Headache Disorders

Topics > Pain > Headache Disorders

Key Insights

• Headache disorders affect 40% of the global population, causing disability and economic burdens. Despite various treatments, many patients require combined approaches for effective symptom management.
• Psychedelics show promise for headaches through 5-HT2A activation, modulating pain signals and reducing inflammation. Early research with LSD, psilocybin, and ketamine suggests they may abort attacks and extend remission periods.
• Companies like Ceruvia and Tactogen are creating non-hallucinogenic psychedelic therapies for headaches, aiming to provide safer, more accessible treatment options for patients.

Author: Chiara Corpetti. This page was made possible by Chiara Corpetti, PhD, in Pharmacology and Toxicology.

Headache Disorders

Headache disorders include many different conditions that cause ongoing or repeated headaches. These range from mild to severe, happen often or rarely, and have various causes. The main types include migraines (characterised by throbbing pain, sensitivity to light and sound, and sometimes nausea), tension headaches (causing dull, band-like pressure), and cluster headaches (extremely severe, one-sided pain occurring in cycles). Secondary headaches result from underlying issues like infections, head injuries, or medication overuse. Headaches affect many people globally, seriously reducing life quality and work ability.

Affecting approximately 40% of the global population—over 3 billion people in 2021—headache disorders impact women more frequently than men. Migraines alone affect about 12% of people worldwide, with women three times more likely to experience them than men due to hormonal influences. These conditions rank among the leading causes of disability, particularly in people aged 15-49, with migraines being the second most disabling condition worldwide in this age group. The economic impact is staggering, costing the global economy an estimated $160 billion annually through direct healthcare expenses and lost productivity. Despite their widespread prevalence, up to 60% of headache sufferers never seek medical attention, and many who do receive inadequate diagnosis and treatment, highlighting the need for greater awareness and improved management strategies [1].

Mechanisms of Headache Disorders

Headache disorders are complex neurological conditions with mechanisms that remain only partially understood. Research points to several interconnected factors that trigger and maintain headache pain. The trigeminovascular system plays a central role—when activated, it stimulates neurons in the trigeminal ganglion (a bundle of nerve cells) that connect to blood vessels in the brain. This activation releases calcitonin gene-related peptide (CGRP) and other chemical messengers that initiate headache pain and related symptoms [3].

Inflammation also contributes significantly to headache development. The release of inflammatory markers creates a cascade effect that amplifies pain signals and sensitizes nerve pathways. This explains why many headaches worsen with movement or persist beyond the initial trigger. Brain chemistry changes are equally important, particularly involving serotonin—a neurotransmitter that regulates pain perception and mood. Changes in serotonin levels and alterations in specific serotonin receptors (particularly 5-HT2A receptors) appear to influence both headache severity and how often attacks occur [3]. This serotonin connection helps explain why some antidepressants that affect serotonin levels can be effective preventive treatments for certain headache disorders.

Standard treatments

Treatment depends on the condition’s type and severity, involving both medication and lifestyle approaches. Acute medications include simple analgesics (acetaminophen, NSAIDs), triptans (which target serotonin receptors to reduce inflammation and constrict blood vessels), and, in severe cases, opioids or corticosteroids. Preventive treatments are recommended for frequent headaches and include beta-blockers (propranolol, metoprolol), anticonvulsants (topiramate, valproate), antidepressants (amitriptyline), and newer CGRP inhibitors (erenumab, fremanezumab) that block pain pathways specific to migraines.

Many patients benefit from combining medications with non-drug approaches. These include identifying and avoiding triggers (certain foods, sleep disruption, stress), maintaining regular sleep patterns, using stress management techniques, and moderate exercise. Cognitive behavioral therapy helps patients develop coping strategies for pain, while biofeedback trains individuals to control physiological responses like muscle tension. Other helpful approaches include acupuncture, massage therapy, and nerve stimulation devices that can interrupt pain signals. For those with persistent or severe headache disorders, emerging therapies like transcranial magnetic stimulation, new drug formulations, and personalised treatment plans based on genetic profiles offer hope for improved long-term management. Multidisciplinary headache clinics coordinating specialists often provide the most comprehensive care for complex cases [1,2].

Psychedelics and Headache Disorders

With the resurgence of interest in psychedelics over the past decade, researchers have been exploring their therapeutic potential for a range of conditions, including depression, anxiety, substance use disorders, neurodegenerative diseases, chronic pain, and headache disorders.

Recent studies have primarily focused on three psychedelic compounds: LSD, psilocybin, and ketamine. Ongoing and planned clinical trials aim to evaluate their prophylactic effects, safety, efficacy, and mechanisms of action in treating cluster headaches and chronic migraines. While the precise mechanisms underlying headache disorders remain unclear, psychedelics appear to act on existing therapeutic pathways, suggesting their potential as alternative or adjunct treatments.

Mechanisms of Action of Psychedelics

Researchers believe that psychedelics primarily work by activating serotonin 2A receptors (5-HT2A) in the brain, setting off a chain of brain changes [3,4,5]. In simpler terms, when psychedelics bind to these specific receptors, they change how pain signals are processed. Pain typically travels from sensory nerves through the spinal cord to the brain, but when 5-HT2A receptors are activated, they help block these pain signals in both the brain (central) and body (peripheral) pain systems, effectively reducing pain perception.

Psychedelics also have mild anti-inflammatory effects through this same receptor activation. By reducing inflammation, especially in areas involved in pain processing, these substances may provide additional relief beyond their direct pain-blocking effects.

Perhaps most importantly, psychedelics appear to help “rewire” problematic brain connections involved in chronic pain. The brain of someone with chronic headaches often develops unhealthy communication patterns between different regions. Psychedelics seem to disrupt these established patterns temporarily, creating a window of opportunity for healthier connections to form. This “brain plasticity” effect might explain why some patients report lasting benefits even after the drugs themselves have left the body—the brain has essentially developed new, less pain-focused connection patterns that remain after treatment [5,6].

Current Research on LSD

Early research into LSD for cluster headaches showed remarkable promise. One of the first studies examining both LSD and psilocybin found that these compounds could effectively stop ongoing headache attacks, end entire cluster periods, and extend remission times—often requiring just a single dose. While most headache medications must be taken daily, researchers found that a single dose of LSD was usually enough to stop an entire cluster period. Similarly, psilocybin rarely required more than three doses to achieve these effects.

Interestingly, some patients reported benefits even when taking amounts too small to cause hallucinations. This low-dose regiment suggests that the headache-relieving effects might work through different brain mechanisms than those causing acute psychedelic experiences. However, these early studies had important limitations—they didn’t randomly assign patients to treatment groups, include placebo controls, or standardise dosing methods.

Later surveys through organisations like Clusterbusters found that about 60% of LSD users reported significant reductions in cluster headache frequency. A Dutch study similarly found that cluster headache patients use psychedelics more often than the general population, with many reporting substantial benefits for attack frequency and duration.

A promising development is BOL-148, a non-hallucinogenic LSD derivative being researched for cluster headache prevention. In an open-label study, three doses of BOL-148 within 10 days either completely stopped a cluster cycle or significantly reduced attack frequency and intensity, with benefits lasting many months.

Current Research on Psilocybin

Research on psilocybin for headache disorders has produced compelling early evidence. In a study with migraine patients, researchers found that a single low dose of psilocybin (10mg/70kg) significantly reduced migraine days compared to placebo over a two-week period. Specifically, patients experienced about 1.65 fewer migraine days per week after psilocybin compared to only 0.15 fewer days with placebo.

An interesting aspect of this research was that the reduction in migraine frequency didn’t correlate with how intense the psychedelic experience was. This decoupling suggests that psilocybin’s headache benefits might work through different brain mechanisms than those causing the mind-altering effects.

For cluster headaches specifically, researchers found (also reported in this study) that a “pulse regimen” of psilocybin—three moderate doses given about five days apart—reduced attack frequency by about 30% on average. One patient even experienced complete freedom from cluster headaches for 21 weeks. Brain imaging studies showed that these improvements correlated with changes in connectivity between the hypothalamus (a key brain region involved in cluster headaches) and other brain areas.

Additional research found that psilocybin’s effects on headaches might involve the same brain pathways that regulate pain signals. When psilocybin activates serotonin 2A receptors, it appears to trigger pain-blocking processes in both the brain and body while reducing inflammation in pain-processing regions.

Notably, surveys conducted by Clusterbusters found that psilocybin was rated as more effective than many conventional medications, with about 50% of users reporting reductions in both attack frequency and duration. Users typically reported benefits from infrequent dosing—often just a few times per year—with some achieving extended periods of remission.

Current Research on Ketamine

Unlike classical psychedelics, ketamine works through different brain mechanisms but shows promise for treating severe headache disorders. In a pilot study testing intranasal ketamine for acute cluster headache attacks, researchers gave patients 15 mg doses every six minutes, up to five times total.

While ketamine didn’t achieve the primary goal of reducing pain by 50% within 15 minutes, it did show significant benefits by the 30-minute mark. At this point, pain intensity had decreased by 59% on average, with most patients (69%) reporting their pain level had dropped to 4 or lower on a 10-point scale. Although four patients needed additional rescue medication, no serious side effects occurred.

Half of the study participants preferred ketamine to standard treatments like oxygen or injectable sumatriptan. This suggests that ketamine might be valuable for patients who don’t respond well to first-line treatments or who have contraindications to them.

Ketamine’s potential effectiveness for headache disorders likely stems from its ability to block NMDA receptors, which play a key role in pain transmission. It may also affect the hypothalamus, which is believed to be central in cluster headache development.

Psychedelic Industry and Future Research

The rapid advancement of research within the psychedelic renaissance is driving the development of novel therapeutic approaches for headache disorders. What began as grassroots patient experimentation has evolved into rigorous scientific investigation, with pharmaceutical companies, academic institutions, and nonprofit organisations now actively exploring these compounds.

Companies with Ongoing Studies

Ceruvia Lifesciences (formerly Heffter Research Institute) leads the industry in developing non-hallucinogenic psychedelic derivatives specifically for headache disorders. Their flagship compound, BOL-148 (2-bromo-LSD), has shown promise in treating cluster headaches. Unlike LSD, BOL-148 doesn’t produce psychedelic effects but retains therapeutic benefits. In early clinical studies (see above), three doses administered over 10 days induced complete remission in some patients and significantly reduced attack frequency in others, with benefits lasting 2-3 months for most participants. Ceruvia is currently conducting Phase II trials, with plans to begin Phase III studies by late 2025.

Tactogen is pursuing a different approach by developing TACT908, a novel compound that acts as a 5-HT1B agonist and partial 5-HT2A agonist. This dual mechanism targets both pain pathways and neuroinflammation without causing hallucinogenic effects. Currently in preclinical development, TACT908 represents a potential breakthrough for patients seeking relief without psychoactive experiences.

Other notable companies include Beckley Psytech, which investigates low-dose psilocybin for cluster headaches and 5-MeO-DMT for treatment-resistant headache disorders. Their Phase IIa trial for psilocybin using a novel intranasal formulation began recruiting in early 2024. Meanwhile, MindMed has expanded its focus to include LSD derivatives for cluster headache treatment, with their compound MM-120 showing promising results in early trials for both cluster headaches and migraines.

Usona Institute, a nonprofit organisation, conducts research on standardised psilocybin formulations across multiple headache conditions. Their approach emphasizes rigorous methodology and collaboration with academic medical centres, which helps establish credibility for psychedelic treatments within mainstream medicine.

Emerging Clinical Trials

The clinical trial landscape for psychedelics in headache disorders has expanded significantly since 2020, with several important studies now underway across multiple institutions. Current trials are focusing on three main psychedelic compounds: psilocybin, LSD, and ketamine.

Psilocybin research has advanced beyond early exploratory studies to more rigorous investigations. Several centres are now conducting trials that examine different dosing protocols, from single high-dose sessions to multiple low-dose “pulse” regimens. These studies include investigations for various headache disorders, including chronic migraines, cluster headaches, and even concussion-related headaches. Researchers are particularly interested in understanding whether the frequency, duration, and intensity of various headache types respond differently to psilocybin intervention.

LSD trials have also gained momentum, with multiple centers investigating “minidosing” protocols—using approximately 25μg every third day for several weeks—specifically for chronic cluster headaches. This sub-hallucinogenic dosing strategy aims to provide therapeutic benefits while minimising perceptual effects and regulatory concerns. Current Phase II studies evaluate efficacy and safety profiles compared to placebo conditions.

Ketamine research has evolved to include innovative combination approaches. One notable ongoing trial is investigating ketamine combined with magnesium sulfate for refractory chronic cluster headaches, while others are examining high-dose ketamine infusions for chronic daily headache syndrome. These studies represent a shift toward more targeted applications of ketamine beyond its established use in emergency settings.

A significant development in trial design is the inclusion of brain imaging components, particularly functional MRI, to correlate clinical improvements with changes in neural activity. These mechanistic studies are critical for understanding how these compounds affect headache pathophysiology, which may lead to the development of more targeted therapies.

Future Research Directions

Several key areas warrant further investigation in the field of psychedelics for headache disorders. First, determining optimal dosing regimens remains critical—current evidence suggests that sub-hallucinogenic or “mini” doses may provide therapeutic benefits without perceptual effects, but more comparative studies are needed to confirm this finding across different compounds and headache types.

Developing non-hallucinogenic derivatives that retain therapeutic properties represents another promising direction. Compounds like BOL-148 demonstrate that the pain-relieving mechanisms may be separable from the psychoactive effects, potentially offering treatments with fewer regulatory barriers and broader clinical applications.

Comparative effectiveness research will be essential to position these treatments within existing care paradigms. Studies directly comparing psychedelics to current first-line treatments (such as CGRP inhibitors for migraine or oxygen for cluster headaches) would help clinicians make evidence-based recommendations about where these treatments belong in treatment algorithms.

Researchers also need to address important questions about long-term safety and efficacy. While short-term studies show promising results, the durability of effects and potential for tolerance or adverse effects with repeated dosing remains inadequately understood.

Finally, practical implementation research will be necessary to develop protocols that work in real-world clinical settings. This includes standardised screening procedures, monitoring guidelines, and integration with existing headache management approaches.

As the evidence base grows, these research directions will help determine whether psychedelic compounds can move from promising experimental treatments to established therapeutic options for the millions suffering from debilitating headache disorders.

External References for Headache Disorders and Psychedelics

All resources available on Blossom are directly linked on this topic page. Find even more background about this topic with these external references.

1. World Health Organization. (2024, March 6). Migraine and other headache disorders. https://www.who.int/news-room/fact-sheets/detail/headache-disorders

2. Kissoon, N. R., & Steel, S. Patient education: Headache causes and diagnosis in adults (Beyond the Basics). https://www.uptodate.com/contents/headache-treatment-in-adults-beyond-the-basics/print

3. Henderson, I., Elsaadany, R., Chan, G., Bajaj, V., Duarte, D., Goodman, S., … & Duarte, R. A. (2025). Exploring the Potential of Psychedelics in the Treatment of Headache Disorders: Clinical Considerations and Exploratory Insights. Current Pain and Headache Reports, 29(1), 1-14.

4. Robinson, C. L., Fonseca, A. C., Diejomaoh, E. M., D’Souza, R. S., Schatman, M. E., Orhurhu, V., & Emerick, T. (2024). Scoping review: the role of psychedelics in the management of chronic pain. Journal of Pain Research, 965-973.

5. Kooijman, N. I., Willegers, T., Reuser, A., Mulleners, W. M., Kramers, C., Vissers, K. C., & van Der Wal, S. E. (2023). Are psychedelics the answer to chronic pain: A review of current literature. Pain Practice, 23(4), 447-458.

6. Schindler, E. A. (2022). Psychedelics as preventive treatment in headache and chronic pain disorders. Neuropharmacology, 215, 109166.