Ketamine-Assisted Therapy: What Every Provider Needs to Know Before Starting

Stephanie Karzon Abrams, Clinical Pharmacology, Founder of Beyond Consulting

There is a version of ketamine-assisted therapy that works, and a version that doesn't. The difference is rarely the molecule.

Ketamine has been a controlled substance since 1970, a Schedule III anesthetic with a long track record in emergency medicine and pediatric surgery. Its off-label use for depression began appearing in the literature in the early 2000s, and by the time esketamine (Spravato) received FDA approval in 2019 for treatment-resistant depression, the clinical conversation had already been underway for nearly two decades. The science didn’t really change, but the infrastructure around it did,

The regulatory pathway for ketamine is clear in a way that psilocybin is not yet. And yet the gap between a clinic that produces meaningful outcomes and one that is essentially administering IV infusions and calling it therapy is wide, and the field has not been particularly honest about that gap.

This is a clinical overview for providers who are considering adding ketamine-assisted therapy to their practice, or who have already started and want to do it better.

If you’re new to the space, we’ve got you. And if you’re knowleagable and ready to expand your current practice, we’ve got you too!

Pharmacology 101 - skip ahead if you’re familiar

Ketamine is a dissociative anesthetic that works primarily as an NMDA (N-methyl-D-aspartate) receptor antagonist. At subanesthetic doses — the range used therapeutically — it produces rapid antidepressant effects through a mechanism that differs fundamentally from SSRIs and SNRIs. Rather than targeting serotonin reuptake over weeks, ketamine triggers a rapid release of glutamate, which in turn activates AMPA receptors and promotes the expression of BDNF (brain-derived neurotrophic factor), a protein essential for synaptic plasticity and neuronal growth.

The clinical implication is that the antidepressant effect can emerge within hours of a single infusion, which is genuinely unlike almost anything else in the psychiatric pharmacopeia. For a patient who has been treatment-resistant for years, that window matters enormously.

What the pharmacology doesn't explain is why two patients with identical diagnoses and identical dosing protocols can have dramatically different outcomes. That is where the rest of the clinical picture comes in.

Routes of Administration

Ketamine can be delivered several ways, and each carries different clinical and practical considerations.

Intravenous (IV) infusion remains the most studied route, delivering ketamine directly into the bloodstream at controlled rates over 40 minutes. It allows for precise titration and is the modality with the most efficacy data behind it. It also requires nursing oversight, IV access, and monitoring equipment.

Intramuscular (IM) injection produces a faster onset and a more intense dissociative experience than IV for equivalent doses. Many practitioners find it produces stronger psychedelic-adjacent effects, which may enhance the therapeutic component. The trade-off is less control over the experience curve.

Sublingual lozenges have become the most accessible route in outpatient settings. Bioavailability is lower and less consistent than IV, and the experience tends to be gentler, but the lower barrier to access means more patients can engage with the treatment. Spravato (esketamine nasal spray) operates in a similar niche, with the added layer of REMS requirements.

Oral ketamine is occasionally used in maintenance protocols but has the lowest and most variable bioavailability of all routes, making dosing less predictable.

The choice of route should reflect the clinical goals, the patient's history, and the setting in which you are practicing. There is the right modality for the right patient in the right context with the right support.

Patient Selection

This is where many providers underinvest their clinical attention, and where the quality of outcomes diverges most sharply.

Ketamine is not indicated for everyone presenting with depression or anxiety. The contraindication list is meaningful: uncontrolled hypertension, active psychosis or a history of schizophrenia, active substance use disorder (particularly with dissociatives or stimulants), and certain cardiovascular conditions all warrant careful evaluation before proceeding. Pregnancy is a contraindication. So is a history of mania without mood stabilization.

Beyond the absolute contraindications, there are a range of relative considerations that require clinical judgment. Patients with a history of dissociative episodes outside of the therapeutic context may find the ketamine experience dysregulating rather than therapeutic. Patients who are highly avoidant, or who have significant trauma histories without any prior therapeutic relationship, may need more preparation than a standard intake permits.

The patients who tend to respond best are those who are genuinely treatment-resistant (having failed at least two adequate antidepressant trials), psychologically curious rather than highly defended, and willing to engage with the non-ordinary state rather than fight it. That last quality is harder to assess on paper and easier to evaluate in conversation.

The Session

Ketamine-assisted therapy, done well, is not an infusion with background music. The set and setting matter — a phrase that predates clinical psychedelic research by decades and has been verified by it.

The physical environment should feel safe, calm, and aesthetically intentional. Dim lighting, a comfortable reclining surface, a blanket, eyeshades. Not a recovery bay. Music matters more than most providers initially appreciate; a 2018 study by Kaelen et al. found that the nature of the music experience during psilocybin sessions was more predictive of outcomes one week later than general drug intensity. The same principle applies to ketamine.

A trained guide or therapist present during the session is not a luxury. Their role is not to intervene in the experience but to hold the container: to be a calm, consistent presence that allows the patient to move through whatever arises without the additional anxiety of being alone in a dissociative state. For IM and IV modalities especially, the session should not be treated as over when the acute effects resolve. How a patient is received back into ordinary consciousness — what is said, what is asked, what space is created — shapes how the experience is metabolized.

Integration

Integration is the most underbuilt component of ketamine practice in the US, and arguably the one with the GREATEST therapeutic leverage.

Ketamine creates a window of neuroplasticity, a period in which the brain is more receptive to forming new patterns and associations. What goes into that window matters. A patient who receives a ketamine infusion and goes home to the same environment, the same relationships, the same behavioral patterns, without any structured reflection or therapeutic engagement, is leaving most of the potential benefit on the table.

Integration doesn't require a licensed therapist for every session, though it benefits from one. It requires structure: a follow-up conversation, a framework for making meaning of the experience, and some scaffolding for behavioral change. Whether that happens within your practice or through a referral relationship with a therapist, it needs to happen. The licensed practitioners or perhaps, simply the therapeutic modality applied can really bring value: part work/ ifs, mindfulness, somatic therapy, etc. You have a real opportunity to personalize support.

OK, if you were jumping ahead, start to slow your roll here…

What Separates Good Practice from Mediocre Practice

The clinical literature on ketamine is largely a literature about pharmacology. What it does not capture well is the human dimension of the work, and that is precisely where most of the variance in outcomes lives.

Good ketamine-assisted therapy practices have invested in their physical space. They have thought carefully about their music. They have built a preparation protocol that goes beyond intake paperwork. Their clinical team is diverse (in every sense of the word!) and has done some version of their own inner work, enough to be comfortable sitting with a patient in a non-ordinary state without projecting anxiety into the room. They have integration infrastructure, whether internal or through referral. And they have been honest with themselves about which patients they are positioned to serve well and which they are not.

The molecule is the same everywhere. The practice is not.

What's Coming

COMP360 — Compass Pathways' synthetic psilocybin — is on a regulatory pathway toward FDA approval, with a rolling NDA submission targeted for late 2026. The FDA has directed Compass to look to the Spravato REMS as a reference point — a detail Compass disclosed in its own communications — and the clinics best positioned to add psilocybin-assisted therapy to their offerings are those that have already built the monitoring infrastructure, staff training, and clinical culture that ketamine requires.
(Developments in Psychedelic Regulation for COMP360, Psychiatric Times — https://www.psychiatrictimes.com/view/developments-in-psychedelic-regulation-for-comp360)

Ketamine practice, notable Spravato, in this sense, is not just clinically valuable in itself. For many practices, it is the foundation on which everything that comes next will be built.

If you're at the beginning of that process, our Introduction to Ketamine & Ketamine-Assisted Therapy course is a $20 self-paced primer covering pharmacology, protocols, patient selection, and the role of music in session design.
It can also be live taught to your team virtually or in person! For practices ready to go deeper, our clinic consulting services are designed for exactly this stage of the build.

Stephanie Karzon Abrams, Clinical Pharmacology | Founder, Beyond Consulting