Cannabis 101

In recent years, cannabis has demonstrated efficacy in the treatment of a variety of sleep-related maladies, including insomnia. Unfortunately, many who use cannabis to improve sleep end-up self-medicating, using sub-optimally (even unsafely) and overspending on products. Some shouldn’t be using cannabis at all.

For these reasons, before beginning treatment we recommend you review the benefits and risks of cannabis care for sleeplessness and consult with an eo team member or your primary care doctor if you have any concerns or questions.

Sleep disorders have been treated with cannabis throughout history. Currently, there’s growing evidence for the effectiveness of cannabis in treating sleep-specific and sleep-related maladies such as insomnia, anxiety, depression, and chronic pain.[1,2]

What do the studies tell us? Each individual's sleep-relevant reactions can be different for both CBD and THC based products.[3,4] While low doses of CBD are stimulating, medium and high doses can offer heightened sensations of relaxation.[5,6] There is even early evidence that CBD may help individuals with Parkinson’s disease control deep-sleep behavior disorder.[7]

Additionally, THC can decrease the time it takes to fall asleep, though of course the specific effects of THC are often dose-dependent.[8,9] THC can be an effective sleep aid when the appropriate dose is adjusted for that particular individual.

Recently, a study tested cannabis on patients with chronic insomnia. These patients saw significantly improved sleep patterns compared to placebo, felt more rested when they woke up, and overall fatigue, stress, and social functioning improved.[11]

It’s also worth noting that unlike cannabis, many common prescription sleep medications disrupt sleep architecture and affect the REM sleep pattern. Cannabis doesn't interfere with sleep cycles if used under proper guidance, which can help patients achieve higher quality sleep.

And there’s another potential benefit of using cannabis to improve sleep: If cannabis is consumed and dosed correctly, it often reduces or even replaces the need for stronger, more addictive medications like benzodiazepines, barbiturates, and other sedatives. (Note, however, that any reduction in the use of these drugs should be done only under the close supervision of a physician, since withdrawal from sedatives can be dangerous and even fatal.)

While the research so far is promising, it’s clear that further study is needed to better understand the effects of specific cannabinoids on sleep. Current research also points to the importance of examining the impact of cannabinoid ratios, dose, timing, and route of administration in future studies since these factors can all influence outcomes.

For seniors, products that include intoxicating THC can increase the risk of falling. So it’s particularly important for older patients to start with very low doses of THC (typically no more than 2.5mg).

Also, it’s important to know that cannabis products contain chemicals such as THC and CBD that can interact with prescription medications. Those interactions can be potentially dangerous, increase or decrease prescription medication efficacy, and might cause adverse events.[12, 13]

These medications include antibiotics such as Erythromycin, cardiac medications such as Diltiazem and Verapamil, seizures medications such as Clobazam, antiviral medications such as Ritonavir, and life-saving blood-thinning medications such as Warfarin. Potential medication interactions are just one reason an expert cannabis clinician should always provide cannabis care.

The long-term use of THC has also been linked to a diminished circadian rhythm as well as daytime sleepiness, late sleep onset (particularly at high doses and over time), and psychological effects such as adverse mood alteration and memory impairment.[14, 15]

Cannabis can also cause reversible liver enzyme increases when combined with antiseizure drugs. In fact, the European Academy report found that cannabis use may lead to more frequent bronchitis if smoked on a regular basis.

Another concern is that cannabis can increase the heart rate and either raise or lower blood pressure. These effects may impact frail, older adults with balance issues, who may have an increased risk of dizziness and falling when using cannabis.18

And of course, anyone using THC/intoxicating cannabis products should refrain from driving, operating heavy machinery, or any other activities in which intoxication might pose a health or safety risk to themselves or others.

Adolescents, individuals with a history of psychotic, mood or anxiety disorders, women who are pregnant, or planning to be pregnant, and people with cardiovascular diseases should only consider cannabis care after an extensive clinical evaluation and consultation with a licensed cannabis clinician.[16]

Cannabis can help to achieve better sleep by reducing nighttime cortisol, which the body produces when stressed.[2]

Additionally, both CBD and THC can be useful in treating several conditions which might be causing a sleep disorder in the first place, such as anxiety or chronic pain. And CBD has also been shown to support sleep processes by interacting with natural adenosine pathways.

THC may also reduce rumination, promote positive memories and lower the intensity of negative experiences. When appropriately used, THC has even been shown to change how we remember dreams and can help reduce the memory of traumatic events. This can of course be particularly beneficial for those living with PTSD.[18]

Finally, CBD and THC appear to be helpful in achieving restful sleep because of the way CBD and THC interact with the endocannabinoid system (which we’ll introduce in greater depth below). Notably, endocannabinoid messenger molecule levels appear to be cyclical and correlate with the time of day, which might contribute to cannabis's effectiveness in supporting sleep and wake cycles.[17]

What is the endocannabinoid system? It’s complex—and rarely taught in medical school. But it can be helpful to think of the endocannabinoid system as one of the body’s master regulators.

Briefly stated, it’s a neuroregulatory system that keeps physiologic functions in balance or homeostasis. It plays a crucial role in inflammation, immune response, pain detection, the sleep-wake cycle, mood, memory, appetite regulation, reproduction, and fertility. It consists of three major components: naturally produced chemicals (self-made endocannabinoids acting as transmitters), the receptors those endocannabinoids bind to (located on neurons, immune cells, etc.), and the enzymes which synthesize and degrade these components.

The human body uses two naturally derived signaling molecules called endocannabinoids: anandamide (aka the bliss molecule) and 2-arachidonoylglycerol (2-AG). Endocannabinoids are structurally similar to, but distinct from, the cannabinoids found in cannabis plants, though they act on the same receptors.

Cannabinoids derived from plants are usually referred to as phytocannabinoids. These plant-based cannabinoids consist of a wide variety of active cannabinoid molecules, with nearly 150 discovered to date. The best known molecules are tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THCA), cannabidiol (CBD), cannabigerol (CBG), or cannabinol (CBN).

In addition to these 150 cannabinoids, the cannabis plant produces hundreds more organic compounds called terpenes and flavonoids. These unsaturated hydrocarbons may not activate the endocannabinoid receptors directly, but they modulate and fine-tune the functions of the activated receptors. This effect (of interaction with the receptors and molecules is known as the "entourage effect."

The second component of the endocannabinoid system is the cannabinoid receptor. The biological effects of cannabinoids are controlled by dozens of known cannabinoid receptors, the most relevant being receptors 1 and 2. Cannabinoid receptor 1 is primarily located in the brain, while cannabinoid receptor 2 is present exclusively in immune cells throughout the body. If an endocannabinoid binds to a cannabinoid receptor 1 in the brain, it may help to relieve pain. In contrast, an endocannabinoid that attaches to the cannabinoid receptor 2 in the immune system might help relieve symptoms of inflammation; it can tone down pro-inflammatory markers like cytokines and interleukin.[30]

The third component of the endocannabinoid system are enzymes, which synthesize and break down endocannabinoids. While many enzymes keep the endocannabinoid system balanced, the ones of therapeutic interest are the fatty acid amide hydrolase (FAAH) and the monoacylglycerol lipase (MAGL). The body's endocannabinoid response can be improved by modulating these enzymes for therapeutic purposes.[31] As a result, the endocannabinoid system keeps our body balanced, and cannabis can help support its natural function.

As the evidence grows, it’s increasingly clear: An ongoing partnership with a clinician is essential in order to use cannabis safely and optimally in the treatment of sleep issues.[22-27]

An eo clinician or other expert cannabis clinician with a thorough understanding of your goals, medical record, current medications, and cannabis use history should be involved in formulating initial and ongoing product recommendations, doses, and times of use.

Expert clinical oversight is essential for anyone seeking relief through cannabis. Here’s why:

Safer and more optimal pain relief through cannabis can only be achieved with a personalized care plan that factors in the symptoms and causes of your pain, relevant aspects of your medical record, your cannabis use history, other medications you’re using and your daily schedule.

A period of “test and learn” is typically necessary to arrive at the products, doses and times of use that are most right for you.

Even after achieving a regimen with which you’re satisfied, changes to your medical condition, your cannabis tolerance, daily schedule and shifting product availability all mean your care plan will need to be periodically modified over time in order to maintain high levels of safety and efficacy.

Russo, E.B., G.W. Guy, and P.J. Robson, Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers, 2007. 4(8): p. 1729-43.

Piper, B.J., et al., Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. Journal of Psychopharmacology, 2017. 31(5): p. 569-575.

Babson, K.A., J. Sottile, and D. Morabito, Cannabis, Cannabinoids, and Sleep: a Review of the Literature. Curr Psychiatry Rep, 2017. 19(4): p. 23.

Cousens, K. and A. DiMascio, (-) Delta 9 THC as an hypnotic. An experimental study of three dose levels. Psychopharmacologia, 1973. 33(4): p. 355-64.

Nicholson, A.N., et al., Effect of Delta-9-tetrahydrocannabinol and cannabidiol on nocturnal sleep and early-morning behavior in young adults. J Clin Psychopharmacol, 2004. 24(3): p. 305-13.

Zuardi, A.W., Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action. Braz J Psychiatry, 2008. 30(3): p. 271-80.

Chagas, M.H., et al., Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series. J Clin Pharm Ther, 2014. 39(5): p. 564-6.

Vaughn, L.K., et al., Endocannabinoid signalling: has it got rhythm? Br J Pharmacol, 2010. 160(3): p. 530-43.

Gorelick, D.A., et al., Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers. J Anal Toxicol, 2013. 37(1): p. 11-6.

Kuhathasan, N., et al., The use of cannabinoids for sleep: A critical review on clinical trials. Exp Clin Psychopharmacol, 2019. 27(4): p. 383-401.

Walsh, J.H., et al., Treating insomnia symptoms with medicinal cannabis: a randomized, crossover trial of the efficacy of a cannabinoid medicine compared with placebo. Sleep, 2021. 44(11).

Arellano, A.L., et al., Neuropsychiatric and General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines. CNS Neurol Disord Drug Targets, 2017. 16(5): p. 554-566.

Anderson, G.D. and L.N. Chan, Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. Clin Pharmacokinet, 2016. 55(11): p. 1353-1368.

Perron, R.R., R.L. Tyson, and G.R. Sutherland, Delta9 -tetrahydrocannabinol increases brain temperature and inverts circadian rhythms. Neuroreport, 2001. 12(17): p. 3791-4.

Dzodzomenyo, S., et al., Urine toxicology screen in multiple sleep latency test: the correlation of positive tetrahydrocannabinol, drug negative patients, and narcolepsy. J Clin Sleep Med, 2015. 11(2): p. 93-9.

Ebbert, J.O., E.L. Scharf, and R.T. Hurt, Medical Cannabis. Mayo Clin Proc, 2018. 93(12): p. 1842-1847.

Silver, R.J., The Endocannabinoid System of Animals. Animals, 2019. 9(9): p. 686.

Mock, E.D., et al., Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nature Chemical Biology, 2020. 16(6): p. 667-675.

Kesner, A.J. and D.M. Lovinger, Cannabinoids, Endocannabinoids and Sleep. Front Mol Neurosci, 2020. 13: p. 125.

Zou, S. and U. Kumar, Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci, 2018. 19(3).

Basavarajappa, B.S., Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett, 2007. 14(3): p. 237-46.

Saeed, O.B., B. Chavan, and Z.T. Haile, Association between e-cigarette use and depression in US adults. Journal of Addiction Medicine, 2020. 14(5): p. 393-400.

Reed, M.K., et al., A Failure to Guide: Patient Experiences within a State-Run Cannabis Program in Pennsylvania, United States. Subst Use Misuse, 2022. 57(4): p. 516-521.

Balu, A., et al., Medical Cannabis Certification Is Associated With Decreased Opiate Use in Patients With Chronic Pain: A Retrospective Cohort Study in Delaware. Cureus, 2021. 13(12): p. e20240.

Ware, M.A., et al., Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The Journal of Pain, 2015. 16(12): p. 1233-1242.

Asselin, A., et al., A description of self-medication with cannabis among adults with legal access to cannabis in Quebec, Canada. Journal of Cannabis Research, 2022. 4(1): p. 26.

Slawek, D., et al., Medical Cannabis for the Primary Care Physician. J Prim Care Community Health, 2019. 10: p. 2150132719884838.

Today, millions of Americans are using cannabis to reduce the symptoms of generalized anxiety disorder, social anxiety and panic disorders. Most end-up self-medicating, using sub-optimally (even unsafely) and overspending on products. Some shouldn’t be using cannabis at all.

For these reasons, before beginning treatment we recommend you review the benefits and risks of cannabis care for anxiety and consult with an eo team member or your primary care doctor if you have any concerns or questions.

The role that cannabis can play in treating anxiety is the subject of ongoing research. While there’s much more to learn, cannabis appears to have potential for minimizing the symptoms of a range of anxiety disorders: including generalized anxiety disorder (chronic anxiety, tension, and worry), panic disorder (unexpected or repeated episodes of intense fear), post-traumatic stress disorder (after being exposed to a traumatic event in which physical harm occurred or was threatened), and social anxiety disorder (overwhelming anxiety and excessive self-consciousness in everyday social situations). [1,2]

Cannabis has also shown promise in the management of anxiety caused by phobias. According to some studies, CBD enhances the effects of exposure therapy, enabling patients to dissociate certain stimuli from a fear response and cognitive behavioral therapy.[1]

Other related illnesses may benefit from cannabis treatments, too.[3] For instance, recent research suggests that cannabis may contribute to the treatment of obsessive-compulsive disorder. However, the effects were short-lived and involved low levels of THC combined with high levels of CBD.[4,5]

Cannabis can also help with complex maladies of multifactorial origin that include anxiety as a common component, such as Autism Spectrum Disorder (ASD).[6] Statistically, ASD affects one in 44 children, with boys being four times more vulnerable.[7] Traditional medication cannot address autism causatively but does target some comorbid symptoms, such as aggressive behavior or anxiety. Fortunately, evidence has been forming that CBD offers a low-side-effect alternative for patients.[8]

A 2017 ASD study assessed the safety and efficacy of CBD and found that one-third of patients reported significant improvement, and more than half reported moderate improvement in ASD symptoms.[9] International studies with parent-reported outcomes showed a more than 60% improvement in behavioral symptoms, and adverse events mainly included difficulty sleeping and reduced appetite.[8, 10, 11] Randomized placebo-controlled trials are still sparse, but more clinical investigations are underway, showing favorable preliminary results.

Overall, an increasing number of patients have reported that cannabis may be helpful as an effective treatment for anxiety disorders and can be used as a holistic alternative to prescribed medications with fewer adverse side effects. Consulting with an expert cannabis clinician who can help choose the most suitable strains and dosing regimens will help ensure the most satisfactory outcomes.

For seniors, products that include intoxicating THC can increase the risk of falling. So it’s particularly important for older patients to start with very low doses of THC (typically no more than 2.5mg).

In certain situations, and with certain products, THC use can lead to increases in anxiety, especially in people new to cannabis or those approaching cannabis alone, without an experienced support system. Some find that high THC strains cause them to become anxious or paranoid.[6] While the combination of THC and CBD seems to reduce temporary anxiety induced by THC alone, long-term impact of the effects is still a subject of sharp debate, in the medical community.[7]

In addition, it’s essential to understand that cannabis products contain compounds such as THC and CBD that can interact with prescription medications. Those interactions can be potentially dangerous, increase or decrease prescription medication efficacy, and might cause adverse events.[8,9]

These medications include antidepressants such as Zoloft (sertraline) and Paxil (paroxetine), antifungal medications such as itraconazole and ketoconazole, asthma medications such as Singulair (montelukast), and some heart medications, such as Plavix (clopidogrel). Potential medication interactions are just one reason an expert cannabis clinician should always provide cannabis care.

Some research has also shown that, heavy long-term cannabis consumption may affect the gray matter in the brain. As a result of some observational data that noted differences in the brain nerves of those consuming large amounts of cannabis over time vs those who did not, caution is typically recommended, with teenagers in particular, due to potential long-term impact, which is not yet fully understood.

It’s also good to keep in mind that, for some individuals, the ability of cannabis to ease anxiety can lead to a tendency to rely on cannabis to eliminate distress on a regular basis, which may be a risk factor for problematic overuse.

Cannabis therapy for adolescents comes with specific challenges and uncertainties. Clinical trials among young individuals under the age of 20 are rarely performed. Therefore evidence-based recommendations for treating diseases emerging at an early age, like autism spectrum disorder, are sparse. Physicians must exercise caution when recommending cannabis to young patients and their families.

And of course, anyone using THC products should refrain from driving, operating heavy machinery, or engaging in any other activities in which intoxication might pose a health or safety risk to themselves or others.

Adolescents, individuals with a history of psychotic, mood or anxiety disorders, women who are pregnant, or planning to be pregnant, and people with cardiovascular diseases should only consider cannabis care in consultation with an experienced, licensed cannabis clinician.[10]

If you’re someone who suffers from anxiety disorders, it’s best to avoid strains with a high THC content. Products which contain a higher level of CBD and a low or moderate level of THC are better for people with anxiety, as CBD is known to have anxiolytic and relaxing properties.

The endocannabinoid system is essential in limiting the impact of anxiety and can become impaired after stress exposure. In other words, a well-functioning endocannabinoid system is crucial in counter-balancing anxiety; it can soothe stress-related systems of nerves in the brain using specific messenger molecules (2-AG)[11], which are part of the brain's anxiety-managing endocannabinoid system.

These messenger molecules move along a brain path that connects an area that handles emotion to another area that helps us make decisions. As they move, they inhibit the movement of stress-related chemicals. Recent research has found that substantial stress can overwhelm the endocannabinoid system and allow anxiety-related chemicals to speed through the brain. Cannabis, in the correct dosing regimen, can help restore endocannabinoid system homeostasis and help to control stress and anxiety.

What is the endocannabinoid system? It’s complex—and rarely taught in medical school. But it can be helpful to think of the endocannabinoid system as one of the body’s master regulators.

Briefly stated, it’s a neuroregulatory system that keeps physiologic functions in balance or homeostasis. It plays a crucial role in inflammation, immune response, pain detection, the sleep-wake cycle, mood, memory, appetite regulation, reproduction, and fertility. It consists of three major components: naturally produced chemicals (self-made endocannabinoids acting as transmitters), the receptors those endocannabinoids bind to (located on neurons, immune cells, etc.), and the enzymes which synthesize and degrade these components.

The human body uses two naturally derived signaling molecules called endocannabinoids: anandamide (aka the bliss molecule) and 2-arachidonoylglycerol (2-AG). Endocannabinoids are structurally similar to, but distinct from, the cannabinoids found in cannabis plants, though they act on the same receptors.

Cannabinoids derived from plants are usually referred to as phytocannabinoids. These plant-based cannabinoids consist of a wide variety of active cannabinoid molecules, with nearly 150 discovered to date. The best known molecules are tetrahydrocannabinol (THC), tetrahydrocannabinol acid (THCA), cannabidiol (CBD), cannabigerol (CBG), or cannabinol (CBN).

In addition to these 150 cannabinoids, the cannabis plant produces hundreds more organic compounds called terpenes and flavonoids. These unsaturated hydrocarbons may not activate the endocannabinoid receptors directly, but they modulate and fine-tune the functions of the activated receptors. This effect (of interaction with the receptors and molecules is known as the "entourage effect."

The second component of the endocannabinoid system is the cannabinoid receptor. The biological effects of cannabinoids are controlled by dozens of known cannabinoid receptors, the most relevant being receptors 1 and 2. Cannabinoid receptor 1 is primarily located in the brain, while cannabinoid receptor 2 is present exclusively in immune cells throughout the body. If an endocannabinoid binds to a cannabinoid receptor 1 in the brain, it may help to relieve pain. In contrast, an endocannabinoid that attaches to the cannabinoid receptor 2 in the immune system might help relieve symptoms of inflammation; it can tone down pro-inflammatory markers like cytokines and interleukin.[30]

The third component of the endocannabinoid system are enzymes, which synthesize and break down endocannabinoids. While many enzymes keep the endocannabinoid system balanced, the ones of therapeutic interest are the fatty acid amide hydrolase (FAAH) and the monoacylglycerol lipase (MAGL). The body's endocannabinoid response can be improved by modulating these enzymes for therapeutic purposes.[31] As a result, the endocannabinoid system keeps our body balanced, and cannabis can help support its natural function.

As the evidence grows, it’s increasingly clear: An ongoing partnership with a clinician is essential in order to use cannabis safely and optimally in the treatment of anxiety.[20-25]

An eo clinician or other expert cannabis clinician with a thorough understanding of your goals, medical record, current medications, and cannabis use history should be involved in formulating initial and ongoing product recommendations, doses, and times of use.

Expert clinical oversight is essential for anyone seeking relief through cannabis. Here’s why:

Safer and more optimal pain relief through cannabis can only be achieved with a personalized care plan that factors in the symptoms and causes of your pain, relevant aspects of your medical record, your cannabis use history, other medications you’re using and your daily schedule.

A period of “test and learn” is typically necessary to arrive at the products, doses and times of use that are most right for you.

Even after achieving a regimen with which you’re satisfied, changes to your medical condition, your cannabis tolerance, daily schedule and shifting product availability all mean your care plan will need to be periodically modified over time in order to maintain high levels of safety and efficacy.

Blessing, E.M., et al., Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics, 2015. 12(4): p. 825-36.

Sachedina, F., et al., Medical cannabis use in Canada and its impact on anxiety and depression: A retrospective study. Psychiatry Research, 2022. 313: p. 114573.

Bergamaschi, M.M., et al., Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology, 2011. 36(6): p. 1219-26.

Mauzay, D., E.M. LaFrance, and C. Cuttler, Acute Effects of Cannabis on Symptoms of Obsessive-Compulsive Disorder. J Affect Disord, 2021. 279: p. 158-163.

Szejko, N., C. Fremer, and K.R. Müller-Vahl, Cannabis Improves Obsessive-Compulsive Disorder-Case Report and Review of the Literature. Front Psychiatry, 2020. 11: p. 681.

Chaste, P. and M. Leboyer, Autism risk factors: genes, environment, and gene-environment interactions. Dialogues Clin Neurosci, 2012. 14(3): p. 281-92.

CDC, https://www.cdc.gov/ncbddd/autism/data.html.

Silva, E.A.D.J., et al., Cannabis and cannabinoid use in autism spectrum disorder: a systematic review. Trends Psychiatry Psychother, 2022. 44: p. e20200149.

Bar-Lev Schleider, L., et al., Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy. Sci Rep, 2019. 9(1): p. 200.

Aran, A., et al., Brief Report: Cannabidiol-Rich Cannabis in Children with Autism Spectrum Disorder and Severe Behavioral Problems-A Retrospective Feasibility Study. J Autism Dev Disord, 2019. 49(3): p. 1284-1288.

Barchel, D., et al., Oral Cannabidiol Use in Children With Autism Spectrum Disorder to Treat Related Symptoms and Co-morbidities. Front Pharmacol, 2018. 9: p. 1521.

Crippa, J.A., et al., Cannabis and anxiety: a critical review of the evidence. Human Psychopharmacology: Clinical and Experimental, 2009. 24(7): p. 515-523.

Sarris, J., et al., Medicinal cannabis for psychiatric disorders: a clinically-focused systematic review. BMC Psychiatry, 2020. 20(1): p. 24.

Arellano, A.L., et al., Neuropsychiatric and General Interactions of Natural and Synthetic Cannabinoids with Drugs of Abuse and Medicines. CNS Neurol Disord Drug Targets, 2017. 16(5): p. 554-566.

Anderson, G.D. and L.N. Chan, Pharmacokinetic Drug Interactions with Tobacco, Cannabinoids and Smoking Cessation Products. Clin Pharmacokinet, 2016. 55(11): p. 1353-1368.

Ebbert, J.O., E.L. Scharf, and R.T. Hurt, Medical Cannabis. Mayo Clin Proc, 2018. 93(12): p. 1842-1847.

Marcus, D.J., et al., Endocannabinoid signaling collapse mediates stress-induced amygdalo-cortical strengthening. Neuron, 2020. 105(6): p. 1062-1076. e6.

Zou, S. and U. Kumar, Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System. Int J Mol Sci, 2018. 19(3).

Basavarajappa, B.S., Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett, 2007. 14(3): p. 237-46.

Saeed, O.B., B. Chavan, and Z.T. Haile, Association between e-cigarette use and depression in US adults. Journal of Addiction Medicine, 2020. 14(5): p. 393-400.

Reed, M.K., et al., A Failure to Guide: Patient Experiences within a State-Run Cannabis Program in Pennsylvania, United States. Subst Use Misuse, 2022. 57(4): p. 516-521.

Balu, A., et al., Medical Cannabis Certification Is Associated With Decreased Opiate Use in Patients With Chronic Pain: A Retrospective Cohort Study in Delaware. Cureus, 2021. 13(12): p. e20240.

Ware, M.A., et al., Cannabis for the Management of Pain: Assessment of Safety Study (COMPASS). The Journal of Pain, 2015. 16(12): p. 1233-1242.

Asselin, A., et al., A description of self-medication with cannabis among adults with legal access to cannabis in Quebec, Canada. Journal of Cannabis Research, 2022. 4(1): p. 26.

Slawek, D., et al., Medical Cannabis for the Primary Care Physician. J Prim Care Community Health, 2019. 10: p. 2150132719884838.