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Ketamine's opioid-like qualities raise addiction fears for depression treatment

Anaesthetic-turned-recreational drug ketamine has become the subject of intense research in recent years, as scientists hunt for new and improved treatments for depression, writes Nick Labars for New Atlas. Now a Stanford study has highlighted some parallels between ketamine and opioids, raising red flags.

While the research into ketamine has produced many promising results, the study – published in the American Journal of Psychiatry – has sparked scientists’ concerns about the potentially addictive qualities of the drug.

Evidence uncovered by scientists in recent years has pointed to a protein receptor in the brain called N-methyl-D-aspartate (NMDA) as being pivotal to the antidepressant effects of ketamine. Recent research has shown that by blocking this receptor, the drug is suppressing the brain's anti-reward center, which plays the unsavoury role of blocking pleasure-giving neurotransmitters like dopamine and serotonin.

But one team of Stanford scientists had a sense that something else was at play beyond the mere NMDA-blocking capacity of ketamine. So they designed a study to explore a possible relationship between the antidepressant effects of ketamine and the body's opioid receptors.

The study was small but its findings are significant, largely because they are unexpected and mark the first time that an opioid receptor site has been shown as necessary to the antidepressant effects of ketamine. For so long, ketamine had been classed as a non-opioid drug, yet this new evidence points to the contrary.

[link url=""]Full article on the New Atlas site[/link]


Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism


Authors: Nolan R. Williams, Borris D Heifets, Christing Blasey, Keith Sudheimer, Jaspreet Pannu, Heather Pankow, Jessica Hawkins, Justin Birnbaum, David M Lyons, Carolyn I Rodriguezand Alan F Schatzberg.

In addition to N-methyl-D-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.


In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.


In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.


The findings suggest that ketamine’s acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

[link url=""]Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism[/link]

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