Since its discovery in 1962, ketamine has predominantly been known for its use in veterinary and human anesthesia. However, in recent years, its application in psychiatry has gained significant attention due to its rapid-acting antidepressant effects. While the FDA has only approved intranasal esketamine for treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior, research has extended to various psychiatric disorders in addition to depression. In this review, we delve into the therapeutic potential of ketamine across a spectrum of mental health conditions, including bipolar disorders, social anxiety disorder, and other anxiety disorders, as well as suicidal ideation, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), eating disorders, and substance use disorders, exploring ketamine’s potential implications that extend beyond treatment for depression.
For over two decades, clinical studies have extensively explored the therapeutic effects of ketamine for treating unipolar depression and major depressive disorder. These studies consistently emphasize ketamine's robust and rapid antidepressant effects. They demonstrate a significant reduction in depression severity within hours post-infusion, with effects lasting weeks, and often even longer.
While some studies focus on a single intravenous (IV) infusion, repeated administrations of IV ketamine (i.e., series of six infusions) have yielded more pronounced and prolonged antidepressant effects, even in treatment-resistant cases. The time for relapse is often greatly lengthened when ketamine is offered as a series of infusions rather than a single infusion.
Various routes of administration, including intravenous, intranasal, and oral, have demonstrated variability in efficacy, with differences in onset and duration of action. For example, effects appear to peak at 2-6 days for IV ketamine, while for oral ketamine, delays of up to 6 weeks are possible before one can expect meaningful and significant antidepressant effects, similar to conventional antidepressants such as selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs) like Prozac, Lexapro, and Cymbalta.
I am often asked by prospective clients if we offer a single infusion to “try it out.” While some may fortuitously notice benefits after a single infusion, my recommendation is to complete a series with the goal of achieving a more pronounced antidepressant effect with a longer duration of action.
There are a number of studies investigating ketamine treatment for social anxiety disorder and generalized anxiety, with results showing a significant decrease in anxiety levels following ketamine treatment. Interestingly, higher doses of ketamine (i.e., 1 mg/kg) appear to be associated with the most prolonged anxiolytic effects, with most individuals reporting a 50% or more reduction in anxiety.
Additionally, studies have shown that patients who responded to initial ketamine treatment remained in remission with maintenance treatment often lasting over three months. However, the recurrence of symptoms may occur within weeks of stopping treatment, suggesting that patients with anxiety may require maintenance treatment with repeated doses depending on their individual response.
Other studies demonstrated that, specifically for social anxiety, ketamine when given at a lower dose (0.5mg/kg), like those used to treat depression, led to a significant reduction in anxiety symptoms.
At our clinic, we have noted the added benefit of using slightly higher doses for those who suffer from anxiety, which can lead to more pronounced effects. In many instances, we have witnessed patients experiencing complete alleviation of their anxiety symptoms, sometimes even taking effect after just a few infusions.
Research on ketamine's efficacy in bipolar disorder has primarily focused on treatment-resistant cases and adjunctive therapy, such as oral antidepressants and mood stabilizers. Like depression, findings suggest a rapid onset of antidepressant effect, with onset as early as four hours, but with conflicting results regarding duration.
Comparisons between individuals with unipolar and bipolar depression suggest that ketamine's effects on depressive episodes do not differ significantly between major depressive disorder (MDD) and bipolar disorder. In other words, despite the distinct characteristics of MDD and bipolar disorder, ketamine appears to have similar effects in alleviating depressive symptoms in both conditions.
Many ketamine providers consider a patient's history of mania and/or psychosis as a contraindication to ketamine therapy due to concerns about inducing manic episodes in bipolar patients. However, studies indicate very transient and rare manic symptoms post-infusion, with symptoms typically resolving quickly within 1 or 2 hours.
At Innerbloom, we have found that patients suffering from depression associated with Type 2 bipolar disorder can safely undergo IV ketamine therapy and can expect similar response rates to those with major depressive disorder.
Emerging evidence strongly supports the effectiveness of ketamine in reducing suicidal ideation. This effect is often observed within hours after treatment and can last up to a week. In a notable meta-analysis, researchers tracked suicide attempts for up to 28 days post-treatment and found that during this period, not a single participant who received ketamine attempted suicide.
It is important to highlight that most research in this area focuses on the use of IV ketamine. However, there have been studies exploring intranasal esketamine, known under the brand name Spravato. In one such study, participants faced challenges in self-administering the required doses due to side effects. This raises concerns about the tolerability of intranasal ketamine.
Significantly, ketamine's ability to reduce suicidal thoughts appears to be distinct from its antidepressant effects, suggesting that another mechanism could be at play as to why ketamine may have such a dramatic and unique effect for suicidal patients. This offers promising prospects for individuals at high risk of suicide.
We often witness the rapid alleviation of negative intrusive thoughts, including those associated with self-harm, with ketamine treatment. Patients frequently experience immediate improvement after an infusion, sometimes even while still in the clinic, noticing significant enhancements in mood, outlook, and symptom relief.
Studies exploring the treatment of PTSD for active military personnel and veterans have also shown promising results. Recently published in the Journal of Clinical Psychiatry, one study demonstrated the effectiveness of IV ketamine treatment for veterans battling treatment-resistant depression. With over 200 veterans enrolled, the study showed that after receiving six IV ketamine infusions, significant relief of PTSD symptoms was noted: half of the veterans experienced a meaningful drop in depression scores, with one-third seeing their depression scores halved.
Other studies have shown that veterans suffering from chronic PTSD experienced relief of symptoms as soon as 24 hours after the administration of ketamine. At two weeks post-treatment, 80% were in remission from post-traumatic stress disorder symptoms, and 40% remained in remission at the end of the two-month follow-up period.
PTSD is one of the most common indications for ketamine therapy that we treat in our clinic. While some have developed symptoms due to combat or other military-related trauma, the majority seeking treatment for PTSD have experienced stress and trauma from various life-related events. These include the loss of a loved one, physical injury, childhood trauma, sexual assault, or trauma related to medical illness.
Although limited, some studies have investigated the use of ketamine in patients with chronic and treatment-resistant obsessive-compulsive disorder (OCD), showing lower OCD scores within hours after a single IV ketamine infusion. In one study, half of the ketamine recipients demonstrated a reduction in OCD symptoms.
Most research on ketamine's use for treating eating disorders focuses on anorexia nervosa, often in combination with other treatments like psychotherapy. Studies demonstrate promising results, with some showing significant and sustained improvements in normal eating behavior and acceptance of normal weight, while others report long-lasting remission.Notably, King's College in the UK was recently granted £1.45 million for a trial exploring ketamine for depression with anorexia nervosa, so stay tuned for more research on the horizon.
While research has shown the potential for a fast onset of action and good tolerability of ketamine for OCD, these principal studies only used single-session IV ketamine treatments. It's important to note that most ketamine therapy protocols utilize a series of multiple treatment sessions. Therefore, I am hopeful for improved results following these treatment strategies.
Today, ketamine therapy is being utilized to address substance use disorders involving substances such as alcohol, cocaine, cannabis, opioids, and tobacco. In one study combining ketamine with aversive therapy, 70% of participants in the ketamine group remained abstinent after one year. Another study compared patients who underwent Ketamine-Assisted Psychotherapy (KAP) versus conventional psychotherapy, revealing a one-year abstinence rate of 66% in the ketamine group compared to only 24% in the control group.
Similar to the treatment of generalized anxiety disorder, studies suggest increased efficacy with slightly higher doses. In a randomized controlled trial where participants received a single intravenous ketamine infusion at a higher dose (0.71 mg/kg) alongside specific therapy for alcohol dependence, significantly higher abstinence rates were observed, along with reduced alcohol use and heavy drinking, and extended time to relapse. At the 6-month follow-up, 75% of those in the ketamine group reported abstinence.
Moreover, ketamine may assist in alcohol detoxification, helping individuals manage withdrawal symptoms. Studies evaluating the use of ketamine for managing alcohol withdrawal syndrome have demonstrated that ketamine is safe and effective.
Ketamine shows promise in the treatment of cocaine and opioid use disorders. In individuals with cocaine use disorders, studies demonstrate that ketamine administration reduces craving, increases motivation to quit cocaine, and leads to significant reductions in cocaine use. The effects appear to be mediated by ketamine-induced mystical experiences. Similarly, in patients with heroin use disorders, ketamine-assisted psychotherapy reduces craving and increases abstinence rates, with higher doses showing greater efficacy. Ketamine may also assist in opiate withdrawal, requiring less additional medication to manage acute withdrawal symptoms.
In our clinic, we have treated several patients with alcohol use disorder, and we've observed individuals who have achieved long-term sobriety, with some attributing ketamine as the only intervention that worked for them. However, it is important to note that all patients underwent psychotherapy alongside ketamine therapy and they were not actively using at the time of treatment.
Interest in ketamine therapy for mental health has surged, evidenced by the increased number of publications and research studies. Recent FDA approvals for esketamine in treatment-resistant depression mark a significant milestone, signaling a growing demand for ketamine in mental health treatment. The ever-growing number of studies on ketamine's therapeutic potential beyond depression offers promising avenues for the treatment of various mental health conditions.
While challenges such as optimal dosing and long-term effects remain, the evidence underscores ketamine's role as a valuable addition to mental health treatment. Further research is warranted to elucidate its mechanisms of action, optimize treatment protocols, and expand its clinical applications.
Our firsthand experience utilizing specifically IV ketamine aligns with findings supported in high-quality studies, emphasizing the importance of finding a ketamine therapy provider with extensive real-world experience. Such providers can tailor treatment specific to an individual, mindful of their diagnosis, their response, and other unique factors. It is crucial to rely on a clinic that follows evidence-based best practices to maximize therapeutic potential.
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