thoughts
Treatment with ketamine was associated with a moderate to large reduction in suicidal ideation. These effects appeared within the first four hours of treatment and persisted for an average of three days, and up to one week. Among participants who showed remission of suicidal ideation within 24 hours of treatment, the treatment effect persisted for up to one week in approximately 85% of participants. Ketamine may have anti-suicidal effects independent of its antidepressant effects.
Social Anxiety and Generalized Anxiety Disorder
Patients who received multiple sessions of ketamine-assisted therapy (sublingual and/or intramuscular) in a private practice showed a significant reduction in anxiety after treatment compared to baseline. Several studies have found that a higher dose of ketamine (1 mg/kg) produces the greatest and most long-lasting anxiolytic effects. Ketamine led to a significantly greater number of responders achieving at least a 35% reduction in clinical anxiety scores compared with placebo.
Obsessive-Compulsive Disorders
Patients without depression who had chronic, treatment-resistant obsessive-compulsive disorder and received a single dose of intravenous ketamine showed lower obsessive-compulsive disorder scores than those who received a placebo, from four hours to seven days after the infusion.
Post-Traumatic Stress Disorder (PTSD)
An open-label trial involving six infusions (0.5 mg/kg) over 12 days in 15 military veterans with chronic post-traumatic stress disorder and depression reported a significant reduction in symptoms of post-traumatic stress and depression 24 hours after the final infusion. At 14 days post-treatment, 80% of the sample was in remission from symptoms of post-traumatic stress disorder, and 40% remained in remission at the end of the 56-day follow-up period. In another open-label study, 30 participants received six ketamine infusions starting at 1 mg/kg; a significant reduction (44%) in post-traumatic stress symptoms was observed from baseline through the sixth infusion.
Eating Disorders
An open-label ketamine infusion trial (20 mg/h for 10 hours) among hospitalized patients diagnosed with eating disorders reported that nine out of 15 patients showed a marked and sustained return to normal eating behavior and acceptance of a normal weight.
Substance Use Disorders (Addictions)
Alcohol Use Disorder
Follow-up evaluations suggested that intensive psychotherapy programs were critical to the effectiveness of ketamine in the treatment of alcohol-use disorders. One study examined ketamine in combination with aversive therapy approaches. It was found that 70% of participants in the ketamine group remained abstinent after one year, compared with 24% of participants who received only aversive therapy. A subsequent study compared inpatients who chose KAP with those receiving conventional psychotherapy, reporting 12-month abstinence rates of 66% for the ketamine group, compared with 24% for the control group. Ketamine may also play a role in the detoxification phase of treatment: three retrospective cross-sectional studies on the safety and efficacy of ketamine for the management of alcohol withdrawal syndrome concluded that ketamine was safe.
Cocaine Use Disorder
A clinical trial involving 55 patients used ketamine (0.5 mg/kg) or midazolam (0.025 mg/kg) in combination with mindfulness-based relapse prevention therapy. At the end of the 14-day study period, 48% of participants in the ketamine group (n = 27) remained abstinent compared to 11% in the midazolam group (n = 28), demonstrating a significant effect of ketamine. Craving scores were also 58% lower in the ketamine group. At the six-month follow-up, 44% of the ketamine group reported abstinence from cocaine, compared with no abstinent patients in the midazolam group.
Opioid Use Disorder
A trial comparing a higher dose of ketamine (2 mg/kg) with a lower dose (0.2 mg/kg) in 70 detoxified heroin-dependent individuals showed that both doses reduced the urge to use heroin, but the higher dose had a greater effect. The craving to use remained low in the high-dose group at 24 months, but did not last longer than one month in the low-dose group. The abstinence rate was also higher in the high-dose group at both time points. A subsequent longitudinal study comparing single administrations of ketamine versus three sessions of KAP among 53 heroin-dependent patients reported that participants who received three sessions of KAP demonstrated a significantly higher abstinence rate of 50% compared with 22% for those who received a single session.
Adverse effects and risks of ketamine
The most common adverse effects reported in studies were mild and transient increases in blood pressure, which returned to baseline levels within 30–120 minutes. Tachycardia and bradycardia—particularly at higher doses of ketamine—and more serious cardiac effects, including intermittent atrial fibrillation and ventricular extrasystoles, were observed in two patients with preexisting conditions; both patients made a full recovery.
Most studies also reported transient, dose-dependent dissociative and psychotomimetic effects, including unusual thought content, visual hallucinations, and conceptual disorganization, which peaked during and immediately after ketamine infusion and resolved rapidly within two hours after the infusion.
Throughout the review, in two separate studies—one involving 41 patients and the other 31—participants discontinued the study due to dissociative or hallucinatory effects. Dysphoria and treatment-emergent suicidal ideation were reported in one study.
In addition, there have been some reports of transient mania and hypomania that resolved within 80 minutes after the infusion among patients with bipolar disorder who underwent ketamine infusion with or without ECT (Electroconvulsive Therapy). Transient increases in anxiety during ketamine infusions are also frequently reported, with symptoms typically subsiding within 80–120 minutes, although the review also included two cases of anxiety that persisted for up to 1–2 days after the infusion.
Non-dissociative effects associated with ketamine administration included mild sedation, agitation, nausea and vomiting, headaches, dizziness, blurred vision, dry or numb mouth, delirium, irritability, sensory changes, urinary problems, vertigo and drowsiness; these were overwhelmingly reported to have dissipated within 1-2 hours of the infusion.
