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What Is Low-Dose Ketamine Therapy?
Traditionally used as an anesthetic, ketamine is now being utilized as an anti-depressant.
Up to 30% of people who have depression are resistant to traditional treatments1, highlighting a desperate need for new and innovative therapies.
Research demonstrates that ketamine acts as a highly effective, fast-acting antidepressant2 in treatment-resistant cases, with evidence showing potential for conditions like post-traumatic stress disorder (PTSD)3 and severe alcohol use disorders. Early studies also show it can provide rapid relief for obsessive-compulsive disorder (OCD); however, these effects are often transient and require longer-term trials.
Dr. Brian Boyle, Chief Psychiatrist at Stella Mental Health, who has been selected by Johnson & Johnson as a 2026 National Spravato Bureau Speaker, breaks down the facts and myths about low-dose ketamine therapy.
Low-Dose Ketamine Therapy, Explained
When used as a depression treatment, ketamine therapy is delivered in lower doses and can be administered via a number of routes. These include: intravenously (IV), intramuscularly, intranasally, or orally via tablets or lozenges.
Importantly, Dr. Boyle highlights the two different aspects of ketamine therapy for depression — ketamine as a biological treatment for depression in evidence-based dosing ranges, and ketamine therapy as an adjunct to psychotherapy (an additional or secondary, concurrent treatment).
Ketamine as a biological treatment focuses on achieving rapid antidepressant effects within hours rather than weeks. In clinical practice, this model is most commonly delivered either through off-label 40-minute intravenous (IV) infusions of racemic ketamine, or via the FDA-approved intranasal esketamine spray (Spravato), approved for treatment-resistant depression
Known as ketamine-assisted psychotherapy (KAP), ketamine therapy as an adjunct to psychotherapy has been suggested in research to potentially enhance the antidepressant effects of ketamine4, finding significant reductions in depressive symptoms. Research shows the therapy also provides significant relief from depression and anxiety5.
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Dr. Boyle explains that ketamine as a biological treatment for depression and KAP often get confused.
“Ketamine assisted psychotherapy (KAP) is where we use ketamine, often in lower doses to achieve what is sometimes called a “psycholytic”, but not even necessarily fully psychedelic effect,” says Dr. Boyle.
“It is this psycholytic effect that allows certain things to happen in psychotherapy that might not otherwise happen, or might happen much more slowly over time.
“It acts as an accelerant or augmentation of psychotherapy, wherein the therapy itself is still the mechanism of action, but the ketamine is serving a supporting role, which is a complete inversion of the other model.”
Boyle says that in the biological treatment model, slightly higher doses are administered and the focus is on what happens in the days and weeks in between.
“We are assessing the treatment the same way we might assess having titrated an SSRI,” says Dr. Boyle.
In this regard, Boyle highlights the importance of diagnostic clarity and assessing a patient’s needs when they present with depression symptoms.
“Diagnosis should guide treatment decisions,” says Dr. Boyle.
“For example, if someone is presenting with genuine, severe, debilitating, treatment, resistant, major depressive disorder, unable to perform any of the functions they need to in their lives, we shouldn’t be doing KAP, we should be doing a series of ketamine infusions to try to get them to a point where their depression is under better control.”
On the other hand, Boyle explains, KAP is more suited for patients who need to make psychodynamic progress in their therapy.
How Ketamine Therapy Works For Depression
Conventional pharmacological treatments for depression work differently than ketamine therapy.
For example, SSRIs work by affecting serotonin receptors in the brain, inhibiting reuptake of serotonin6, and thereby increasing its levels in the brain.
Ketamine works by targeting multiple brain regions. Research7 has found that part of how ketamine works is by blocking certain NMDA receptors8 causing a rapid, paradoxical surge of glutamate in the prefrontal cortex. This can change glutamate activity, a vital process in regulating mood in the brain. Research also shows that ketamine’s antidepressant efficacy relies on complex, synergistic interactions with the brain’s endogenous opioid system.
Its impact on these multiple brain processes is thought to contribute to creating plasticity in the brain, enabling the brain to create new neuronal connections, and which researchers believe helps to foster long-term mental health benefits9.
Boyle explains that one way to think about any sort of psychodynamic therapy is “pushing against resistance”.
“That really is the therapy, resistance being this unconscious, internal mechanism that gets in the way of change,” explains Boyle.
“The idea with KAP is that we’re essentially pushing against these defensive structures that drive resistance, that get us stuck in therapy and make it hard to get over the “hump”.
“This can sometimes take the form of the surfacing or elucidation of certain memories of trauma, or feelings or thoughts associated with trauma.
“This can be really important to help draw out in the context of a patient case, where maybe these are so heavily defended against that certain progress has been inhibited in psychotherapy work.”
The aim is to achieve the sustained benefit that research suggests has to do with the mechanism of neuroplasticity, says Boyle.
“That underpins the antidepressant phenomenon we are observing.”
What Are The Side Effects And Risks?
Ketamine is approved for use as an anesthetic, and when used as a treatment for depression it is used off-label.
While its approval means it has been tested for safety as an anesthetic, further research is needed10 into its long-term use as an anti-depressant.
Reported side effects of ketamine therapy11 include symptoms such as hallucinations, panic attacks, nausea or vomiting, and cardiovascular stimulation.
“Clincians are always going to think about the potential cardiovascular risk,” says Boyle.
“During these treatments people get a transient increase in blood pressure. For patients who have at baseline, untreated or uncontrolled hypertension, it should be managed before considering one of these treatments.”
A further contraindication, Boyle highlights, is any history of aneurysm or aneurysmal disease.
“If there’s any set of risks that might predispose someone through this transient increase in blood pressure, or other less well characterized cardiovascular effects, that these treatments might bring, clinicians will not treat the patient,” he says.
Boyle emphasizes that these treatments are series based in their administration, meaning they do not require a molecule to be in a patient’s body 24/7 to see effects.
“When we think about side effects, with ketamine therapy, they are confined to the session or maybe a few hours afterwards,” says Boyle.
“This is a fundamental difference to how we think about side effects and risks as compared to traditional treatments.”
Ketamine abuse is another risk factor. Long-term misuse of the substance can lead to liver or gallbladder inflammation — organs which are involved in the metabolism and excretion of ketamine.
This can cause ketamine induced cystitis — a phenomenon that causes urinary tract inflammation and eventually debilitating damage to the bladder.
Boyle says that it is vital that ketamine therapies are delivered with careful application to mitigate the risks of effects from overuse.
The Future of Ketamine Therapy
From its beginnings as an anesthetic to its now off-label use as a treatment of depression, ketamine’s applications are now expanding.
While research is still early, Boyle says that innovative uses — such as in substance use disorder (AUD) — are beginning to test our current ideas of ketamine application.
A systematic review of research suggests that ketamine as an intervention for AUD12 is safe and possibly effective for alcohol consumption and cravings, as well as alcohol withdrawal.
“This is a paradigm shift, because now we are moving toward it as a potential indication for the treatment – there is so much we are still learning about this,” says Boyle.
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Phase II clinical trials investigating ketamine for Alcohol Use Disorder (AUD) have yielded promising results. Trial participants receiving intravenous ketamine alongside cognitive behavioral therapy (CBT) demonstrated a 50% reduction in heavy drinking days and a 86% abstinence rate for six months post-treatment.
“Ketamine is but the beginning of what is a growing and exciting new trend and the direction in the development of biological therapies in psychiatry,” says Boyle.
“The next wave likely being in the realms of either MDMA or psilocybin related compounds, or both.
“I think what will ultimately happen is that we’ll come to appreciate where each of these compounds play a role most effectively — ketamine will be but one tool in an armamentarium that is ever growing in this area of psychiatry.”
While more research is needed before the safety and efficacy of ketamine as a treatment for depression is fully understood, this new area offers hope for mental healthcare that is in desperate need of innovation.
Expert Board Member
This article provides a clear, practical overview of low-dose ketamine therapy, expertly distinguishing between purely biological treatments and ketamine-assisted psychotherapy. By incorporating valuable clinical insights, it successfully bridges complex neurobiology with real-world applications. It serves as an accessible, highly informative resource for readers seeking to understand the mechanisms, safety profiles, and emerging indications of modern ketamine treatment in psychiatric care.
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