Cannabinoids and Hallucinogens for Headache

Brian E. McGeeney, MD, MPH


Headache. 2013;53(3):447-458. 

In This Article


The term hallucinogen is derived from the Latin alucinari ("to wander in the mind"), and as a group, is able to induce significant changes in sensory perception and thinking without a reduced level of consciousness. The naturally occurring mescaline and psilocybin along with synthetic lysergic acid diethylamide (LSD) fall under the "hallucinogen" category and in the broadest sense so do certain N-methyl-D-aspartate (NMDA) antagonists like ketamine. The often used term "psychedelic" is derived from the Greek words psyche (mind) and delos (visible). Despite altering the content of consciousness, hallucinogens are not toxic to any organ system and death due to the direct effect of LSD for instance is unknown.[51] The history of ritual use of hallucinogenic mushrooms goes back hundreds of years, including Mayan and Aztec cultures of Mexico and contemporary Mazatec Indians of southern Mexico. Hallucinogens were used for a variety of purposes, including recreational, medicinal, religious, and cultural.[52]

Hallucinogen Biology

The indole ring (composed of a benzene ring fused to a pyrrole ring) is the primary structure of serotonin, tryptophan, and most hallucinogenic compounds. Activation of the serotonin2A (5-HT2A) receptor plays a primary mechanistic role in mediating the behavioral effects of indoleamine serotonergic hallucinogens.[53] 5-HT2A antagonists block most of the subjective and behavioral effects of these hallucinogens.[54] The family of serotonin receptors is large.[55] Serotonin is one of the most ancient signaling molecules, speculated to be 700–750 million years old. Single-celled eukaryotes such as the Paramecium contain serotonin, which can modulate swimming behavior. Even Drosophila contains 3 serotonin receptor types.

Hallucinogenic effects of psilocybin-containing mushrooms were first recorded in the medical literature in 1799.[56] The clinical effect of hallucinogens for a given dose varies considerably from person to person, thought to be due to non-pharmacological variables such as subject mood and emotional state along with the setting of the experience.[57] A recent study, in contrast to earlier experiments, failed to demonstrate a relationship between neuroticism-anxiety ratings and negative reactions to psilocybin.[58] In addition to hallucinations, ingestion of hallucinogens causes physical effects including mydriasis, elevated temperature, blood pressure, and heart rate; dizziness; insomnia; nausea; and anorexia. Interestingly, cerebral vascular tone is increased with these 5-HT2A agonists and this effect may be helpful in headache. There is a high concentration of 5-HT2A receptors in glutamatergic neurons in layer 5 of the cerebral cortex and also on GABA-ergic interneurons.[59,60] Hence hallucinogenic actions may be the result of a combined effect on both excitatory and inhibitory neuronal pathways.[61] In contrast, a recent study using functional magnetic resonance imaging noted a surprising decrease in neuronal activity in critical areas like the anterior and posterior cingulate cortex and thalamus while under the influence of psilocybin that was not just a primary reduction in blood flow.[62] Functional coupling between the anterior and posterior cingulate cortex was also decreased. Overall, the neurobiology of hallucinogens is still poorly understood.

Hallucinogens and Headache

The first comment on improvement in headache with hallucinogens is attributed to Prentiss and Morgan, experimenting with peyote (mescaline) in 1894.[63] Before the synthesis of LSD, mescaline was a well-known naturally occurring but much less potent hallucinogen, with effective doses in the 200 mg-400 mg range, compared with LSD which starts to become hallucinogenic at doses above 30 μg. Mescaline is still used during religious services of the Native American Church in the form of peyote, which is a small spineless cactus native to southwestern Texas and Mexico. Prentiss and Morgan also attributed headache to the effects of mescaline on healthy volunteers, as did the neurologist Weir Mitchell who documented occurrence of headache when self-administering mescaline. Early American and European peyote users complained that peyote actually caused headache.[64]

LSD was originally synthesized in Sandoz Research Labs, Basal, Switzerland, by Alfred Hofmann and Arthur Stoll, who were looking for compounds with diverse uses such as to treat migraine and facilitate childbirth. Testing in 1938 was initially uninteresting and it was not taken further until 1943 when Hofmann synthesized more and inadvertently absorbed a significant amount through his skin, resulting in unwellness with hallucinations. Hofmann suspected that his synthesized compound had produced these profound effects and decided to challenge himself a few days later with what he thought was an extremely small amount. He dosed himself with 250 μg which was a very large dose indeed.

LSD has been successfully used in the treatment of headache and migraine in non-hallucinogenic doses, with credit to Dr. Federigo Sicuteri (1963).[65] Ling and Buckman detailed the clinical use of LSD for cases of anxiety, migraine, and other ailments, based on their treatment of over 350 patients at Marlborough Day Hospital (in London).[66] Snow outlined his personal use of LSD to treat migraine attacks and periodic administration for prophylaxis.[67] An intriguing experiment testing for hypersensitivity to LSD and psilocybin in headache patients (presumably migraine) was published in 1974. Thirty normal (non-migraine) subjects were studied with 72 headache sufferers. Subjects were tested on their response to either LSD or psilocybin along with a placebo. The dose of LSD was 350 ng/kg and the dose of psilocybin was 20 μg/kg, both doses being standardly sub-hallucinogenic. There were 3 outcomes, grade 0 being no reaction, grade 1 being simple psycho-affective reactions such as nervousness, slight anxiety, or euphoria, and grade 2 being psycho-affective reactions plus perceptive distortions and/or hallucinations. No normal subjects reached a grade 2. In headache subjects, 18% of the group administered LSD had a grade 2 outcome. The grade 2 outcome of the headache subjects administered psilocybin was also 18%. In addition, considerably more of the headache subjects had a grade 1 reaction, compared with normal subjects. The authors demonstrated a hypersensitivity in headache sufferers to hallucinogens and hypothesized that this was due to a relative serotonin deficiency in the those with headache.[68]

Methysergide, used for prophylaxis of migraine and cluster headache (although removed from the US market in 2002), is a close derivative of LSD and is clearly hallucinogenic at doses higher than standardly used.[69] However, hallucinations have been described with methysergide at therapeutic doses, and Bana describes such a patient, where the hallucinations helped solve a complicated engineering problem with considerable benefit.[70]

The tasteless and odorless anesthetic ketamine is a potent NMDA antagonist sometimes included in the hallucinogen category and is a schedule 3 controlled substance in the United States. Ketamine has a variety of other actions including modulation of sodium and calcium channels, influencing dopamine receptors and cholinergic transmission, as well as amine re-uptake interactions.[71] Ketamine has analgesic properties at sub-anesthetic doses which makes it useful to chronic pain specialists in particular and is still used in human and veterinary anesthesia. Ketamine distorts perceptions of sight and sound, and produces feelings of detachment that are not so much hallucination-like effects and better described as dissociative effects; hence ketamine is known as a dissociative anesthetic. Dextromethorphan is another example. Nicolodi and Sicuteri studied the migraine abortive potential and prophylactic ability of ketamine in two 17-subject groups in a randomized, double-blind cross-over study design.[72] Administration of 80 μg/kg subcutaneously but not placebo produced marked relief of migraine pain and the same dose 3 times a day for 3 weeks was an effective prophylactic agent. Ketamine has also been used to abort aura in patients with familial hemiplegic migraine[73] and to treat migraine in an outpatient setting.[74]

Hallucinogen Use in Cluster Headache

In 1998, a 35-year-old Scottish man wrote to an online cluster headache forum stating he had episodic cluster for many years. One year, he skipped his fall cluster cycle and speculated that starting recreational use of LSD during the summer caused this absence. The observation was met with skepticism but prompted an ongoing discussion that led to sufferers trying to repeat the results with some success (B. Wold, founder of, personal communication). The frequent failure of medical therapy, especially in chronic cluster headache leaves open the opportunity for other treatment approaches. Three different hallucinogens are used by the cluster headache population, lysergic acid amide (LSA) containing seeds, psilocybin-containing mushrooms, and the difficult to obtain LSD. The most commonly used sources of LSA are Rivea Corymbosa seeds, Hawaiian Baby Woodrose seeds, or Morning Glory seeds (certain strains). Rivea Corymbosa, a perennial climbing vine with white flowers, is native through Latin America, where it is known as Ololiuqui and was probably the most common entheogen (psychoactive substance used in a spiritual context) used by the natives. A typical dose would consist of 60–100 seeds and the clinical effect would last 4–8 hours. Hawaiian Baby Woodrose is a climbing vine now present worldwide, and the Morning Glory flowering plant also spreads by way of long creeping stems. Ingestion of LSA-containing seeds is commonly accompanied by nausea and vomiting and is less likely to induce visual abnormalities compared with psilocybin or LSD. Hence use of LSA seeds is often regarded as an unpleasant experience and thought to have a lower abuse potential compared with the other hallucinogens (LSA belonging to schedule 3).

Psilocybin, the psychoactive constituent of "magic mushrooms," is metabolized in the body by alkaline phosphatases, cleaving the O-phosphoryl ester to generate the hydroxyl compound psilocin, and it is only psilocin that is biologically active, hence psilocybin is a prodrug.[75] Psilocybin is taken orally, and peak effect is typically 1–1.5 hours after ingestion with total cessation of effects in 4–6 hours.[76] The duration of effect of LSD is longer, from 8–12 hours. Although dose is a strong determinant of response, preparation by the subject, personality, mood along with the environment in which the drug is taken are also very important to the psychoactive outcome and this applies to all the hallucinogens. Cluster headache patients using psilocybin would typically grow their own supply, no easy task given the strict conditions required. The newly initiated would often receive advice from fellow growers and sufferers to successfully cultivate mushrooms indoors. Harvested plants can be dried and stored for long periods. A typical treatment to induce a remission would be dosing on days 1, 5, and 10, and not daily. Experiencing hallucinations does not appear to be required for benefit. The conventional way of spreading out the treatments derives from concern that the very notable tolerance that builds up to the hallucinogenic effects with repeated dosing may also apply to the alleged benefit in headache sufferers. Some patients dose every few weeks to months in order to keep cluster periods away. There is no literature support for this regimen.

The potent hallucinogen N,N-dimethyltryptamine (DMT) is naturally occurring and the psychoactive plant brew containing DMT (ayahuasca) is used largely as a religious sacrament in Peru and Brazil. A survey of 496 neurologist diagnosed cluster headache patients (many using hallucinogens due to the population studied) found 3 patients who use DMT to abort cluster attacks.[77] The author has used ketamine nasal spray in selected patients to abort cluster attacks. The bioavailability of the nasal route is 25–50% as opposed to oral bioavailability of 17%.[78,79] Plasma peak levels of intranasal ketamine are reached in 15 minutes.

Legal Issues With Hallucinogens

Before prohibition, psilocybin and LSD were used in psychotherapy.[80] Increasing use of LSD in the United States and concern about adverse events led the US Congress to pass the Drug Abuse Control Amendment of 1965, making the manufacture and sale of LSD illegal. Medical and scientific use was exempt. At that time, possession was still legal; however, further legislation later including the 1970 Controlled Substances Act made it illegal to possess LSD and related hallucinogens.

In the United States, it is legal to buy, sell, and cultivate LSA-containing seeds. LSA, however, is schedule 3 and ingestion is illegal. Possession of psilocybin-containing mushrooms and LSD is illegal (schedule 1). Mushroom spores do not contain psilocybin and are not illegal in most US states. Spores are illegal in California, Georgia, and Idaho. A New Mexico appeals court ruled in 2005 that growing psilocybin mushrooms for personal use could not be considered "manufacturing a controlled substance" under state law.[81]

Literature Support for Hallucinogens in Cluster Headache

In 2006, Sewell and colleagues published a survey of 53 cluster headache patients who used psilocybin or LSD to treat their condition.[82] Ten of 20 chronic cluster subjects who used psilocybin reported a complete cessation of attacks. Two chronic cluster subjects used LSD at sub-hallucinogenic doses, and both had cessation of attacks. Sewell has also shown that the amount of LSA in purchased seeds can vary tremendously from batch to batch and the amount correlates with ability to switch off a cluster cycle.[83]

Recently, there has been renewed interest in 2-bromo-lysergic acid diethylamide (BOL-148) in the prophylaxis of cluster headache. This compound is produced by bromination of the LSD molecule and has no hallucinogenic potential but appears to retain potential for inducing a cluster headache remission. An open, non-randomized case series of 5 German cluster headache patients (4 chronic, 1 episodic) who failed verapamil and various other prophylactic agents with BOL-148 resulted in remissions.[84] Three subjects had remission of attacks (at least 1 month), one had a profound reduction in attack frequency, and the final subject only had a 30% reduction in attack frequency. In the United States, a company called Entheogen is hoping to conduct trials of BOL-148 in the near future (From and J. Halpern, personal communication). Whether BOL-148 is completely without hallucinogenic potential has been questioned, based on a single case report where the subject developed lightheadedness, anxiety, and a panic feeling but no clouding of consciousness or hallucinations.[85,86] The subjects' symptoms are better explained by an anxiety reaction.[87]