Psychedelics like psilocybin (magic mushrooms), lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT), and other indoleamine 5-hydroxytryptamine 5-HT2A receptor agonists are the latest drugs to gain attention for their potential to relieve migraine headaches. [1, 2] Migraine headache disorders effect about 12% of the US population, and have multiple triggers such as diet, weather changes, stress, hormones, odors, and more.  Likewise, there are multiple biological targets for migraine medications. Triptans, analgesics (pain killers), BOTOX injections, and antiepileptic drugs are traditional migraine medications, however, they are not well tolerated by all patients which is why there is much hope and potential for the use of psychedelics as a treatment for cluster headaches.
Cluster Headaches and Standard Treatments
Cluster headaches are also known as suicide headaches because of the pain that they induce, and the higher prevalence of suicide amongst those who suffer from them. They can occur for weeks or months at a time. The cause of these types of headaches is currently not known.
For migraines, in general, triptan drugs such as Sumatriptan (Imitrex) reduce symptoms by activating 5-HT1B receptors. This leads to pharmacological effects like vasoconstriction (making it unsafe for patients with hypertension or cardiovascular disease). Other treatments may include rest or pain-relief medications, but these latter two methods likely won’t provide much relief for sufferers of cluster headaches. Common treatment methodologies for cluster headaches include triptans, lidocaine, oxygen, and dihydroergotamine, an ergot alkaloid. Ergot is a fungus that grows on rye and other cereal grains, and lysergic acid diethylamide was first synthesized from lysergic acid, which, in turn, was derived from ergotamine. Migranal, a brand using dihydroergotamine has been on the market since 1997. 
Psilocybin and LSD for Cluster Headaches
Despite their schedule I status (which means no accepted medical applications), psychedelics have demonstrated strong potential for relieving the symptoms of cluster headaches, which significantly impacts the lives of those who must endure this condition. In a 2006 study, 53 cluster headache patients were given either psilocybin or LSD.  The majority of participants in the study found that both compounds were effective in terminating cluster headaches and also reported an extended period of headache remission after use.
While researchers still don’t know exactly how psilocybin alleviates migraines, they do have some theories. First, there’s its ability to stimulate 5-HT serotonin receptors.  This is something that triptans and Botox also do.
The non-hallucinogenic LSD derivative BOL-148 has also shown the ability to stop or reduce the severity of cluster headaches in just three small (30µg/kg) oral doses. Neuroplastic, genetic, and psychological processes, along with the neuroendocrine system are all thought to play a role in the lasting therapeutic benefits of psychedelics.  Along with the 5-HT serotonin system, dopaminergic, glutamatergic, and GABAergic systems have been associated with the pharmacology of psychedelics.
In a survey of 496 people suffering from cluster headaches, psilocybin, LSD, and lysergic acid amide, provided similar or better relief than conventional treatment options. 
Psychedelics are showing great potential as a treatment for migraine headaches, but there are some concerns. One major concern is that these compounds are not widely available in a standardized dose. The potency of psilocybin-containing mushrooms can vary widely and can also contain contaminants. However, psychedelics’ therapeutic benefits appear to persist after limited exposure.  Whereas a pharmaceutical medication typically must be taken daily, treatment with psychedelics can be more infrequent. This is a very intriguing feature that is not seen in standard drugs used to treat cluster headaches.
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 Schindler EAD, Wallace RM, Sloshower JA, D’Souza DC. Neuroendocrine associations underlying the persistent therapeutic effects of classic serotonergic psychedelics. Frontiers in Pharmacology. 2018;9. doi:10.3389/fphar.2018.00177 [journal impact factor = 5.988; times cited = 21]
 Silberstein SD, Shrewsbury SB, Hoekman J. Dihydroergotamine (DHE) – then and now: A narrative review. Headache. 2020;60(1):40-57. [journal impact factor = 4.041; times cited = 18]
 Sewell RA, Halpern JH, Pope HG. Response of cluster headache to psilocybin and LSD. Neurology. 2006;66(12):1920-1922. doi:10.1212/01.wnl.0000219761.05466.43 [journal impact factor = 9.901; times cited = 178]
 Schindler EA, Gottschalk CH, Weil MJ, Shapiro RE, Wright DA, Sewell RA. Indoleamine hallucinogens in cluster headache: Results of the Clusterbusters medication use survey. J Psychoactive Drugs. 2015;47(5):372-381. [journal impact factor = 2.748; times cited = 39]
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