Psychedelic and Dissociative Drugs as Medicines

Ketamine has one of the more unusual biographies in modern pharmacology. It started as a battlefield anesthetic in the Vietnam War — fast-acting, with a wide safety margin, keeping soldiers conscious enough to breathe during surgery in field conditions. It became a veterinary staple. It became, in the 1980s and 1990s, a recreational drug with a specific cultural cache in rave and club scenes, where its dissociative effects — the sensation of leaving one’s body, of perceiving the self from outside — were sought rather than feared. It became, in 2019, the first genuinely new antidepressant mechanism in decades when the FDA approved Spravato (esketamine nasal spray) for treatment-resistant depression under a restricted access program called REMS, requiring clinical supervision for each dose.

Now, at the 2026 American Society of Addiction Medicine annual meeting, it is being discussed as a potential dual-target treatment for one of the most difficult clinical combinations in the field: comorbid major depressive disorder and alcohol use disorder. The data presented at ASAM showed what Phase 2 trials have been building toward — rapid antidepressant effects in people who meet criteria for both conditions, combined with measurable reductions in alcohol craving and increased abstinent days. The simultaneous treatment of two conditions that typically require separate, often competing interventions is the kind of clinical result that, if it holds in Phase 3, would be significant.

A 2026 paper in Frontiers in Psychiatry titled “Treating Addiction with an Addictive Drug: The Ketamine Paradox Revisited” names the tension that the clinical enthusiasm tends to skip past.

What ketamine actually does to the brain

Ketamine is a glutamate antagonist — specifically, it blocks NMDA receptors, the primary excitatory receptors in the central nervous system. This mechanism is why it produces anesthesia at high doses and dissociation at sub-anesthetic doses: glutamate is the gas pedal of the brain’s signaling system, and blocking NMDA receptors takes the brain out of normal excitatory patterns.

The antidepressant mechanism, which took researchers decades to understand, runs through neuroplasticity. Blocking NMDA receptors in specific circuits triggers a downstream cascade that increases levels of BDNF (brain-derived neurotrophic factor) and rapidly induces new synaptic connections in the prefrontal cortex — the region most damaged by chronic depression, the one where depressed patients show measurable loss of dendritic density. The antidepressant effect happens within hours, sometimes within a single treatment session, rather than the two to six weeks required for conventional SSRIs and SNRIs to produce clinical benefit. For patients with severe treatment-resistant depression who have failed multiple medication trials, this speed is not merely convenient — it can be the difference between surviving a crisis and not.

The alcohol use disorder connection runs through overlapping pathways. Alcohol also activates glutamate signaling (via GABA suppression and direct NMDA effects), and heavy alcohol use produces neuroadaptations in the very circuits that ketamine’s antidepressant mechanism addresses. Depression and alcohol use disorder share a neural substrate — the prefrontal circuits involved in emotional regulation, decision-making, and reward valuation — and ketamine appears to address damage in those circuits regardless of which condition produced it. This is the mechanistic basis for the ASAM 2026 dual-target hypothesis.

The paradox: ketamine’s own addiction liability

Ketamine produces psychological dependence. This is not contested. The debate is about the scope and clinical significance of that dependence, and the 2026 evidence suggests the picture is more reassuring than critics fear and more complicated than proponents acknowledge.

A systematic review published in PMC in 2025, examining 16 studies and 2,174 patients in clinical ketamine treatment settings, found low rates of documented addiction in supervised therapeutic contexts. The REMS program for Spravato — which requires that each dose be administered in a certified healthcare setting, with patients remaining under observation for at least two hours afterward — was specifically designed to prevent the diversion and escalation that characterize recreational ketamine dependence. The review found no cases of clinical addiction meeting DSM criteria in patients receiving standard Spravato protocols.

The review found no cases of clinical addiction meeting DSM criteria in patients receiving standard Spravato protocols.

The recreational picture is different. Among heavy recreational ketamine users — people using daily at high doses for months or years — documented dependence includes a withdrawal syndrome characterized by craving, fatigue, poor appetite, and anxiety. A structural MRI study from medrxiv documented widespread cortical thickness reductions in people with ketamine dependence: the brain, after chronic heavy use, shows physical changes consistent with harm. NIDA’s research division has been tracking this trajectory and the gap between therapeutic and recreational patterns.

The clinical catch is Spravato’s exclusion criteria. People with a history of moderate to severe substance use disorder — including alcohol use disorder, which is exactly the population the ASAM 2026 dual-target data is excited about — were excluded from the original Spravato clinical trials. The FDA label carries explicit language about increased risk for patients with a history of drug abuse or dependence. There is real-world Spravato prescribing data accumulating for people with comorbid psychiatric and substance use conditions, and the 2025-2026 literature suggests it is cautiously being used — but it is being used outside the original evidence base, in a population the trials were designed to exclude.

The psychology of dissociation in treatment

The therapeutic mechanism of ketamine involves, in part, its dissociative properties. The sense of ego dissolution or perspective shift that ketamine produces at sub-anesthetic doses appears to be part of how it breaks the cognitive loops of rumination and self-critical thought that characterize severe depression. Patients frequently describe ketamine infusion sessions as producing a felt separation from their ordinary patterns of thought — an experiential interruption that, when paired with integration support, may allow new ways of engaging with old psychological material.

This is where ketamine’s pharmacology and its psychological mechanism overlap with psychedelic-assisted therapy in ways that are only beginning to be systematically studied. The dissociative experience is not an incidental side effect — it appears to be part of the treatment, which means that treating ketamine purely as a neurochemical intervention misses what the 2026 clinical data is actually describing. The ASAM 2026 presentation on comorbid MDD and AUD didn’t just show lab measures and alcohol craving scores. It showed that patients reported psychological shifts: reduced negative self-view, reduced alcohol as a coping mechanism, increased motivation to engage with recovery.

For addiction medicine specifically, the psychological dimension is what makes ketamine distinctive compared to naltrexone or buprenorphine. Those medications work pharmacologically — they block or partially activate receptors that mediate the reinforcing effects of opioids or alcohol. Ketamine appears to work partly by disrupting the psychological relationship between the patient and their substance, not just the neurochemical one. That is a different kind of treatment, and the field is still learning how to measure and replicate it.

Where the research goes from here

ClinicalTrials.gov lists multiple ongoing trials examining ketamine for substance use disorders beyond depression — including an active trial for comorbid opioid use disorder and depression. The dissociative class more broadly is entering a period of therapeutic investigation that would have been unimaginable a decade ago, driven partly by the failure of existing treatments to address the full scope of addiction’s psychological and neurological dimensions.

The 2026 ASAM data is preliminary. Phase 2 trials are not Phase 3 trials. The comorbid MDD-AUD population presents some of the highest clinical complexity in behavioral health — patients with both conditions have significantly worse outcomes on either condition treated alone, carry higher suicide risk, and cycle through treatment systems at high rates. If ketamine can interrupt that cycle, the clinical value is substantial. If the addiction paradox the Frontiers paper names plays out at scale — people developing ketamine dependence while being treated for alcohol dependence — the ethical stakes are comparable.

The honest position, going into the next round of trials, is that both things are true: ketamine probably helps some people with comorbid depression and addiction disorders, meaningfully and verifiably, and it carries its own addiction risk that is real and not fully characterized in the populations who need it most. The field’s job is to figure out, with precision, which patients benefit and which patients are at risk — and to build the clinical structures that make it possible to offer the treatment where it helps without creating the harms where it doesn’t. That’s harder than enthusiasm about a promising drug and harder than fear of a controlled substance. It requires exactly the kind of careful, population-stratified research that 2026 is beginning to produce.

It requires exactly the kind of careful, population-stratified research that 2026 is beginning to produce.