2020 has been quite the year for people the world over, and the US in particular. An election that has proved more divisive than any other in recent US history, racial and economic injustices that sparked protests around the world, and of course the coronavirus pandemic, which has seen many different businesses shut up shop.

Medical cannabis and telehealth, meanwhile, have been managing to keep afloat during this difficult time. In fact, it is arguable that the pandemic has prompted greater acceptance than ever, with cannabis legalization sweeping the US since November, 2020. Telehealth we can understand, as people need to be able to speak to doctors whilst maintaining social distancing. But why has medical cannabis done so well? Here’s some good reasons why:

• Telehealth opening up in a greater number of states.
• Medical cannabis being seen as an essential service, making cannabis certification and cards more sought-after.
• Many states adding anxiety as a qualifying condition.

How Medical Cannabis Helped People During the COVID-19 Pandemic

Statistics Breakdown

Leafwell, which brings together the worlds of cannabis and telehealth, has been at the forefront of this explosion. Here’s some of the key findings over the last 12 months.

• There was an astounding 1211% increase in the number of patients certified for medical cannabis online between January and December, 2020.
• 55.5% of patients were male; 44.08% female; approximately 0.4% answered “other”.
• 15.1% of patients were aged between 0 and 20.
• 47.6% of patients were aged between 21 and 40.
• 27.2% of patients were aged between 41 and 60.
• 10.1% of patients were aged 60+.
• The youngest patient was just 1 year old. The oldest, 100.
• The average age of a Leafwell patient is 38 years-old.
• The average amount of time spent in the virtual waiting room is 5.4 minutes.
• The average onboarding/registering time is a total of 19 minutes.

As for the most common qualifying conditions (taking into account that a person can suffer from more than one qualifying condition), these are:

• Chronic pain – 43.86%
• Anxiety – 40.6%
• Insomnia – 19.06%
• Post-traumatic stress disorder (PTSD) – 17.72%
• Depression – 10.43%

Less commonly chosen, but still of interest as they are symptoms that are common for several conditions, are:

• Muscle spasms – 4.48%
• Severe nausea – 3.1%

Headaches and migraines were also a commonly listed symptom people sought relief from, but are not very common qualifying conditions on their own.

Medical Marijuana and Chronic Pain

Chronic pain is the most common qualifying condition. This is likely because chronic pain is associated with pretty much every health problem. Suffering from chronic pain also increases the likelihood of suffering from anxiety, depression and insomnia. These conditions feed into one another and form a vicious cycle, making pain worse, and increasing the number of pills being prescribed.

Chronic pain is treated by several different medications, including analgesics like Tylenol/paracetamol (acetaminophen), non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, steroid-based medications such as dexamethasone, antidepressants such as duloxetine, gabapentin (nerve pain), and opioid-based drugs like hydrocodone. Opioids are addictive, and the others can have severe side-effects if too much is used or if use is long-term. Combined, they can increase the chances of overdose.

Cannabis can work for chronic pain because:

• • The cannabis plant contains many anti-inflammatory compounds, [1] including THC, CBD, linalool, myrcene and beta-caryophyllene.
  • THC and beta-caryophyllene have analgesic (painkilling) effects.
  • CBD acts as an allosteric modulator  of the mu- and delta- opioid receptors, [2] meaning it can help change the way pain signals are processed. Allosteric modulators can change the shape of receptors, meaning they process signals differently.CBD can help “turn down the volume” of pain signals.
  • CBD also “turns off” the vanilloid receptor, [3] helping reduce pain and inflammation – ibuprofen works in a similar way, but is far more dangerous if too much is taken.
  • It can be used for various kinds of pain, including neuropathic, emotional and even spiritual pain, as well as physical. This is due to cannabis’ “entourage effect” and the fact that several different receptor systems are being affected by the endocannabinoid system (ECS), whether directly or indirectly.
  • Cannabinoids may be the ideal treatment for difficult-to-treat pain, such as neuropathic (nerve) pain and pain arising from fibromyalgia.
  • There is a substantial amount of evidence suggesting that increased levels of anandamide in the body via suppressed fatty acid amide hydrolase (FAAH) inhibition can suppress pain. [4]

Medical Marijuana and Anxiety

Anxiety disorders are one of the most common forms of mental illness in the United States, affecting 40 million adults  in the US aged 18 and over, or around 19.1% of the population, every year. [5] Anxiety is often comorbid with conditions such as depression and bipolar disorder, and also plays a part in chronic pain, irritable bowel syndrome (IBS) and other inflammatory bowel diseases (IBDs) as well. PTSD is sometimes listed as an anxiety disorder as well.

Due to anxiety’s effect on serotonin receptors, selective serotonin reuptake inhibitors (SSRIs) are the most common first port-of-call. In some cases, treatment can include benzodiazepines such as lorazepam (Ativan), alprazolam (Xanax) and diazepam (Valium), but problems include addiction and inefficacy for some types of anxiety disorder.

Here’s why medical cannabis can work for treating anxiety:

• • Cannabis contains a number of anxiolytic terpenes that serve to act as stress busters. Linalool, [6] beta-caryophyllene [7] and borneol [8] are a few of them.
  • Cannabidiol (CBD) could improve regional cerebral blood flow (rCBF)  in the brain, [9] which helps reduce anxiety.
  • Pinene could possibly help prevent hyperventilation during anxiety/panic attacks, which can cause chest pains and further anxiety.
  • Beta-caryophyllene targets CB2 receptors, helping reduce anxiety. [10]
  • Low doses of THC  can help reduce anxiety, whereas high doses can prompt anxiety. [11]

Medical Marijuana and Insomnia

Approximately 30% of the population of the US suffers from some form of sleep disturbance[12], with 10% having symptoms associated with insomnia. There are two main types of insomnia: primary and secondary. Primary insomnia is insomnia that stands alone and is not related to any other health problem. Secondary insomnia occurs due to the side-effects of other conditions. Exercise-induced anxiety and insomnia is also a problem for athletes.

There are three main types of insomnia: transient insomnia, which is insomnia that lasts less than a week; acute insomnia, aka short-term insomnia, which lasts less than a month; and chronic insomnia, which is insomnia that lasts longer than a month. Those with high levels of stress hormones and drastic shifts in the body’s level of cytokines (small proteins important for cell signalling) are more likely to suffer from insomnia. These changes in hormones and levels of cytokines is one of the reasons why insomnia leads to a weakened immune system and joint pain. [13]

Cannabis can help treat insomnia because:

• Sedatives can be highly addictive, and cannabis can be a much better alternative.
• Endocannabinoids play a significant role in the regulation of the sleep-wake cycle  – phytocannabinoids may help restore a disturbed sleep-wake cycle in insomniacs. [14]
• Cannabis contains cannabinoids and terpenes that help aid sleep [15], including THC, linalool, myrcene and ocimene.
• Cannabis may reduce the amount of time it takes for a person to get to sleep. [16]

Medical Marijuana and PTSD

Approximately 5% of Americans – around 13 million people – have PTSD  at any one given time. It is estimated that approximately 8% of adults, or 1 in 13 people, in the US will develop PTSD during their lifetime. [17] PTSD leads to an increased risk of suicide and addiction to substances, and being constantly stressed may well make one more susceptible to other illnesses. Warfare, assault, rape/sexual assault, traffic collisions and threats to a person’s life are common causes of PTSD. PTSD has a genetic componentto it as well. [18]

Antidepressants – particularly of the SSRI subgroup – and counselling are the first treatments for those suffering from PTSD. However, these treatments are not always effective, and many medications like benzodiazepines may make things much worse. Whilst cannabis’s efficacy for PTSD isn’t definitively proven as of yet, many veterans  have used it to alleviate the symptoms of “shell shock“. [19] [20] There is also a solid body of evidence suggesting that cannabinoids can be used in place of sedatives. A paper produced by Steep Hill Labs suggests that using 2.5-5mg of cannabinol (CBN)  has the same results as using 5-10mg of diazepam (Valium). [21]

People suffering from PTSD have much lower levels of the endocannabinoid, anandamide (our body’s own natural THC). [22]

Cannabis can help treat PTSD because:

• CBD and caryophyllene work on CB2 receptors, helping reduce anxiety
• CBD may improve regional cerebral blood flow (rCBF) in the brain, helping reduce anxiety and increasing the amount of important hormones and nutrients moving through the brain.
• It may help keep the mind off of reliving traumatic experiences.
• THC may help restore an anandamide shortage.
• It promotes a good night’s sleep and reduces the likelihood of anxiety dreams or nightmares.

Medical Marijuana and Depression

Alongside anxiety, depression is one of the most common types of mental health conditions in the U.S., affecting just over 26% of the population.  Major depression affects around 16.1 million Americans, which is 6.7% of the population. [23] Depression may be comorbid with many other conditions, and can both be a factor in causing another mental or physical health problem, as well as a symptom of another, deeper underlying problem.

Depression is one of the most common mental health problems. However, it is often forgotten that depression is often linked to stress, which in turn is linked to pain. Indeed, one of the most common side-effects and causes of recurring physical pain is stress and depression. [24] This is perhaps not surprising – being in pain everyday is a stressful experience.

Antidepressants as they currently stand have a very high therapeutic index, and are not highly addictive. They work by increasing the levels of neurotransmitters like serotonin (selective serotonin reuptake inhibitors – SSRIs) and noradrenaline (noradrenaline and specific serotonergic antidepressants – NASSAs). The increasing levels of neurotransmitters may also disrupt pain signals,  making them a mainstay in treating chronic pain conditions. [25]

Cannabis can help treat depression because:

• Cannabinoids have antidepressant-like actions [26] due to their interaction with serotonin receptors, which could help for those who are resistant to antidepressants, and possibly even reduce or replace their usage.
• Antidepressants have side-effects such as nausea, vomiting and headaches – all of which cannabis can help alleviate.
• Cannabinoids work quicker than antidepressants, making them potentially very valuable for depressive episodes in the short-term.
• Very useful for depression arising from chronic pain.
• The cannabis plant contains a huge number of stress- and anxiety-busting terpenes, such as limonene, alpha- and beta-pinene and linalool. [27]

Medical Marijuana and Muscle Spasms

A muscle spasm is a sudden, involuntary movement in one or more muscles. They are also called muscle cramps or twitches. Muscle spasms and spasticity are caused by damage to the brain and spinal cord, causing an imbalance in the inhibitory and excitatory signals sent to the muscles.

Spasms can cause tightness, soreness and tenderness. Muscle spasms are associated with neurological conditions like multiple sclerosis (MS), Parkinson’s disease and epilepsy, where spasticity is a common symptom. Diabetes, irritable bowel diseases and kidney disease can also cause muscle spasms.

Common antispasmodic (muscle relaxing) medications include dicyclomine (Bentyl), hyoscyamine (Levsin), baclofen (Lioresal), metaxalone (Skelaxin) and cyclobenzaprine (Amrix). Common side effects include blurred vision, dizziness or drowsiness, and dry mouth. Benzodiazepine-based sedatives may also be prescribed for muscle spasms. Many antispasmodic drugs should not be used in the long-term.

Cannabis can help treat muscle spasms as:

• It returns balance to the inhibitory and excitatory signals sent to the muscles. [28]
• Reduces the pain and inflammation associated with muscle spasticity and spasms.
• Reduce neuropathic pain associated with neurological disorders and diabetes. [29]
• Allows for longer-term treatment compared to other antispasmodic drugs, on top of having fewer negative side-effects.
• CBD has anticonvulsant properties. [30]
• Terpenes like linalool, pinene and limonene, as well as THC and THCA, have relaxing effects that can soothe stiff muscles.
• For those with neurological conditions, pinene, CBD and CBC can be used to mitigate some of the negative effects THC has on short-term memory and boost focus. [31]

Medical Marijuana and Nausea/Vomiting Mitigation

Although nausea and vomiting were not often chosen as the main qualifying symptoms, this may partially be due to the fact that, as with symptoms like appetite loss, insomnia and anxiety, it is not necessarily a qualifying condition on its own. Many cancer patients, for example, could be choosing chronic pain or another qualifying condition. States sometimes list nausea only if it is “severe” or “intractable”.

Nausea is a common aspect of many conditions and illnesses, as well as medications and treatments, e.g. chemotherapy, antibiotics, colds and flus, narcotic pain medications. Common causes of nausea include low blood sugar, gastroenteritis (stomach infection), food poisoning, morning sickness in the first trimester of pregnancy, migraine, motion sickness, dizziness and fainting. Anxiety, depression and disgust (e.g. seeing or smelling something particularly nasty) may also cause nausea. There is also a rare condition known as “cyclic vomiting syndrome” (CVS), which may cause sudden, repeated attacks of nausea and vomiting.

Medications used to prevent and treat nausea are called antiemetics. The most commonly prescribed antiemetics include promethazine (a strong sedative with weak psychoactive effects), metoclopramide (Primperan, Reglan) and ondansetron (Zofran).

Dopamine (D2) receptors, serotonin (5HT3) receptors, neurokinin receptors (NK1), antihistamine, acetylcholine and TRPV1 (vanilloid) receptors all play a role in causing the sensation of nausea.

Cannabis may be useful for treating nausea / vomiting because:

• Many antiemetic medications currently prescribed have many side-effects. Cannabinoids have much fewer.
• Vanilloid receptors are responsible for heat and temperature detection – they act as the body’s thermometer. CBD and cannabidivarin (CBDV) desensitize vanilloid receptors, [32] helping beat the “overheating” associated with nausea and vomiting.
• Cannabinoids may well work for rare conditions such as CVS. [33]
• CBG, CBD, THC are a few of the cannabinoids in the cannabis plant that have antiemetic effects. Moderate doses of cannabigerol (CBG) may, however, reverse CBD’s antiemetic effects. [34]
• Cannabinoids can be very useful for the treatment of chemotherapy-induced nausea. [35]
• Cannabinoids act as selective agonists (i.e. “turn on”) of serotonin receptors, helping mitigate nausea. [36]

Medical Marijuana and Headaches / Migraines

Headaches and migraines cost the United States approximately between $13 and $17 billion per year. [37] There is not always a known cause of headache and migraine, although it is a common feature of many other ailments, and it usually involves the restriction of blood vessels in the brain, reducing the amount of oxygen received.

Pain, depression, diet, other medications, hormonal changes, stress, illnesses such as cold and flu, and environmental factors (e.g. a lack of oxygen in the air) may cause headaches and migraines. Headaches and migraines may be the result of abnormal brain activity resulting in the nerves, blood vessels and chemicals in the brain being affected.

As the precise causes of headaches/migraine are unknown, treating them – especially long-lasting, persistent ones – is a mystery as well, as they don’t always respond to standard pain relievers. Migraines in particular are difficult to treat, and the usual course of ibuprofen or paracetamol (acetaminophen) may not work.

Cannabis may prove to be an effective migraine-killer without the need to use opioids and other potentially addictive and/or dangerous non-steroidal anti-inflammatory drugs (NSAIDs). CBD could help “calm down” nerves, and its action on serotonin receptors [38] may make it particularly useful for treating headaches.

The mechanism behind the relief to migraines cannabis provides is unknown, but it could be because of an endocannabinoid deficiency and an abnormal inflammatory response. [39] Cannabis may also dilate blood vessels, allowing more oxygen to circulate around the brain.

Currently, a class of drugs known as “triptans” are used as they work by blocking proinflammatory compounds in the brain. However, triptans are expensive, have lots of side-effects such as nausea and vomiting, and insurance companies often limit the amount of triptans that can be dispensed to patients.

Cannabis may be useful for treating headaches / migraines because:

• Safer and cheaper than many drugs used to beat migraines.
• Cannabinoids may bind to areas of the brain that modulates pain transmission, which can cause migraines.
• THC and CBD may reduce serotonin release, [40] which blocks vomiting and pain in migraine sufferers. Serotonin can cause blood vessels to narrow, which can trigger a migraine.

Overall

Due to greater acceptance of medical marijuana, a better understanding of the science behind it, cannabis’ ability to reduce intake of more addictive drugs or medications (in particular alcohol, sedatives and opioids), implementation of shelter-in-place and social distancing policies, and a push towards better health during the COVID-19 pandemic, we expect 2021 to be even busier than last year. Improvements in telemedicine technology and the opening up of more medical and recreational cannabis markets will help move this trend along.

You can find out more about how medical cannabis helps with different medical conditions on our blog. Plus, sign up to our newsletter for regular updates:

Sources

[1] ‘Cannabinoids as novel anti-inflammatory drugs‘, Pragash Nagarkatti et al. Future Med Chem. Author manuscript; available in PMC 2010 Aug 1. Published in final edited form as: Future Med Chem. 2009 Oct; 1(7): 1333–1349. doi: 10.4155/fmc.09.93

[2] ‘Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors‘, Markus Kathmann et al., Naunyn Schmiedebergs Arch Pharmacol. 2006 Feb;372(5):354-61. doi: 10.1007/s00210-006-0033-x. Epub 2006 Feb 18.

[3] ‘Cannabinoids in the management of difficult to treat pain‘, Ethan B. Russo, Ther Clin Risk Manag. 2008 Feb; 4(1): 245–259. Published online 2008 Feb. doi: 10.2147/tcrm.s1928

[4] ‘Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism‘, Jason R. Clapper et al., Nat Neurosci. 2010 Oct;13(10):1265-70. doi: 10.1038/nn.2632. Epub 2010 Sep 19.

[5] National Alliance on Mental Illness (NAMI), ‘Anxiety Disorders‘

[6] ‘Linalool Odor-Induced Anxiolytic Effects in Mice‘, Hiroki Hirada et al. Front Behav Neurosci. 2018; 12: 241. Published online 2018 Oct 23. doi: 10.3389/fnbeh.2018.00241

[7] ‘β-Caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice‘, Amine Bahi et al., Physiol Behav. 2014 Aug;135:119-24. doi: 10.1016/j.physbeh.2014.06.003. Epub 2014 Jun 13.

[8] ‘Effects of cannabidiol (CBD) on regional cerebral blood flow‘, José Alexandre de Souza Crippa et al., Neuropsychopharmacology. 2004 Feb;29(2):417-26. doi: 10.1038/sj.npp.1300340.

[9] ‘Cannabis and the Anxiety of Fragmentation—A Systems Approach for Finding an Anxiolytic Cannabis Chemotype‘, Brishna S. Kamal et al., Front Neurosci. 2018; 12: 730. Published online 2018 Oct 22. doi: 10.3389/fnins.2018.00730

[10] ‘Anxious behavior induces elevated hippocampal Cb2 receptor gene expression‘, James M. Robertson et al., Neuroscience
Volume 352, 3 June 2017, Pages 273-284.

[11] ‘Low-dose THC can relieve stress; more does just the opposite‘, University of Illinois at Chicago, June 2, 2017

[12] ‘Insomnia: Definition, Prevalence, Etiology, and Consequences‘, Thomas Roth, PhD, J Clin Sleep Med. 2007 Aug 15; 3(5 Suppl): S7–S10.

[13] ‘Joint Pain + Insomnia + Depression = Doctor’s Appointment’, Michael Dolan, August 28, 2018. Everyday Health.

[14] ‘Endocannabinoids and sleep‘, Oscar Prospéro-García et al., Neurosci Biobehav Rev. 2016 Dec;71:671-679. doi: 10.1016/j.neubiorev.2016.10.005. Epub 2016 Oct 15.

[15] ‘The use of cannabinoids for sleep: A critical review on clinical trials‘, Nirushi Kuhathasan et al., Exp Clin Psychopharmacol. 2019 Aug;27(4):383-401. doi: 10.1037/pha0000285. Epub 2019 May 23.

[16] ‘Cannabis and Insomnia‘, Rolando Tringale, MD and Claudia Jensen,MD, O’Shaughanessy’s, Autumn 2011, pp. 31 – 32

[17] ‘Traumatic Stress Disorder Fact Sheet‘, Sidran Institute: Traumatic Stress Education and Advocacy

[18] ‘Large Study Reveals PTSD Has Strong Genetic Component Like Other Psychiatric Disorders‘, October 08 2019, Heather Buschman, PhD, UC San Diego Health.

[19] ‘PTSD: National Center for PTSD’, US Department of Veterans Affairs (VA)

[20] ‘What does the evidence show about cannabis for veterans with PTSD?‘, April 02 2018, written by Corinne Hodgson, DHealth, assessed for accuracy by the Directors of CMCR. Michael G. DeGroote Centre for Medicinal Cannabis Research, McMaster University

[21] ‘Beyond CBD: Exploring the Health Benefits of CBN in Cannabis‘, February 12 2019, George Mouratidis, Analytical Cannabis

[22] ‘Cannabidiol as a Therapeutic Alternative for Post-traumatic Stress Disorder: From Bench Research to Confirmation in Human Trials’, Rafael M. Bitencourt and Reinaldo N. Takahashi. Front. Neurosci., 24 July 2018 | https://doi.org/10.3389/fnins.2018.00502

[23] ‘Major Depression‘, February 2019, National Institute of Mental Health (NIMH)

[24] ‘Depression and Chronic Pain‘, October 23 2020, Jennifer Casarella, MD, WebMD

[25] ‘Antidepressants: Another weapon against chronic pain‘, September 07 2019, by the Mayo Clinic Staff, Mayo Clinic

[26] ‘Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L‘, Abir T. El-Alfy et al. Pharmacol Biochem Behav. 2010 Jun; 95(4): 434–442. Published online 2010 Mar 21. doi: 10.1016/j.pbb.2010.03.004

[27] ‘Linalool and β-pinene exert their antidepressant-like activity through the monoaminergic pathway‘, Silvia Laura Guzmán Gutiérrez et al. March 2015 Life Sciences 128(205) DOI:10.1016/j.lfs.2015.02.021

[28] ‘Cannabinoids in the management of spasticity associated with multiple sclerosis‘, Anna Maria Malfitano, Maria Chiara Proto, and Maurizio Bifulco, Neuropsychiatr Dis Treat. 2008 Oct; 4(5): 847–853. doi: 10.2147/ndt.s3208

[29] ‘More evidence cannabis can help in neuropathic pain‘, Henry J. McQuay, DM, CMAJ. 2010 Oct 5; 182(14): 1494–1495.
doi: 10.1503/cmaj.100799

[30] ‘Cannabidiol–antiepileptic drug comparisons and interactions in experimentally induced seizures in rats‘, P. Consroe and A.Wolkin, J Pharmacol Exp Ther. 1977 Apr;201(1):26-32.

[31] ‘Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects‘, Ethan B. Russo, Br J Pharmacol. 2011 Aug; 163(7): 1344–1364. doi: 10.1111/j.1476-5381.2011.01238.x

[32] ‘Nonpsychotropic Plant Cannabinoids, Cannabidivarin (CBDV) and Cannabidiol (CBD), Activate and Desensitize Transient Receptor Potential Vanilloid 1 (TRPV1) Channels in Vitro: Potential for the Treatment of Neuronal Hyperexcitability‘, Fabio Arturo Iannotti et al. July 2014 ACS Chemical Neuroscience 5(11) DOI:10.1021/cn5000524. Source: PubMed.

[33] ‘Patterns of Cannabis Use in Patients With Cyclic Vomiting Syndrome‘, Thangam Venkatesan et al. Clinical Gastroenterology and Hepatology. Volume 18, Issue 5, May 2020, Pages 1082-1090.e2. https://doi.org/10.1016/j.cgh.2019.07.039

[34] ‘Interaction between non-psychotropic cannabinoids in marihuana: effect of cannabigerol (CBG) on the anti-nausea or anti-emetic effects of cannabidiol (CBD) in rats and shrews‘, Erin M. Rock et al. Psychopharmacology (Berl) . 2011 Jun;215(3):505-12. doi: 10.1007/s00213-010-2157-4. Epub 2011 Jan 18.

[35] ‘Mechanisms of Broad-Spectrum Antiemetic Efficacy of Cannabinoids against Chemotherapy-Induced Acute and Delayed Vomiting‘, Nissar A. Darmani, Pharmaceuticals (Basel). 2010 Sep; 3(9): 2930–2955. Published online 2010 Sep 3. doi: 10.3390/ph3092930

[36] ‘Regulation of nausea and vomiting by cannabinoids‘, Linda A Parker, Erin M Rock, and Cheryl L Limebeer. Br J Pharmacol. 2011 Aug; 163(7): 1411–1422. doi: 10.1111/j.1476-5381.2010.01176.x

[37] ‘Hospital Burden of Migraine in United States Adults: A 15-year National Inpatient Sample Analysis‘, Huay-Zong Law, MD et al. Plast Reconstr Surg Glob Open. 2020 Apr; 8(4): e2790. Published online 2020 Apr 23. doi: 10.1097/GOX.0000000000002790

[38] ‘How a Migraine Happens‘, John Hopkins Medicine

[39] ‘The endocannabinoid system and migraine‘, Rosaria Greco et al. Experimental Neurology Volume 224, Issue 1, July 2010, Pages 85-91

[40] ‘Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain‘, Danilo De Gregorio et al. Pain. 2019 Jan; 160(1): 136–150. Published online 2018 Dec 28. doi: 10.1097/j.pain.0000000000001386