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(searched for: Therapeutic Role of Marijuana in Migraine)
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Simrat Kaur Batth
Archives of Internal Medicine Research, Volume 04, pp 54-61; doi:10.26502/aimr.0056

Abstract:
Marijuana has been known for a long time to have a variety of therapeutic implications in pain management. The role of the cannabinoid system in regulation of migraine headaches highlights the potential of marijuana as a treatment option. Marijuana has the ability to modulate the migraine associated pain pathway via the cannabinoid receptors. Endocannabinoid deficiency has been theorized to contribute to the pathophysiology of migraine. People who have used marijuana for their migraine headaches have reported a decrease in the frequency of their headaches, especially the population who failed to show response with the conventional treatment options. Also, marijuana has a more tolerable side effect profile and administering this along with conventional treatment options can help reduce their dosages and side effects. Large scale clinical trials are needed to further find out about the different strains, formulations, prefer- red delivery method and doses of marijuana required for effective treatment.
Frontiers in Molecular Neuroscience, Volume 13; doi:10.3389/fnmol.2020.625714

Abstract:
Editorial on the Research Topic Novel Molecular Targets for the Treatment of Pain The chronic pain and opioid epidemics are two interdependent public health crises that have challenged the United States, in particular, and the world in general for more than 20 years. Chronic pain affects more than 100 million people in the USA, is growing in incidence as the population ages, can severely impact patient quality of life, and has economic costs of more than $600 billion in the USA alone (Breivik et al., 2009; Gaskin and Richard, 2012). In response, opioid prescribing has risen rapidly for two decades, resulting in an opioid abuse and overdose crisis that claims more than 40,000 lives annually in the USA (Lozano et al., 2012; Warner et al., 2016). These twin crises highlight the vast medical and social need to develop new treatments for chronic pain that are non-opioid or mitigate the negative effects of opioid therapy. However, despite a rapid increase in our understanding of the basic science of the pain and opioid systems, this knowledge has not yet translated into new therapies (Woodcock et al., 2007; Olson et al., 2017). By identifying new targets and new approaches to treat pain, we may be able to design new therapies to efficaciously treat chronic pain without the drawbacks of current opioid therapies. This collection of novel basic science research articles titled “Novel Molecular Targets for the Treatment of Pain” is intended to stimulate research into these novel targets by the scientific community, which could then lead to the clinical development of new drugs. This collection naturally falls into several themes, the first of which is novel regulation of the mu opioid receptor (MOR), the primary target of clinical opioids like morphine (Matthes et al., 1996; Olson et al., 2019). Original research from the Briddon and Canals groups demonstrated novel molecular events for the MOR after stimulation by the high efficacy agonist DAMGO; understanding of exactly how the MOR desensitizes and internalizes could lead to new methods to manipulate this process to improve opioid therapy (Gondin et al.). Several review articles also highlighted new areas of research into MOR regulation. The Filizola group reviewed recent advances in modeling the MOR activation process using molecular dynamics simulation (Ribeiro and Filizola). The Traynor group reviewed the role of Regulator of G Protein Signaling (RGS) proteins in regulating MOR activation, including the use of novel inhibitors to produce opioid-sparing or enhancement of endogenous opioid activity (Senese et al.). Lastly, the Veldhuis group reviewed exciting recent advances in separating membrane from internalized receptor signaling, how internalized signaling contributes to pain states, and how these disparate signaling states can be targeted by location-biased drugs (Retamal et al.). The next major theme consisted of targeting other anti-nociceptive receptor systems to achieve pain relief without the side effects of MOR stimulation, particularly addiction, and respiratory depression. The Massotte group used elegant peripherally-restricted knockout of the delta opioid receptor (DOR) to demonstrate that the β2-adrenergic agonist formoterol produced efficacious anti-nociception in a neuropathic pain model via peripheral DOR (Ceredig et al.). This finding suggests that formoterol could be re-purposed from its current use as an adrenergic agonist as a novel non-opioid analgesic. The DOR has been a target of great interest for some time due to its ability to produce anti-nociception without addiction or respiratory depression, especially in inflammatory pain states. An overview of the DOR in pain and how it can be targeted in the future was written by the Gendron group, with a special emphasis on DOR intracellular trafficking, which strongly impacts receptor competency to relieve pain (Quirion et al.). The DOR has been implicated in other uses as well, such as the treatment of migraine pain (Charles and Pradhan, 2016). Another alternate receptor system of interest is the cannabinoid receptor type-1 (CB1R). The CB1R can also produce anti-nociception, and while it can have unwanted psychoactive side effects, these side effects do not rise to the severity of addiction and respiratory depression caused by opioids (Rabgay et al., 2020). The CB1R is also the main target of the phytocannabinoid Δ9-tetrahydrocannabinol from the plant Cannabis sativa, and is thus of great interest considering the growth in recreational and medicinal marijuana (Morales et al., 2017). A study in this collection from the Laprairie group found that the non-steroidal anti-inflammatory drug indomethacin acts as a positive allosteric modulator of the CB1R (Laprairie et al.). This finding establishes a new CB1R drug scaffold for the creation of novel therapeutics. The third theme of our collection is inflammatory regulation, which can contribute to both pain and the side effects of opioid drugs (Okun et al., 2011; Pan et al., 2016). Original research from the Schmidt group showed that granulocyte-colony stimulating factor (G-CSF) induced the recruitment of Ly6G positive neutrophils to the site of oral cancer, which released endogenous opioids to prevent or block oral cancer pain (Scheff et al.). This suggests that G-CSF could be used as a novel therapeutic for oral cancers. Work from the Jang-Hern Lee group showed that interleukin-1β was released in the early stages of spinal cord neuropathic pain to repress P450c17 expression and slow the development of neuropathic pain (Choi et al.), suggesting that enhancing activity of this pathway could slow or prevent the development of neuropathy. Lastly, the Laumet group provided a comprehensive review of the role of T cells in pain, including in the transition to chronic pain and resolution of pain, suggesting new ways to manipulate these cells to improve different pain states (Laumet et al.). The last...
Headache: The Journal of Head and Face Pain, Volume 58, pp 1139-1186; doi:10.1111/head.13345

Abstract:
Background Comprehensive literature reviews of historical perspectives and evidence supporting cannabis/cannabinoids in the treatment of pain, including migraine and headache, with associated neurobiological mechanisms of pain modulation have been well described. Most of the existing literature reports on the cannabinoids Δ9‐tetrahydrocannabinol (THC) and cannabidiol (CBD), or cannabis in general. There are many cannabis strains that vary widely in the composition of cannabinoids, terpenes, flavonoids, and other compounds. These components work synergistically to produce wide variations in benefits, side effects, and strain characteristics. Knowledge of the individual medicinal properties of the cannabinoids, terpenes, and flavonoids is necessary to cross‐breed strains to obtain optimal standardized synergistic compositions. This will enable targeting individual symptoms and/or diseases, including migraine, headache, and pain. Objective Review the medical literature for the use of cannabis/cannabinoids in the treatment of migraine, headache, facial pain, and other chronic pain syndromes, and for supporting evidence of a potential role in combatting the opioid epidemic. Review the medical literature involving major and minor cannabinoids, primary and secondary terpenes, and flavonoids that underlie the synergistic entourage effects of cannabis. Summarize the individual medicinal benefits of these substances, including analgesic and anti‐inflammatory properties. Conclusion There is accumulating evidence for various therapeutic benefits of cannabis/cannabinoids, especially in the treatment of pain, which may also apply to the treatment of migraine and headache. There is also supporting evidence that cannabis may assist in opioid detoxification and weaning, thus making it a potential weapon in battling the opioid epidemic. Cannabis science is a rapidly evolving medical sector and industry with increasingly regulated production standards. Further research is anticipated to optimize breeding of strain‐specific synergistic ratios of cannabinoids, terpenes, and other phytochemicals for predictable user effects, characteristics, and improved symptom and disease‐targeted therapies.
Pinja Leimuranta, , , Pinja Leimuranta, ,
Published: 24 April 2018
Frontiers in Pharmacology, Volume 9; doi:10.3389/fphar.2018.00420

Abstract:
In this mini-review, we summarize recent discoveries and present new hypotheses on the role of cannabinoids in controlling trigeminal nociceptive system underlying migraine pain. Individual sections of this review cover key aspects of this topic, such as: (i) the current knowledge on the endocannabinoid system (ECS) with emphasis on expression of its components in migraine related structures; (ii) distinguishing peripheral from central site of action of cannabinoids, (iii) proposed mechanisms of migraine pain and control of nociceptive traffic by cannabinoids at the level of meninges and in brainstem, (iv) therapeutic targeting in migraine of monoacylglycerol lipase and fatty acid amide hydrolase, enzymes which control the level of endocannabinoids; (v) dual (possibly opposing) actions of cannabinoids via anti-nociceptive CB1 and CB2 and pro-nociceptive TRPV1 receptors. We explore the cannabinoid-mediated mechanisms in the frame of the Clinical Endocannabinoid Deficiency (CECD) hypothesis, which implies reduced tone of endocannabinoids in migraine patients. We further discuss the control of cortical excitability by cannabinoids via inhibition of cortical spreading depression (CSD) underlying the migraine aura. Finally, we present our view on perspectives of Cannabis-derived (extracted or synthetized marijuana components) or novel endocannabinoid therapeutics in migraine treatment.
Headache: The Journal of Head and Face Pain, Volume 55, pp 885-916; doi:10.1111/head.12570

Abstract:
The use of cannabis, or marijuana, for medicinal purposes is deeply rooted though history, dating back to ancient times. It once held a prominent position in the history of medicine, recommended by many eminent physicians for numerous diseases, particularly headache and migraine. Through the decades, this plant has taken a fascinating journey from a legal and frequently prescribed status to illegal, driven by political and social factors rather than by science. However, with an abundance of growing support for its multitude of medicinal uses, the misguided stigma of cannabis is fading, and there has been a dramatic push for legalizing medicinal cannabis and research. Almost half of the United States has now legalized medicinal cannabis, several states have legalized recreational use, and others have legalized cannabidiol-only use, which is one of many therapeutic cannabinoids extracted from cannabis. Physicians need to be educated on the history, pharmacology, clinical indications, and proper clinical use of cannabis, as patients will inevitably inquire about it for many diseases, including chronic pain and headache disorders for which there is some intriguing supportive evidence. To review the history of medicinal cannabis use, discuss the pharmacology and physiology of the endocannabinoid system and cannabis-derived cannabinoids, perform a comprehensive literature review of the clinical uses of medicinal cannabis and cannabinoids with a focus on migraine and other headache disorders, and outline general clinical practice guidelines. The literature suggests that the medicinal use of cannabis may have a therapeutic role for a multitude of diseases, particularly chronic pain disorders including headache. Supporting literature suggests a role for medicinal cannabis and cannabinoids in several types of headache disorders including migraine and cluster headache, although it is primarily limited to case based, anecdotal, or laboratory-based scientific research. Cannabis contains an extensive number of pharmacological and biochemical compounds, of which only a minority are understood, so many potential therapeutic uses likely remain undiscovered. Cannabinoids appear to modulate and interact at many pathways inherent to migraine, triptan mechanisms ofaction, and opiate pathways, suggesting potential synergistic or similar benefits. Modulation of the endocannabinoid system through agonism or antagonism of its receptors, targeting its metabolic pathways, or combining cannabinoids with other analgesics for synergistic effects, may provide the foundation for many new classes of medications. Despite the limited evidence and research suggesting a role for cannabis and cannabinoids in some headache disorders, randomized clinical trials are lacking and necessary for confirmation and further evaluation.
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