A recent study published in the Journal of Psychopharmacology has offered encouraging preliminary findings for individuals with severe obsessive-compulsive disorder who have not responded to standard treatments. Researchers discovered that a single injection of ketamine, an anesthetic medication, led to a rapid reduction in obsessive thoughts and compulsive behaviors. This improvement was significantly greater compared to an active control medication, suggesting ketamine might be a valuable option for those who find little relief from existing therapies.
Obsessive-compulsive disorder, often called OCD, is a mental health condition characterized by persistent, intrusive thoughts and repetitive actions. These unwanted thoughts, known as obsessions, can cause significant anxiety and distress. To manage this anxiety, people with OCD often engage in compulsions, which are repetitive behaviors or mental acts they feel compelled to perform.
While the exact number of people affected varies, it’s estimated that between 0.5% and 3% of the population will experience OCD at some point in their lives. This condition can severely impact daily life, often disrupting work, relationships, and overall well-being to a degree comparable to major depression or schizophrenia. Unfortunately, many individuals with OCD also struggle with other mental health conditions like depression and anxiety disorders, making treatment even more complex.
Typical treatments for OCD include antidepressant medications and various forms of psychotherapy, such as cognitive behavioral therapy. However, a significant portion of individuals with OCD do not experience sufficient relief from these conventional approaches. Medications can take weeks to become effective, and even then, many people continue to have troublesome symptoms. Psychotherapy can be helpful, but it also requires time and commitment. Approximately one in four individuals with OCD do not respond to current treatments at all. Given these limitations and the substantial suffering associated with treatment-resistant OCD, there is a pressing need to explore new and potentially faster-acting treatment options.
Ketamine, a medication that affects brain signaling, has gained attention for its rapid antidepressant effects, particularly in cases where standard antidepressants have failed. While research on ketamine for other mental health conditions is growing, its potential for treating OCD is less understood. Prior to this study, only one small, controlled trial had investigated ketamine for OCD, using intravenous infusions. That study suggested benefit, but more research was needed to confirm these findings, explore different ways of administering ketamine, and determine the most effective dose.
Researchers in New Zealand aimed to address these gaps by conducting a new trial to evaluate ketamine injections for OCD in a community setting. They wanted to compare different doses of ketamine against a psychoactive control medication to understand how well it works, how safe it is, and what the optimal dose might be for individuals with treatment-resistant OCD.
“Ketamine treatment for depression is the most exciting psychiatric treatment that has emerged in decades. As there are many similarities between ketamine and other psychiatric disorders including OCD, our focus was whether there are also benefits associated with ketamine treatment for OCD,” said study author Ben Beaglehole, an associate professor at the University of Otago.
To conduct their study, the researchers recruited individuals from the community who had been diagnosed with severe OCD that had not responded to previous treatments. Participants were required to have a score of 26 or higher on the Yale-Brown Obsessive-Compulsive Scale, a standard questionnaire used to measure the severity of OCD symptoms. They also had to be between 18 and 50 years old, in generally good health, and have tried at least two different antidepressant medications and one type of psychotherapy without sufficient improvement. Individuals with other serious medical or psychiatric conditions, such as schizophrenia or bipolar disorder, or those with current substance abuse problems, were excluded from the study to ensure the safety and focus of the research.
The study employed a randomized, double-blind, active-controlled crossover design. This means that participants were randomly assigned to receive different treatments in different sessions, and neither the participants nor the researchers administering the medication knew which treatment was being given at any particular time. The “active-controlled” aspect means that instead of comparing ketamine to a placebo (an inactive substance), it was compared to fentanyl, a strong pain medication that also has psychoactive effects. This was used as a control to account for some of the subjective experiences that might influence how participants reported their symptoms.
The treatments were given as single intramuscular injections, similar to a flu shot, in the arm muscle. Participants received three injections in total, each at least a week apart, in a randomized order. The three injections were: a lower dose of ketamine (0.5 milligrams per kilogram of body weight), a higher dose of ketamine (1.0 milligrams per kilogram of body weight), and fentanyl (50 micrograms). To help prevent nausea, a common side effect of ketamine, participants were given an anti-nausea medication an hour before each injection.
Throughout the study, researchers carefully monitored participants’ OCD symptoms, safety, and how well they tolerated each treatment. Before each injection session and at various time points afterwards (1, 2, 24, and 168 hours), participants completed the Yale-Brown Obsessive-Compulsive Scale to assess their OCD symptom severity. Researchers also measured vital signs like blood pressure and heart rate at regular intervals. To assess dissociation, a common side effect of ketamine involving feeling detached from reality, they used the Clinician-Administered Dissociative States Scale. Participants were also asked about any adverse events or side effects they experienced during and after each treatment session. Two hours after each injection, participants were assessed to ensure they were safe to leave the clinic.
The study found that both doses of ketamine led to a greater reduction in OCD symptoms compared to fentanyl. This reduction was observed as early as one to two hours after the injection and persisted for at least 24 hours. When looking at whether individuals responded to treatment – defined as a 50% or greater reduction in OCD symptoms after 24 hours – the lower dose of ketamine (0.5 milligrams per kilogram) appeared particularly promising. Sixty percent of participants showed a positive response to the lower dose of ketamine, compared to only 18% with the higher dose and 10% with fentanyl. Although both doses of ketamine were more effective than fentanyl in reducing overall OCD scores, the higher dose did not show a significantly greater reduction than the lower dose.
Regarding safety and tolerability, both doses of ketamine caused temporary increases in blood pressure and heart rate, which returned to normal within about an hour. As expected, ketamine also caused dissociative symptoms in all participants, starting shortly after the injection and peaking within 15 to 30 minutes. These dissociative effects were more pronounced with the higher dose of ketamine. Fentanyl, in contrast, caused minimal dissociative effects, mainly just some drowsiness.
Two participants dropped out of the study after receiving the higher dose of ketamine because they found the dissociative effects too distressing. This suggests that while ketamine can be effective, the higher dose may be less tolerable for some individuals with OCD, particularly due to its dissociative effects.
It is important to consider the preliminary nature of the study. The number of participants was relatively small, which means the findings need to be confirmed in larger studies. The study only examined the short-term effects of a single dose of ketamine, so it does not provide information about the long-term benefits or the effects of repeated ketamine treatments for OCD.
“This was a small study so the finding that ketamine was associated with benefits for OCD should be regarded tentatively,” Beaglehole told PsyPost. “The average person should watch this space to see if more positive studies emerge.”
Another challenge was the difficulty in keeping participants and researchers unaware of which treatment was being given. Because ketamine has noticeable psychoactive effects, particularly dissociation, it is likely that participants could tell when they received ketamine. This lack of perfect blinding could potentially influence the results, as expectations about ketamine’s effects might have played a role in the reported symptom improvements.
“One of the main concerns with ketamine studies is the challenge with blinding participants to the medication they are receiving,” Beaglehole explained. “In this case of our study, we suspect participants knew which doses were fentanyl and which were ketamine. There is no easy solution to this problem but perhaps ascending dose studies and the use of oral ketamine with fewer side effects provide a partial answer.”
“Most psychiatric disorders are long-term conditions. However, many of the new ketamine and psychedelic studies evaluate outcomes over the short-term. We are shifting our research focus to using oral ketamine delivered over repeated doses to provide a better tolerated experience and see if benefits can be sustained. We are also researching the role of psychotherapy combined with ketamine to see if this prevents the relapse that often occurs when short-term courses of ketamine finish.”
The study, “Ketamine for treatment-resistant obsessive-compulsive disorder: Double-blind active-controlled crossover study,” was authored by Ben Beaglehole, Paul Glue, Shona Neehoff, Shabah Shadli, Neil McNaughton, Bridget Kimber, Chrissie Muirhead, Aroha de Bie, Rachel Day-Brown, and Natalie J Hughes-Medlicott.
