Cannabis for Migraines: Does It Really Work – or Is It Just Hype?

TL;DR

Cannabis may help reduce migraine pain because it interacts with the body’s endocannabinoid system – a regulatory network that controls pain signaling, inflammation, and excitatory neurotransmitters like glutamate. THC directly activates cannabinoid receptors in the brain to dampen pain transmission, while CBD modulates inflammation and increases natural endocannabinoid tone. Emerging research suggests that combined THC + CBD formulations may be more effective than CBD alone for acute migraine relief. Cannabis is not a cure and is not appropriate for everyone, but its mechanism aligns closely with the neurobiology of migraine.

Migraines, I say, are the ultimate chronic pain condition. The pain is so clearly concentrated to your head, but that is rarely where the problem is at. Like all chronic pain conditions, the pain is just a symptom. The problem can be anywhere and it can be physical, biochemical, emotional, or normally a combination of all three. The problems are so severe, and have been untreated for so long, that your body chose your head as the sweepstakes winner because severe head pain is impossible to ignore. And if that wasn't bad enough, your body sprinkled in nausea, vomiting, extreme sensitivity, and maybe even some numbness and tingling throughout the rest of your body to get your attention.

In the conventional medical world, treatment options have been limited to symptom suppression and often stop working after a period of time. If they do work, they tend to carry an intense prodrome: the "hangover period" of exhaustion, confusion, and lingering pains after your migraine.

Sufferers desire treatments that work with their body to stop migraines from worsening and to prevent future occurrences.

A newly published study in Headache: The Journal of Head and Face Pain evaluated a THC + CBD combination for acute migraine treatment. The findings add to a growing body of literature suggesting that cannabinoid-based therapies may meaningfully reduce migraine pain and associated symptoms in certain patients.

We break down the findings, but also mechanisms by which cannabis might work for your migraine, because its mechanism is not random, and it is not simply “pain masking.”

What Is the Endocannabinoid System — and Why Does It Matter in Migraine?

The endocannabinoid system (ECS) is one of the body’s primary regulatory networks, similar to your hormonal system. It is not a “drug system.” It is not something cannabis created. It is an internal signaling system that has existed in human physiology long before cannabis was ever used medicinally.

At its core, the endocannabinoid system is responsible for maintaining neurological and immune balance. It modulates:

• Pain perception

• Neurotransmitter release

• Inflammation

• Stress response

• Blood pressure

• Mood and anxiety regulation

• Sleep

• Appetite

In migraine specifically, those systems are not operating normally. Migraine involves dysregulation of excitatory neurotransmitters like glutamate, abnormal trigeminal nerve activation, altered serotonin signaling, and neurogenic inflammation. The ECS sits directly at the intersection of these processes.

The system works through two primary receptors:

CB1 receptors are located primarily in the brain and central nervous system. These receptors regulate neurotransmitter release. When activated appropriately, they reduce excessive excitatory signaling and dampen pain transmission.

CB2 receptors are found primarily on immune cells and peripheral tissues. These receptors regulate inflammatory signaling and cytokine production.

Migraines are not an issue isolated to one body part or system. It is the culmination of many different body systems not going in the right direction. The ECS is built to regulate exactly that.

Some researchers have even proposed the theory of clinical endocannabinoid deficiency – the idea that certain chronic pain conditions, including migraine, may involve inadequate endocannabinoid tone. While still being studied, the hypothesis is biologically plausible given how centrally the ECS regulates pain and inflammation.

How Is the Endocannabinoid System Stimulated — and What Does It Actually Do?

Your body produces its own cannabinoids. The two most well-studied are:

• Anandamide (AEA)

• 2-arachidonoylglycerol (2-AG)

These molecules are produced “on demand” in response to stressors, inflammation, or neuronal activity. Unlike many neurotransmitters, they are not stored in vesicles. They are synthesized when needed and quickly broken down after they are used.

Their role is regulatory.

When excitatory signaling becomes excessive, such as during the early stages of a migraine, endocannabinoids are released to calm the system. They bind to CB1 receptors and reduce neurotransmitter release, particularly glutamate. This helps prevent runaway neural excitation.

At CB2 receptors, endocannabinoids reduce inflammatory signaling and immune activation, helping to control neurogenic inflammation in peripheral nerves and vascular tissue.

In simple terms:

The endocannabinoid system is the body’s braking system for pain and inflammation.

It does not eliminate signaling entirely. It fine-tunes it so that it acts more appropriately.

External cannabinoids, such as THC and CBD , interact with this same system, but in different ways.

THC directly activates CB1 and CB2 receptors, enhancing pain modulation but also producing psychoactive effects due to CB1 stimulation in the brain.

CBD works more indirectly. It inhibits the enzyme FAAH, which breaks down anandamide (from above). When FAAH is inhibited, your own natural endocannabinoid levels increase. CBD also modulates serotonin receptors, TRPV1 pain receptors, and inflammatory pathways independent of CB1 and CB2. The type of things pharmaceuticals tend to act on.

In migraine, where excessive excitatory signaling and inflammation are central features, supporting the ECS can theoretically restore balance to an overactive system.

That is the physiological logic behind cannabinoid therapy for migraine.

What the New Study Evaluated

The recent study in Headache evaluated an acute treatment protocol using a combined THC + CBD preparation for migraine attacks. Patients reported significant reductions in pain intensity and associated migraine symptoms compared to baseline.

Importantly, the therapeutic effect appeared most robust in formulations that included both THC and CBD, not CBD alone.

This distinction matters.

Because THC and CBD do not work the same way.

THC vs CBD: They Are Not Interchangeable

There is a common misconception that “CBD is cannabis without the high,” and that it provides all the same therapeutic benefit without psychoactivity.

That is not pharmacologically accurate.

Let’s break down the differences.

THC: A Direct Activator

THC is a partial agonist at both CB1 and CB2 receptors.

That means:

• It binds directly to the receptor

• It activates it

• But not to its full biological potential

At CB1 (Brain & CNS)

When THC activates CB1 receptors:

• Glutamate (an excitatory neurotransmitter) release decreases

• Pain transmission dampens

• Sensory hypersensitivity lowers

This directly targets the hyperexcitability seen in migraine.

However, CB1 activation also produces psychoactive effects (euphoria, altered perception, anxiety in some individuals). These are inseparable from its mechanism.

At CB2 (Immune System)

THC also activates CB2 receptors:

• Reducing inflammatory signaling

• Modulating cytokine (pain producer) release

• Potentially dampening neurogenic inflammation

This is relevant in migraine, where inflammatory mediators amplify trigeminal (a cranial nerve) nerve signaling.

Bottom line:THC directly stimulates the endocannabinoid system, which is why it produces noticeable analgesic and psychoactive effects.

CBD: An Indirect Modulator

CBD behaves very differently.

CBD does not strongly activate CB1 or CB2 directly.

Instead, it regulates the system in subtler ways.

1. Secondary Inhibition at the CB1 Receptor

CBD binds to a different site on the CB1 receptor than THC does.

This slightly changes the receptor’s shape, which:

• Reduces THC’s intensity

• Lowers the risk of anxiety or paranoia

• Improves tolerability

This is one reason combined THC + CBD products often feel more balanced than THC alone.

2. Inhibits Endogenous Cannabinoid Breakdown

CBD inhibits the enzyme that breaks down anandamide, one of your body’s natural endocannabinoids.

When CBD inhibits this enzyme:

• Anandamide levels increase

• Your own endocannabinoid tone improves

• Natural pain regulation strengthens

Some researchers have proposed that migraine may involve clinical endocannabinoid deficiency. A theory still under investigation but biologically plausible.

3. Non-Cannabinoid Mechanisms

CBD also:

• Activates TRPV1 receptors (involved in pain modulation)

• Modulates serotonin (5-HT1A) receptors

• Influences adenosine signaling (energy)

• Provides antioxidant and anti-inflammatory effects

These mechanisms overlap directly with migraine pathways.

Why Combination Therapy Likely Works Better

The study’s use of a THC + CBD combination likely matters because:

• THC activates CB1 → strong central pain reduction

• CBD reduces inflammatory tone

• CBD improves endocannabinoid tone

• CBD tempers THC psychoactivity

• Together they create analgesia with improved tolerability

This synergy is sometimes referred to as the “entourage effect,” though the term is often used loosely.

The key clinical point: THC provides the direct signal.CBD stabilizes and amplifies the system.

CBD alone often fails to reproduce results seen in studies using combined formulations.

How Cannabis May Interrupt a Migraine

You do not need to fully understand this part, but it is worth noting.

The actual pain of a migraine attacks involves:

1. Cortical spreading depolarization

2. Trigeminal nerve activation

3. CGRP release

4. Neurogenic inflammation

5. Central sensitization

Cannabinoids may intervene at multiple levels:

• Decreasing glutamate release

• Reducing trigeminal activation

• Dampening inflammatory cytokines

• Modulating serotonin pathways

• Altering pain threshold centrally

Few medications target this many overlapping pathways simultaneously which is why cannabis deserves the spotlight as a novel treatment option for migraines and all chronic pain conditions.

Is Cannabis a First-Line Migraine Treatment?

For patients who:

• Want a more natural treatment option with the potential for less side effects

• Cannot tolerate triptans, gepants, CGRP inhibitors, or preventives

• Have not found relief with conventional methods

  
  

The emerging research suggests it is not “random symptom relief.” It is targeted neuromodulation that can be a first-line treatment option for many, but will not be effective for all.

Reframing the Conversation Around Cannabis in Medicine

For many people, even considering cannabis as a medical option feels uncomfortable. That hesitation is understandable. For decades, public messaging around cannabis was shaped by fear-based campaigns and the broader War on Drugs. Not by neuroscience or clinical research. The result is that many patients still associate cannabis with moral concern rather than medical physiology.

But from a biological standpoint, it is worth noting that cannabis is not introducing something foreign into the body. It interacts with the endocannabinoid system – a regulatory system your body already uses every day to control pain signaling, inflammation, mood, stress response, and neurologic balance. THC and CBD do not create artificial pathways. They modulate receptors that already exist. In that sense, cannabinoid therapy is not forcing abnormal physiology, it is engaging a system designed for regulation.

Over the past decade, research into cannabis has expanded significantly as state-level legalization has allowed more structured investigation. Emerging data continue to evaluate safety, dosing strategies, and efficacy in conditions such as migraine, neuropathic pain, multiple sclerosis, and spasticity. Like any therapy, it carries risks and is not appropriate for everyone. But the conversation has shifted from ideology to evidence.

It’s also worth acknowledging that cannabis regulation today is largely managed at the state level, often with strict testing, labeling, and quality controls that did not exist in previous decades. The landscape is very different than it once was.

For patients who have exhausted conventional options, or who are seeking alternatives to long-term opioid or sedative use, cannabinoid therapy is increasingly viewed as a legitimate, physiologically grounded option.

Reducing stigma does not mean ignoring risks. It means evaluating therapies based on mechanism, evidence, and individual context rather than outdated narratives.

The question is no longer whether cannabis has a place in medicine.

The question is whether it makes sense for your physiology.

Important Clinical Considerations

• Dose matters. In this study, participants took four puffs of vaporized cannabis containing 6% THC and 11% CBD. This is a rather ow concentration of either.

• THC:CBD ratio matters. The study directly tested THC and CBD alone and found that the combination of 6% THC and 11% CBD was most effective.

• Delivery method matters. The delivery method can yield inconsistencies in dosing. Vaporized cannabis and edible forms tend to yield the most consistency.

• Patient neurochemistry matters.

Not all migraine patients respond the same way.

And importantly: chronic daily use may alter endocannabinoid receptor density over time.

Cannabis is a tool, not a cure.

And it is also not without risk:

• Psychoactive effects

• Tolerance development

• Potential medication overuse patterns

• Cognitive side effects

• Legal and regulatory considerations

Are all something to consider and talk to your chronic pain specialist about.

The Larger Takeaway

Migraine is a disorder of dysregulated sensory processing and neuroinflammation. The endocannabinoid system sits at the intersection of both.

The new research in Headache strengthens the argument that properly formulated cannabinoid therapy can reduce migraine intensity and associated symptoms in certain patients, especially when THC and CBD are used together.

The takeaway is not that everyone with migraine should use cannabis.

It is that the mechanism makes sense.

And when a therapy’s mechanism aligns with the biology of the disease, it deserves serious consideration, not dismissal.

Written By:

Dr. Jason Winkelmann

Chronic Pain Specialist and Educator

Frequently Asked Questions

Is CBD alone effective for migraine?

CBD alone does not strongly activate CB1 receptors in the brain, which are central to pain modulation. Most migraine research showing meaningful pain reduction involves THC + CBD combinations, not CBD alone. CBD supports the system indirectly by increasing anandamide levels and modulating inflammation, but without THC’s direct CB1 activation, pain relief may be limited for many patients.

How does cannabis actually reduce migraine pain?

Migraine involves excessive excitatory signaling (especially glutamate), trigeminal nerve activation, and neurogenic inflammation. THC activates CB1 receptors in the brain, which reduces neurotransmitter release and dampens pain transmission. CBD modulates inflammatory pathways, serotonin receptors, and natural endocannabinoid levels. Together, they may reduce both central pain amplification and inflammatory signaling.

Is cannabis safer than traditional migraine medications?

Safety depends on the individual and the context. Cannabis does not carry the same vascular risks as triptans and does not suppress respiration like opioids. However, it can cause psychoactive effects, cognitive changes, and tolerance with heavy use. It is not risk-free, but for some patients who cannot tolerate conventional medications, it may represent a reasonable alternative when used thoughtfully.

Will using cannabis for migraine make me “high”?

That depends on the formulation. THC is responsible for psychoactive effects. Products with higher CBD content relative to THC may reduce the intensity of those effects. Dosing, delivery method, and individual sensitivity all matter. Many medical formulations are designed to balance therapeutic benefit with tolerability.