Cannabinoids

Cannabinoids are a class of compounds interacting with cannabinoid receptors. The 3 types of cannabinoids are phytocannabinoids (naturally derived from flora), endocannabinoids (endogenous), and synthetic cannabinoids (artificially produced). Endocannabinoids are endogenous neuropeptide neurotransmitters found in the human nervous system Nervous system The nervous system is a small and complex system that consists of an intricate network of neural cells (or neurons) and even more glial cells (for support and insulation). It is divided according to its anatomical components as well as its functional characteristics. The brain and spinal cord are referred to as the central nervous system, and the branches of nerves from these structures are referred to as the peripheral nervous system. General Structure of the Nervous System. Cannabinoids have a psychotropic effect, which leads to frequent recreational use, but the unique effects of cannabinoids on the CNS also provide pharmacological indications. Prescription cannabinoids treat pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, nausea, vomiting, and seizure disorders and also serve as appetite stimulants Stimulants Stimulants are used by the general public to increase alertness and energy, decrease fatigue, and promote mental focus. Stimulants have medical uses for individuals with ADHD and sleep disorders, and are also used in combination with analgesics in pain management. Stimulants.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Chemistry and Pharmacodynamics

Chemistry

Tetrahydrocannabinol (THC) is the psychoactive component of cannabis:

  • THC is a lipid.
  • Aromatic terpenoid (modified terpene with a removed methyl group or added oxygen atom)
Structure of thc

The structure of tetrahydrocannabinol (THC): the psychoactive component of cannabis

Image: “THC” by Harbin. License: Public Domain

Mechanism of action

  • Cannabinoid receptors are metabotropic (G-protein coupled) and act through secondary messengers to elicit cellular responses.
  • Cannabinoids bind and activate cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2):
    • CB1 receptors: regulate glutamate and GABA neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission (located in CNS and peripheral tissues)
    • CB1 receptors: most widely expressed Gαi-protein coupled receptor in the brain:
      • Gαi → α subunit of G protein inhibits adenylyl cyclase
      • ꞵ and ? subunits released from Gαi: activate K+ channels, inhibit Ca2+ channels 
    • CB2 receptors: regulate pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and emesis (located in immune cells) 
    • CB receptor activation causes ↓ neurotransmitter release through the following mechanisms:
      • Inhibition of presynaptic adenylyl cyclase → inactivation of presynaptic protein kinase A (PKA) 
      • Activation of presynaptic mitogen-activated protein kinase (MAPK)
      • Inhibition of presynaptic voltage-gated Ca2+ channels → ↓ Ca2+ influx
      • Activation of presynaptic inward-rectifier K+ channels → ↑ K+ efflux 

Tetrahydrocannabinol (THC)

  • Presynaptic CB1 agonism 
  • THC prolongs activation of CB1 receptors causing continuous inhibition of neurotransmitter release from GABAergic and glutamatergic presynaptic nerve terminals expressing CB1 receptors: 
    • THC does not mimic the effects of locally released endocannabinoids (e.g., anandamide, 2-arachidonoylglycerol (2-AG)).
    • THC does not induce anandamide and 2-AG synthesis.
  • THC binds to CB1 receptors on inhibitory GABAergic interneurons in the VTA (ventricular tegmental area), causing decreased GABA release and disinhibition of dopaminergic neurons → ↑ dopamine 

Physiologic effects

Cannabinoids bind to peripheral and central receptors:

  • Peripheral receptor activation leads to: 
    • Dry mouth
    • Tachycardia 
    • Hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension 
    • Decreased respiratory effort 
  • Cannabinoids bind to CB receptors in various areas of the CNS causing:
    • Hippocampus: impairment of short-term memory
    • Neocortex: impairment of judgement and changes in sensation
    • Hypothalamus Hypothalamus The hypothalamus is a collection of various nuclei within the diencephalon in the center of the brain. The hypothalamus plays a vital role in endocrine regulation as the primary regulator of the pituitary gland, and it is the major point of integration between the central nervous and endocrine systems. Hypothalamus: increase in appetite
    • Amygdala: paranoia 
    • Brainstem: antiemetic effect
    • Spinal cord: analgesic effect
Cannabinoids form a connection with cannabinoid receptors

Cannabinoids form a connection with cannabinoid receptors:
Neurotransmitters (including dopamine) flood into the synaptic cleft, causing calcium to be pumped into the postsynaptic neuron at higher levels than observed in healthy natural stimuli. The higher amount of neurotransmitters gives the “high” associated with cannabis. Acting through cannabinoid receptors, THC activates the reward system of the brain. Tetrahydrocannabinol also disrupts functioning of the cerebellum Cerebellum The cerebellum, Latin for "little brain," is located in the posterior cranial fossa, dorsal to the pons and midbrain, and its principal role is in the coordination of movements. The cerebellum consists of 3 lobes on either side of its 2 hemispheres and is connected in the middle by the vermis. Cerebellum and basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia, which regulate balance, posture, coordination, and reaction time.
The 1st diagram shows normal activity and the 2nd diagram shows activity with the addition of THC.
A: THC
B: CB1 receptors
C: neurotransmitters
D: postsynaptic receptors
E: cannabinoid

Image by Lecturio.

Pharmacokinetics

Absorption

  • Cannabinoid kinetics differ based on the route of administration and formulation.
  • Kinetics vary for cannabinoids not approved by the FDA (e.g., smoking cannabis, edible cannabis): 
    • Oral administration: 
      • Delayed onset (30–90 minutes) 
      • Low bioavailability due to 1st-pass hepatic metabolism/elimination 
    • Aerosolization: Smoked cannabis is absorbed within seconds.

Metabolism

  • Metabolized in the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
  • Some cannabinoid is stored in fatty tissue.
  • Often metabolized by the cytochrome P450 system (particularly CYP2C9):
    • CYP2C9 inhibitors prevent metabolism.
    • CYP2C9 inhibitor use leads to prolonged intoxication.
  • Hydrocarbons produced from combustion of marijuana inhibit CYP1A2.
  • Dronabinol is heavily bound to plasma proteins (may affect other protein-bound drugs).
  • THC is a substrate of CYP2C9 and CYP3A4.
  • Cannabidiol (CBD) is a substrate of CYP2C19 and CYP3A4.
  • Drugs metabolized by CYP1A2 are more quickly metabolized after consumption of cannabinoids (e.g., olanzapine).

Excretion

  • Cannabinoids are excreted in the feces and urine.
  • Cannabinoids are excreted after hydroxylation and carboxylation.
  • The majority of cannabinoids are excreted after 5 days of consumption.

Drug interactions

Additional potential drug interactions with cannabinoids include: 

  • Warfarin: increased risk of bleeding
  • Clobazam: increased risk of benzodiazepine toxicity
  • Depressant medications: excessive sedation, depression

Classification

  • 3 forms of cannabinoids:
    • Phytocannabinoids: naturally derived
      • THC
      • CBD
    • Endocannabinoids: endogenous
    • Synthetic cannabinoids: artificial
  • FDA-approved cannabinoid medications: 
    • Synthetic THC products in oral capsules and oral solutions: 
      • Dronabinol 
      • Nabilone
    • CBD extract product (oral solution): cannabidiol 
  • Legal considerations:
    • Marijuana and cannabinoid are classified as Schedule I controlled substances by the United States FDA and the United States Drug Enforcement Administration (DEA).
    • Recreational and medical marijuana regulations differ between state and federal laws.
    • Many states have legalized or decriminalized marijuana.
Table: Prescription cannabinoid formulations and indications
Drug Notes on formulations Indications
Dronabinol:
  • Oral capsule Marinol®
  • Oral solution Syndros®
  • Marinol® contains sesame oil (solvent) → impedes extraction and purification of tetrahydrocannabinol (THC) for abuse
  • Syndros® contains 50% ethanol.
  • Cachexia in individuals with AIDS
  • Refractory chemotherapy-induced nausea and vomiting (CINV)
  • The American Society of Clinical Oncology (ASCO) recommends dronabinol or nabilone over medical marijuana.
Nabilone: oral capsule Cesamet® /
  • Refractory CINV
  • ASCO recommends dronabinol or nabilone over medical marijuana.
Cannabidiol: oral solution Epidiolex®
  • Possible to chemically convert cannabidiol (CBD) to THC
  • Epidiolex® solution contains sesame oil (solvent) → impedes extraction and purification of CBD to THC
Refractory childhood-onset seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures in individuals ≥ 2 years of age due to:
  • Dravet syndrome
  • Lennox-Gastaut syndrome

Methods of ingestion

  • Pills and capsules
  • Hash oils
  • Gums
  • Dabbing
  • Pens
  • Tetrahydrocannabinolic acid (THCA) crystals
  • Bongs
  • Vapes
  • Canna oils
  • Bowls/bubblers
  • Sprays
  • THC soda
  • Joints/blunts
  • Drinks
  • Syrups
  • Tinctures
  • Creams
  • Bath soaks
  • Edibles
  • Patches
  • Decarb
  • Sols/butters

Indications

  • Medical marijuana in the United States is mainly authorized to treat:
    • Anxiety
    • Spasticity in amyotrophic lateral sclerosis Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a sporadic or inherited neurodegenerative disease of upper motor neurons (UMNs) and lower motor neurons (LMNs). ALS is the most common progressive motor neuron disease in North America, primarily affecting men and individuals of Caucasian ethnicity. Amyotrophic Lateral Sclerosis (Lou Gehrig disease) and multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis
    • Chronic pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain/cancer pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Cachexia or wasting syndromes (e.g., HIV/AIDS, cancer)
    • Inflammatory bowel disease 
    • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia 
    • Nausea 
    • Parkinson disease
    • Posttraumatic stress disorder Posttraumatic Stress Disorder Posttraumatic stress disorder is a psychiatric illness characterized by overwhelming stress and anxiety experienced after exposure to a life-threatening event. Symptoms last more than 1 month and involve re-experiencing the event as flashbacks or nightmares, avoiding reminders of the event, irritability, hyperarousal, and poor memory and concentration. Posttraumatic Stress Disorder (PTSD)
    • Seizure disorders
    • Pain palliation in terminal illness 
  • Various cannabinoid medications with specific indications:
    • Nabiximol: pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain related to multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis and cancer
    • Dronabinol (Marinol):
      • Poor appetite
      • Sleep apnea
      • Anorexia caused by HIV/AIDS
      • Chemotherapy induced nausea and vomiting
    • Epidiolex®: epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy syndromes (Dravet syndrome, Lennox-Gastaut syndrome)

Adverse Effects and Contraindications

Adverse effects

THC (Dronabinol and Nabilone):

  • CNS:
    • ↑ Appetite
    • Dizziness 
    • Headache
    • Euphoria 
    • Impaired concentration 
    • Somnolence
    • Increased pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain sensation
    • Ataxia
    • Depersonalization
  • GI:
    • Nausea 
    • Vomiting
    • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain

Cannabidiol (Epidiolex®):

  • CNS: 
    • ↓ Appetite 
    • Fatigue
    • Lethargy, sedation
  • GI:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea 
    • Vomiting 
  • Hepatic/metabolic: ↑ liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes

Cannabinoid hyperemesis syndrome (CHS)

  • Cyclic vomiting syndrome due to cannabis use 
  • Symptoms include nausea, vomiting, and abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain occurring on a cyclic basis in the setting of routine cannabis/marijuana use.
  • Seen in individuals using cannabis on a weekly basis for at least 1 year 
  • Pathophysiology unclear
  • Individuals compulsively take hot showers/baths to help relieve symptoms: 
    • Substance P is speculated to be involved in the pathophysiology.
    • Topical capsaicin cream depletes substance P after repeated application to skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and is shown to alleviate symptoms.
  • Nausea and vomiting treatment: 
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines (lorazepam) or haloperidol appear more efficacious than conventional antiemetics Antiemetics Antiemetics are medications used to treat and/or prevent nausea and vomiting. These drugs act on different target receptors. The main classes include benzodiazepines, corticosteroids, atypical antipsychotics, cannabinoids, and antagonists of the following receptors: serotonin, dopamine, and muscarinic and neurokinin receptors. Antiemetics (e.g., ondansetron, metoclopramide).
    • Do not use opioids Opioids Opiates are drugs that are derived from the sap of the opium poppy. Opiates have been used since antiquity for the relief of acute severe pain. Opioids are synthetic opiates with properties that are substantially similar to those of opiates. Opioid Analgesics.
  • Cessation of cannabis is required to completely resolve the syndrome (may take weeks).
Phases of cannabinoid hyperemesis syndrome

Phases of cannabinoid hyperemesis syndrome (CHS)

Image by Lecturio.

Contraindications and drug interactions

Table: Contraindications and drug interactions of cannabinoids
Drugs Warnings Contraindications Drug interactions
Dronabinol
  • Cardiovascular:
    • Syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
    • Tachycardia
  • CNS:
    • Altered perception
    • Exacerbated mania
    • Exacerbated schizophrenia Schizophrenia Schizophrenia is a chronic mental health disorder characterized by the presence of psychotic symptoms such as delusions or hallucinations. The signs and symptoms of schizophrenia are traditionally separated into 2 groups: positive (delusions, hallucinations, and disorganized speech or behavior) and negative (flat affect, avolition, anhedonia, poor attention, and alogia). Schizophrenia
    • Paranoia
    • Unmasked psychosis
  • GI:
    • Cannabinoid hyperemesis syndrome (CHS)
    • Severe nausea, vomiting
  • Pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care and lactation: not recommended for women who are pregnant, breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding, or planning to become pregnant as cannabinoids cross the placenta Placenta The placenta consists of a fetal side and a maternal side, and it provides a vascular communication between the mother and the fetus. This communication allows the mother to provide nutrients to the fetus and allows for removal of waste products from fetal blood. Placenta, Umbilical Cord, and Amniotic Cavity
  • General:
    • Disorder of alcohol
    • Hypersensitivity to alcohol
    • Disorder of substance abuse
  • Dronabinol capsule: allergic to sesame seed oil
  • Dronabinol oral solution: current or recent (within 14 days) therapy with products containing disulfiram or metronidazole
  • Dronabinol may displace other highly protein-bound drugs → ↑ adverse effects (e.g., cyclosporine, warfarin)
  • CNS depressants:
    • Alcohol
    • Anticholinergics
    • Efavirenz
    • Hypnotics
    • Opioids
    • Sedatives (e.g., benzodiazepines, barbiturates)
  • CYP2C9 inhibitors (may need to ↓ THC dose)
  • CYP2C9 inducers (may need to ↑ THC dose)
  • CYP3A4 inhibitors (may need to ↓ THC dose)
  • CYP3A4 inducers (may need to ↑ THC dose)
Nabilone /
  • Disorder of alcohol use
  • Disorder of substance abuse
CNS depressants
Cannabidiol (CBD) (Epidiolex®)
  • CNS: sedation, somnolence (diminishes with continued use)
  • ↑ Hepatotoxicity risk with:
    • Valproic acid
    • Clobazam
    • Hepatotoxic drugs
Allergic to sesame seed oil
  • CNS depressants
  • CYP3A4 inhibitors (can ↑ CBD levels)
  • CYP3A4 inducers (can ↓ CBD levels)
  • CYP2C19 inhibitors (may need to ↓ CBD dose)
  • CYP2C19 inducers (may need to ↑ CBD dose)

References

  1. Fryer, A.D., Christopoulos, A., Nathanson, N.M. (Eds.) (2012). Muscarinic Receptors. Handbook of Experimental Pharmacology, vol 208. Springer: Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-23274-9 
  2. Curry, S.C., et al. (2019). Neurotransmitters and Neuromodulators. In Nelson, L.S., et al. (Eds.), Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill.
  3. Lapoint, J.M. (2019). Cannabinoids. In Nelson, L.S., et al. (Eds.), Goldfrank’s Toxicologic Emergencies, 11e. New York, NY: McGraw-Hill.
  4. Gray, R.A., Whalley, B.J. (2020). The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord. 22(S1), 10–15. https://pubmed.ncbi.nlm.nih.gov/32053110/
  5. Schmitz, N., Richert, L. (2020). Pharmacists and the future of cannabis medicine. J Am Pharm Assoc. 60(1), 207–211. https://doi.org/10.1016/j.japh.2019.11.007 
  6. Hesketh, P.J., et al. (2017). Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 35, 3240–3261. https://doi.org/10.1200/JCO.2017.74.4789 
  7. Federation of State Medical Boards. (2016). Model guidelines for the Recommendation of Marijuana in Patient Care. https://www.fsmb.org/Media/Default/PDF/BRD_RPT_16-2_Marijuana_Model_Guidelines.pdf 
  8. The Marijuana Policy Project. (2020). Marijuana Policy Reform Legislation. https://www.mpp.org/issues/legislation/key-marijuana-policy-reform/ 
  9. Morano, A., et al. (2020). Cannabinoids in the Treatment of Epilepsy: Current Status and Future Prospects. Neuropsychiatr Dis Treat. 16, 381–396. https://doi.org/10.2147/ndt.s203782 
  10. Devinsky, O., et al. (2017). Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 376, 2011–2020. https://doi.org/10.1056/NEJMoa1611618 
  11. Lapoint, J., et al. (2018). Cannabinoid Hyperemesis Syndrome: Public Health Implications and a Novel Model Treatment Guideline. West J Emerg Med. 19(2), 380–386. https://doi.org/10.5811/westjem.2017.11.36368 
  12. Bahji, A., et al. (2020). Prevalence of Cannabis Withdrawal Symptoms Among People With Regular or Dependent Use of Cannabinoids: a systematic review and meta-analysis. JAMA Netw Open. 3(4), e202370. https://doi.org/10.1001/jamanetworkopen.2020.2370 
  13. McCracken, J.L., et al. (2017). Diagnosis and Management of Asthma in Adults: A Review. JAMA. 318(3), 279–290. https://doi.org/10.1001/jama.2017.8372 
  14. Mehta, G.R., et al. (2016). Chronic obstructive pulmonary disease: A guide for the primary care physician. Dis Mon. 62(6), 164–187. https://doi.org/10.1016/j.disamonth.2016.03.002

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