Introduction

Headache is a major public health concern, with enormous individual and societal costs (estimated at $14.4 billion annually) due to decreased quality of life and disability.¹ Each year, ∼47% of the population experience headache, including migraine (10%), tension-type headache (38%), and chronic daily headache (3%).² A sexual dimorphism exists for headache disorders, with women 2–3 times more likely to experience migraine³ and 1.25 times more likely to experience tension-type headache than men.⁴

The present review will focus largely on migraine, tension-type headache, trigeminal autonomic cephalalgias (specifically cluster headache), and medication-overuse headache (MOH). Migraine is classified as a 4–72 h headache that is typically unilateral, pulsating, of moderate-to-severe intensity, and associated with photophobia and phonophobia.^5,6 Tension-type headache is classified as frequent, infrequent, or chronic, typically presenting with bilateral tightening pain of mild-to-moderate intensity and lasting minutes to days.^6,7 Cluster headache is defined as severe unilateral pain in orbital, temporal, and/or supraorbital locations, lasting 15–180 min and typically occurring frequently and at regular intervals.^6,8 MOH is a chronic condition (occurs more than 15 days per month) that develops from frequent use of anti-headache medications.^6,9

The pathophysiology of headache disorders is still under investigation. However, it is believed that migraine and cluster headaches are initiated in the brain in areas such as the hypothalamus, brainstem, or possibly cortex.⁶ Tension-type headaches can not only originate in the central nervous system but may also be triggered by myofascial tissue, often developing in response to stress.¹⁰ Regardless of origin, headaches usually involve overactivation of the trigeminovascular pathway, resulting in the release of vasoactive peptides, such as calcitonin gene-related peptide (CGRP) and substance P, as well as vasoactive mediators such as nitrous oxide (NO), which can lead to further sensitization of nociceptive receptors in the head and neck.¹¹ Serotoninergic signaling, parasympathetic efferents, inflammation, and increased intracranial pressure also play important roles in headache disorders.^12,13

Treatment depends on the underlying headache condition; however, some popular options include NSAIDs for mild headaches and triptans, anti-depressants, verapamil, or ergotamine for more severe or chronic headaches.¹⁴ These may be complemented by nonpharmacological interventions such as cognitive-behavioral therapy or relaxation training.¹⁵ Despite many treatment options, less than half of headache sufferers experience remission, and many continue to develop more severe or chronic headaches throughout their lifetime.¹⁶ Moreover, headache disorders are often underrecognized and undertreated.¹⁷ This current situation warrants an exploration of additional treatment options for headache disorders, with favorable side-effect profiles and efficacy in refractory patients.

One such option, cannabis, has been ignored in the United States for the past several decades but has an established history in the treatment of headaches. Assyrian manuscripts from the second millennium BCE recommended cannabis to “bind the temples,”¹⁸ and Ayurvedic preparations in the third and fourth centuries BCE were indicated for “diseases of the head” such as migraines.¹⁹ The prescription of cannabis was even recommended in ancient Greece, with Pedanius Dioscorides describing its use in his De Maternia Medica as a treatment for “pain of the ears.”²⁰ Other citations documenting the use of cannabis for headache disorders arise from the ninth century in the Al-Aq-rabadhin Al-Saghir, the earliest known document of Arabic pharmacology.¹⁹ Further recommendations are found in Persian texts from the 10th²¹ and 17th centuries.²² Prominent physicians of the Middle Ages, including John Parkinson²³ and Nicholas Culpeper,²⁴ also recommended the use of cannabis for headache.

The reintroduction of cannabis to the West in 1839²⁵ began a century of its use as an effective treatment for headache disorders²⁶ until its illegalization in 1937.²⁷ Notable physicians who espoused the benefits of cannabis for headache disorders included John Russell Reynolds, the personal physician of Queen Victoria,²⁸ American neurologist Silas Weir Mitchell,²⁹ the president of the New York Neurological Society Edouard C. Seguin,¹⁹ William Gowers, a founding father of modern neurology,³⁰ and Sir William Osler, often considered the father of modern medicine.³¹

When cannabis was deemed illegal by the U.S. government, its therapeutic use and research into its medical potential was largely discontinued. To this day, there are few clinical investigations of the use of cannabis for headache; however, the studies that have emerged demonstrate potential efficacy. In addition, numerous pre-clinical investigations¹⁸ have validated the role of endocannabinoids in preventing headache pathophysiology, which suggests a mechanistic role of cannabis in the treatment of these disorders. Although the cannabis plant comprises more than 100 cannabinoids, there has been little study of the individual effects of these cannabinoids on headache disorders; therefore, the present review will focus largely on the clinical potential of the cannabis plant as a whole.

The present review has four unique aims: (1) Highlight common historical trends in the use of cannabis in the treatment of headache to inform future clinical guidelines. (2) Briefly present the current clinical literature on this topic, with a focus on more recent publications that have not been discussed in past reviews. (3) Compile various preclinical studies into a prospective integrated model outlining the role of cannabinoids in the modulation of headache pathogenesis. (4) Outline several^19,32–35 future directions that warrant exploration based on the limited, but promising findings on this topic.

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