Migraine is a complex neurological disorder that affects more than a billion people worldwide. For many, it is not just a headache but a disabling condition marked by severe pain, nausea, sensitivity to light and sound, and cognitive impairment. While numerous preventive and acute treatments exist, a substantial proportion of patients continue to experience frequent or refractory attacks. In this context, ketamine—a drug best known as an anesthetic and, more recently, as a rapid-acting antidepressant—has attracted growing interest as a potential treatment for migraine.
So, does ketamine treat migraine? The short answer is: sometimes, for some patients, under specific circumstances. The longer answer requires understanding how ketamine works, how migraine works, what the current evidence shows, and where the risks and uncertainties lie.
Understanding Migraine: More Than a Headache
Migraine is increasingly understood as a disorder of brain excitability and sensory processing rather than a purely vascular phenomenon. Key features include:
- Abnormal sensory signaling, especially involving pain pathways in the trigeminovascular system
- Central sensitization, where the brain becomes overly responsive to pain signals
- Neurotransmitter imbalances, including glutamate, serotonin, dopamine, and CGRP (calcitonin gene-related peptide)
- Cortical spreading depression, a wave of altered neuronal activity associated with migraine aura
These processes help explain why migraine can become chronic and why standard painkillers often fail. They also provide a rationale for exploring treatments that modulate excitatory neurotransmission—such as ketamine.
What Is Ketamine?
Ketamine is a dissociative anesthetic that has been used in medical settings since the 1960s. Traditionally, it has been employed for:
- Surgical anesthesia
- Procedural sedation
- Pain management, especially in trauma or burn care
In lower doses, ketamine has potent effects on mood and pain perception. Over the last two decades, it has been studied extensively for treatment-resistant depression and chronic pain conditions.
The drug can be administered in several ways:
- Intravenous (IV)
- Intranasal
- Oral (less commonly for migraine)
- Subcutaneous (in some pain clinics)
For migraine, IV ketamine is the most studied and most commonly used route.
How Ketamine Works in the Brain
Ketamine’s primary mechanism of action is NMDA receptor antagonism, meaning it blocks the N-methyl-D-aspartate (NMDA) receptor involved in excitatory glutamate signaling. NMDA receptors are activated by glutamate, the brain’s main excitatory neurotransmitter. Excessive glutamate activity is implicated in:
- Central sensitization
- Chronic pain states
- Migraine progression from episodic to chronic
By blocking NMDA receptors, ketamine can:
- Reduce excessive excitatory signaling
- Interrupt pain amplification pathways
- Modulate neuroplasticity
Ketamine also affects other systems relevant to migraine:
- Opioid receptors (indirectly enhancing analgesia)
- Monoamines (dopamine, serotonin, norepinephrine)
- Inflammatory signaling
- Descending pain inhibitory pathways
These broad effects help explain why ketamine can relieve pain even when traditional analgesics fail.
Why Ketamine Is Being Considered for Migraine
Interest in ketamine for migraine largely comes from its use in refractory pain syndromes, including:
- Complex regional pain syndrome (CRPS)
- Neuropathic pain
- Fibromyalgia
Migraine, especially chronic or status migrainosus (a migraine attack lasting more than 72 hours), shares features with these conditions, particularly central sensitization.
Clinicians began experimenting with ketamine in severe migraine cases where:
- Standard acute treatments failed
- Preventive medications were ineffective or poorly tolerated
- Hospitalization was required for prolonged attacks
What Does the Evidence Say?
Ketamine for Acute Migraine
Evidence for ketamine as an acute migraine treatment is mixed.
Several small studies and emergency department trials have evaluated low-dose IV ketamine for acute migraine attacks, including randomized controlled trials, and found:
- Ketamine was not superior to standard treatments like metoclopramide or prochlorperazine
- Side effects such as dissociation and dizziness were common
- Pain relief, when present, was often short-lived
As a result, ketamine is not recommended as a first-line acute migraine therapy in emergency or outpatient settings.
Ketamine for Status Migrainosus
The picture changes somewhat for status migrainosus, a prolonged and debilitating migraine state.
In inpatient headache units, continuous or repeated IV ketamine infusions have been used for patients who failed:
- Triptans
- Dihydroergotamine (DHE)
- Steroids
- Anti-dopaminergic medications
Case series and observational studies published in specialty headache and pain journals suggest that ketamine can:
- Reduce pain intensity
- Shorten prolonged attacks
- Allow patients to be discharged from the hospital
However, these studies are typically small, uncontrolled, and involve highly selected patients.
Ketamine for Chronic Migraine
For chronic migraine (15 or more headache days per month), ketamine has been explored as a resetting or desensitizing therapy.
Some headache centers report that multi-day ketamine infusions can reduce the burden of headaches, based on inpatient case series and pain medicine consensus guidance. It may:
- Reduce headache frequency for weeks to months
- Improve responsiveness to other preventive treatments
- Decrease allodynia and baseline pain
That said, results are variable. Some patients experience dramatic improvement, while others see little or no benefit.
Intranasal Ketamine
Intranasal ketamine has also been studied in small trials and clinical practice.
Potential advantages include:
- Easier administration
- Lower cost
- Avoidance of IV access
Some patients report relief of severe migraine pain or aura symptoms, but robust evidence is lacking, and dosing protocols vary widely.
Who Might Benefit From Ketamine?
Based on current evidence and expert consensus, ketamine may be considered for:
- Patients with refractory chronic migraine
- Individuals with status migrainosus unresponsive to standard therapies
- Patients with prominent central sensitization or neuropathic pain features
It is generally not used for:
- Mild or infrequent migraine
- First-line acute treatment
- Routine outpatient prevention
Ketamine is typically reserved for specialty headache or pain centers with experience managing its effects.
Potential Benefits of Ketamine for Migraine
When it works, ketamine may offer several advantages:
- Rapid onset of action compared with traditional preventives
- Efficacy in treatment-resistant cases
- Reduction in central sensitization, not just pain masking
- Possible improvement in comorbid depression or anxiety
For patients who have exhausted other options, these benefits can be life-changing.
Risks and Side Effects
Ketamine is not a benign drug, and its risks must be weighed carefully.
Common Side Effects
- Dissociation or feeling “detached”
- Dizziness or vertigo
- Nausea and vomiting
- Increased blood pressure and heart rate
- Sedation or confusion
Psychological Effects
Some patients experience:
- Anxiety or panic
- Hallucinations
- Worsening mood symptoms
These effects are usually dose-dependent and reversible but can be distressing.
Long-Term Concerns
With repeated or high-dose use, ketamine has been associated with:
- Bladder toxicity (ketamine cystitis)
- Cognitive impairment
- Risk of misuse or dependency: These risks are far lower in controlled medical settings than in recreational use, but they are not negligible.
How Ketamine Is Used in Practice
In migraine treatment, ketamine is usually administered as:
- Low-dose IV infusion, often over several hours
- Sometimes repeated over multiple days
Patients are closely monitored for:
- Blood pressure and heart rate
- Mental status changes
- Adverse effects
Protocols vary widely between institutions, reflecting the lack of standardized guidelines.
How Ketamine Compares to Other Migraine Treatments
Ketamine is fundamentally different from migraine-specific drugs such as:
- Triptans
- Gepants
- Ditans
- CGRP monoclonal antibodies
Those treatments target migraine pathways more directly and have far more evidence supporting their use. Ketamine, by contrast, acts broadly on pain and neuroplasticity and is best viewed as a salvage or adjunctive therapy, not a replacement for established migraine care.
What Do Guidelines Say?
At present, major professional societies, including the American Headache Society and the European Headache Federation, state that ketamine should not be used routinely for migraine and is best reserved for refractory cases.
- Major headache society guidelines do not recommend ketamine as a routine migraine treatment.
- Its use is considered off-label.
- Most experts support its use only in highly selected, refractory cases.
Ongoing research may clarify its role, optimal dosing, and long-term outcomes.
The Bottom Line: Does Ketamine Treat Migraine?
Ketamine can treat migraine in some patients, particularly those with severe, refractory, or prolonged attacks that have not responded to standard therapies. It is most often used in specialized settings and is not a first-line or routine treatment.
While ketamine’s ability to modulate central sensitization makes it a compelling option for difficult cases, the evidence remains limited, and the risks are real. For most people with migraine, established acute and preventive treatments remain safer and more appropriate.
Ketamine’s role in migraine care is best understood as a last-resort or bridge therapy, offering hope to a subset of patients while underscoring the need for further research into safer, more targeted treatments.
As our understanding of migraine neurobiology continues to evolve, ketamine may help illuminate new pathways for treating one of the world’s most disabling neurological disorders.