A new TAU study reveals that ketamine’s pain-relieving effects and its influence on consciousness involve separate brain mechanisms, opening possibilities for future treatments with fewer psychological side effects.

A new brain imaging study in humans, led by Tel Aviv University’s Institute for Psychedelic Research in collaboration with TAU-affiliated Tel Aviv Medical Center (Ichilov), has found that ketamine can relieve pain independently of the sense of dissociation it produces. Dissociation is a feeling of detachment from oneself, one’s body, or one’s surroundings. The findings suggest that ketamine’s effects on pain and consciousness involve different brain mechanisms, potentially paving the way for treatments that retain its therapeutic benefits while reducing unwanted psychological side effects.

The study was led by Dr. Noam Goldway, under the supervision of Prof. Talma Hendler and Dr. Haggai Sharon of the Institute for Psychedelic Research at TAU’s Sagol School of Neuroscience, in collaboration with Tel Aviv Medical Center (Ichilov). The findings were published in Neuropsychopharmacology, a journal in the Nature portfolio.

Is Altering Consciousness Necessary for Pain Relief?

In recent years, mind-altering substances have moved from the fringes of popular culture to the forefront of medical research. MDMA is being studied as a potential treatment for post-traumatic stress disorder (PTSD), while psilocybin, the active substance found in magic mushrooms, is being investigated primarily for depression. Ketamine has also attracted considerable interest because of its effectiveness in treating pain and depression, and more recently, its potential for treating PTSD. But alongside this promise, a fundamental question remains: Do these drugs need to alter our state of consciousness to produce their therapeutic effects?

To investigate this question, the researchers focused on ketamine, a drug known both for its ability to relieve pain and for inducing dissociation, a temporary feeling of detachment from oneself, one’s body, or one’s surroundings. For years, physicians and researchers have assumed that these effects were connected: the more detached a person feels, the less intense or threatening their pain may seem.

The study included 37 healthy volunteers, both women and men. Each participant received a ketamine infusion and a placebo infusion in two separate sessions. During the experiment, participants underwent functional magnetic resonance imaging (fMRI) while exposed to controlled pain stimuli. They were also asked to report the intensity of their pain and the degree of dissociation they experienced.

Two Effects, Two Different Brain Mechanisms

According to Dr. Noam Goldway, although ketamine reduced pain and increased dissociation, the researchers found no connection between the intensity of these two effects. Participants who experienced stronger dissociation did not necessarily report greater pain relief, and those who experienced less dissociation could still benefit from the drug’s pain-relieving effects. In other words, the findings suggest that the feeling of detachment is not what causes ketamine to reduce pain.

The brain scans supported this conclusion. Pain relief was associated with reduced activity in regions involved in processing pain, including the insula and the anterior cingulate cortex. Dissociation, meanwhile, was linked to changes in a different brain network known as the default mode network, which plays a role in processing our sense of self. These findings suggest that ketamine’s effects on pain and consciousness are not simply two unrelated experiences, but involve distinct brain mechanisms influenced by the same drug.

Prof. Talma Hendler, Head of TAU’s Institute for Psychedelic Research, explains:

“In recent years, there has been a lively scientific and clinical debate over whether the subjective experience produced by psychoactive drugs is an integral part of their therapeutic effect. Our study shows that, at least in the case of ketamine and pain relief, the answer is apparently no. We were able to show that the drug’s effect on pain is separate from its effect on consciousness – both behaviorally and in terms of brain activity. It is important to note that this cannot be generalized to other psychedelic drugs, such as magic mushrooms. In this case, the burden of proof still rests with us, the scientists.”

Toward Pain Treatments with Fewer Side Effects

According to Dr. Haggai Sharon, Deputy Head and Medical Director of the Institute and a specialist in pain medicine, the study provides further evidence of just how complex the brain’s experience of pain is, and the many ways in which the brain can regulate and change it. This understanding could also have important clinical implications. If researchers can find a way to activate ketamine’s pain-relieving mechanism without triggering dissociation, it may become possible to develop treatments that maintain the drug’s effectiveness while reducing feelings of detachment and other subjective side effects.