Ketamine Treats Pain By Treating Depression, Study Suggests

By reducing chronic pain, ketamine can inadvertently treat depression, according to a new trial.

The study involved over 300 chronic pain patients who received more than one infusion of ketamine over several months. All participants reported pain relief; those with depression experienced “more robust” relief.

Ketamine has previously been shown to treat pain and depression in other studies, but this new paper is one of the first to suggest a relationship between the drug’s effects on both maladies.

The paper was published in JAMA Network Open.

Kétamine et douleur

The trial was conducted across 30 pain clinics in France. After their ketamine infusions, patients with chronic pain (fibromyalgia, neuropathic pain, etc.) were asked to complete questionnaires to rate their levels of pain and depression.

The researchers – who were from Centre Hospitalier Universitaire de Clermont-Ferrand in France – focused on the data of 329 patients who had received more than one ketamine infusion between July 2016 and September 2017. The average age of participants was 51.4 and most (75.7%) were women.

On average, over the course of their treatments, the participants’ pain rating fell from 6.7 to 5.6, their depression scores fell from 8.8 to 7.5, and their anxiety scores dropped from 10.4 to 8.7.

The drug’s analgesic effects were limited, however, to the first infusion. Repeated infusions didn’t appear to diminish pain any more than the initial dose, according to the patient questionnaire results.

Pain reduction was also more pronounced, on average, in the patients who had depression (who accounted for 64% of the cohort).

Based on this finding, the researchers posited that depression is “the main mediator of the analgesic effect of ketamine” and that the drug’s mode of action might be primarily directed at the brain’s prefrontal cortex. This latter assumption was informed by a recent research review into the specific cerebral effects of ketamine.

The study’s authors do acknowledge its limitations. There was no placebo group, for instance, and the depression scores were calculated using the Hospital Anxiety and Depression Scale (which is standard for chronic pain) not the Montgomery-Åsberg Depression Rating Scale (which is standard for depression evaluation). Nonetheless, they remain confident in their assertion that depression, not dose level or anxiety, may be the key mediator of ketamine’s analgesic effects.

“This finding provides new insight into how ketamine may reduce pain primarily by dampening depression,” the researchers write in their conclusion. “This reinforces the need for systematic holistic assessment of patients with chronic pain to diagnose severe depressive symptoms where ketamine would be a very valuable therapeutic option.”

Many of the patients in the trial also experienced unwanted side effects from their infusions, including fatigue, nausea, and headaches. But, overall, the researchers say that ketamine was still well tolerated.

Ketamine therapy

The new study isn’t the first to investigate the anti-depressive effects of ketamine.

Published in the BMJ last year, one study found that many patients hospitalized for severe suicidal ideation reached full remission when given ketamine infusions.

Another study, published in the Journal of Psychiatric Research in 2021, found that individuals with treat-resistant depression who received ketamine therapy went on to experience a greater reduction in suicidal ideation than those on antidepressants with adjunct ketamine.

How can ketamine produce such results? Recent research has identified dendritic spines in the brain as being a key site of action for ketamine’s effects. Dendritic spines are small membranous protrusions that extend off a neuron’s dendrite. In mouse experiments at Yale University, mice tended to have fewer dendritic spines in their frontal cortex when they were experiencing chronic stress. But after a single dose of ketamine, many of these spines were restored.

“[With] the ketamine, even though only a single dose was administered, you see a reversal of these dendritic spines,” Alex Kwan, an associate professor of psychiatry at Yale University, told Analytical Cannabis last year.

“So there’s a loss with stress and then a restoration with ketamine, which is very exciting because it seems like the single dose of ketamine, at least structurally, was able to reverse the atrophy that we’re seeing out of chronic stress.”

“Perhaps psychedelics, through the increase in the formation of dendritic spines, could improve the integration of new experiences,” he added.