Medical Cannabis: A Review of the History- Pharmacology- and Clinical Implications

Medical cannabis: A review of the history, pharmacology, and clinical implications

The recent resurgence of cannabis as an alternative treatment modality has been of interest to the American public, as many states in the United States have passed laws allowing for its sale and possession, in either a medical or recreational capacity.  However, debate continues around the true therapeutic potential of medical cannabis and whether these properties outweigh the possibility of long-term adverse consequences of its use (Bridgeman & Abazia, 2017; Fischer et al., 2017).  To better understand this ongoing debate, this paper will: (1) discuss the history and current status of medical cannabis in the United States, (2) describe the primary pharmacological and pharmacokinetic properties of cannabis, (3) discuss the clinical implications for medical cannabis use, and (4) identify potential adverse effects of using cannabis.

The status of cannabis in the United States: Past and present

Cannabis is one of the first plants to be used for medicinal purposes, dating as far back as 400 A.D. in Asia (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  In the United States, its medicinal use was not well-documented until the early nineteenth century (Bridgeman & Abazia, 2017; Pertwee, 2006).  In 1852, widespread medicinal cannabis use led to its inclusion in the

United States Pharmacopoeia

, officially recognizing cannabis as a therapeutic entity to be legally distributed in pharmacies throughout the country (Bridgeman & Abazia, 2017).  By the mid-twentieth century, prohibition movements and fear surrounding the psychotropic properties of cannabis contributed to the downturn of social acceptance and a decline in medicinal use (Bridgeman & Abazia, 2017). The Marihuana Tax Act of 1937 criminalized the sale and possession of cannabis in all states and led to its removal from the

United Stated Pharmacopoeia

in 1942 (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  More severe legal penalties for possession of cannabis came with the Boggs and Narcotics Control Acts of 1951 and 1956 and federal law prohibition followed under the United States Drug Enforcement Agency’s Controlled Substance Act of 1970 (Bridgeman & Abazia, 2017).  Since the passage of this Act, cannabis continues to be recognized as a Schedule I controlled substance (Bridgeman & Abazia, 2017; “State Medical Marijuana Laws,” 2019).

In 1996, with the passing of the Compassionate Use Act (Proposition 215), California began the trend toward states independently passing laws to legalize the use of botanical cannabis, first for medical purposes, and later for recreational use (Bridgeman & Abazia, 2017).  Thirty-three states, along with Washington D.C., Guam, Puerto Rico, and the U.S. Virgin Islands have passed laws legalizing cannabis in some form for medical and/or recreational use (“State Medical Marijuana Laws,” 2019). The conditions for which medical cannabis has been approved varies from state-to-state, however, the most common across medically-approved conditions are cancer, HIV/AIDS, chronic pain, anorexia and wasting syndrome, seizure disorders, spasticity associated with multiple sclerosis (MS), and posttraumatic stress disorder (PTSD) (“State Medical Marijuana Laws,” 2019).

Pharmacological properties of cannabis and cannabinoids

With over 100 different compounds, called

cannabinoids,

the cannabis plant (also referred to as “marijuana” or “marihuana”) is a complex botanical entity that possesses many psychotropic and nonpsychotropic properties (Abrams, 2017; Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; Pertwee, 2006).  In its purest form, cannabis has two main botanical segregates—

Cannabis sativa

and

Cannabis indica

—and naturally-occurring cannabinoids, called phytocannabinoids (Abrams, 2017; Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  Both varieties of cannabis contain the two most abundant phytocannabinoids, tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA) (Bridgeman & Abazia, 2017; Fasinu, Phillips, ElSohly, & Walker, 2008; Fugh-Berman et al., n.d.; Moreira & Lutz, 2008).  Through the process of decarboxylation, THCA-A and CBDA are converted from chemical compounds in the plant to bioactive compounds, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively ((Bridgeman & Abazia, 2017; Fasinu et al., 2008; Fugh-Berman et al., n.d.; Moreira & Lutz, 2008).

Phytocannabinoids: THC and CBD

THC, the primary psychoactive ingredient in cannabis, has been shown to have pleiotropic effects on the brain and body that is dependent, in part, on the quantity and quality of cannabinoids as well as the administration type (Fowler, 2015).  Research around the impact of THC on several types of animal species has also indicated neuro-protective, anti-nausea, and analgesic effects (Fugh-Berman et al., n.d.; Manzanares, Julian, & Carrascosa, 2006).

CBD is another primary compound found in the Cannabis plant that has similar therapeutic properties of THC without the psychoactive mechanisms (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; MacCallum & Russo, 2018; Manzanares et al., 2006; White, 2019).  As a modulator of the endocannabinoid system, CBD can act on multiple receptors in the body including those in the endocannabinoid system and the serotonergic system (Bridgeman & Abazia, 2017; Silote et al., 2019).  As an agonist of the serotonergic 5-HT1a receptors, CBD can produce similar properties of the neurotransmitter, serotonin, that can help in the regulation of mood, hunger, nausea, sleep, and sexual activity (Silote et al., 2019; White, 2019).  CBD is also identified as having additional pharmacological properties, including anti-inflammatory, anxiolytic, antipsychotic, as well as neuroprotective effects (Bridgeman & Abazia, 2017).

Phytocannabinoids THC and CBD rarely exist in isolation in the cannabis plant.  Depending on the variety of cannabis, qualitative characterizations of the cannabis compound can be identified based on the ratio of THC to CBD (Fugh-Berman et al., n.d.).  For example,

Cannabis sativa

is generally identified as having high levels of THC and low levels of CBD, with therapeutic functions thought to be more stimulating, energizing, and uplifting but greater potential for experiencing adverse psychoactive effects (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).

Cannabis indica

often contains lower levels of THC and higher levels of CBD, with the potential for a more relaxing and sedative experience without the psychoactive component (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  When introduced together, CBD blocks the metabolization of psychoactive THC, mitigating some possible adverse side effects, including the onset of dysphoria, anxiety, panic reactions, and paranoia (Fugh-Bergman et al., n.d.).

Endocannabinoid System

Further scientific understanding of the naturally occurring phytocannabinoids led to the discovery of endocannabinoids (eCBs) in the twentieth century, which are synthetic cannabinoids that can mimic the activity of phytocannabinoids, like THC (Fowler, 2015; Moreira & Lutz, 2008).  This finding informed understanding of the physiological impact of cannabinoids, particularly within the endocannabinoid system and at endogenous cannabinoid receptor sites (Fowler, 2015; Jarvis, Rassmussen, & Winters, 2017).  The endocannabinoid system is made up of eCBs, their endogenous cannabinoid receptors—cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2)—endogenous agonists, and agonist-metabolizing enzymes that can be found in the nervous system, internal organs, connective tissues, glands, and immune cells of the human body (Bridgeman & Abazia, 2017; Ibsen, Connor, & Glass, 2017; Jarvis et al., 2017).  ECBs are produced by their own biochemical pathways and are therefore locally synthesized in postsynaptic terminals (Ibsen et al., 2017; Jarvis et al., 2017).  They are released in particular regions to activate presynaptic cannabinoid receptors situated in specific areas of the brain that assist in the modulation of such bioactivity as pain modulation and anti-emesis (Jarvis et al., 2017; Manzanares et al., 2006).  The endocannabinoid system plays a primary role in the functioning of the human body, including hunger and energy metabolism, neural plasticity, nociception and pain, immune response, connective tissue repair, and human behavior (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; Jarvis et al., 2017).

CB1 Receptors

Cannabinoid receptors (CB1 and CB2) are G-protein coupled receptors in the cell membrane (Bridgeman & Abazia, 2017; Ibsen et al., 2018; Jarvis et al., 2017).  By binding to these receptors, primary and secondary biological effects of the cannabinoid compounds occur (Bridgeman & Abazia, 2017; Jarvis et al., 2017; Manzanares et al., 2006).   Residing primarily within the central nervous system (CNS), CB1 receptors are often associated with the regulation of neurological activity in the brain, with high densities of CB1 receptors found in the basal ganglia, cerebellum, hippocampus, prefrontal cortex, thalamus and amygdala (Abrams, 2017; Bridgeman & Abazia, 2017).  CB1 receptors also exist outside of the CNS, in areas such as the pancreas, liver, small and large intestines (Abrams, 2017; Jarvis et al., 2017).  As a result, the primary receptors of the endocannabinoid system are associated with regulation of emotion, sleep, working memory and other cognitive functions, appetite and gastric mobility, as well as in the modulation of nociceptive information at both peripheral and central levels (Bridgeman & Abazia, 2017; Jarvis et al., 2017; Manzanares et al., 2006).  CB1 receptors in the presynaptic junctions are also associated with the regulation of neurotransmission of dopamine, GABA, glutamate, epinephrine, and choline (Fasinu et al., 2016)

CB2 receptors

As with CB1 receptors, CB2 receptors are known for having analgesic properties, though important differences between the two receptors exist.  Relative to CB1, CB2 receptors are located more peripherally throughout the body (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; Ibsen et al., 2017).  Found primarily within the tissues of the immune system, including the spleen, tonsils, thymus, and bone marrow, as well as the gastrointestinal system, CB2 receptors are more well-known for their role in immune functioning and combatting inflammation in the body (Bridgeman & Abazia, 2017; Ibsen et al., 2017).  However, despite their varying functions and locations, CB1 and CB2 often work in conjunction when acted upon by the agonistic elements of the endocannabinoid system (Ibsen et al., 2017; Jarvis et al., 2017).

Endogenous cannabinoid agonists/ligands

The discovery of CB1 and CB2 receptors led to the uncovering of endogenous ligands, which are produced in the body and bind to receptors that impact cell development and function (Fowler, 2015).  The two most prominent endogenous ligands involved in the endocannabinoid system are anandamide (arachidonoylethanolamide, AEA) and 2-arachindonoylglycerol (2-AG), which are active components in the experience of pain, depression, appetite, memory, and fertility (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; Jarvis et al., 2017; Manzanares et al., 2006). The primary mechanism of action by which eCBs regulate synaptic functioning is through the process of retrograde signaling (Blessing, Steenkamp, & Manzanares, 2015).  Once released from the postsynaptic terminal, AEA interacts with presynaptic CB1 receptors to quickly and efficiently remove the ion from the synaptic cleft, which then results in hydrolyzation by the fatty-acid amide hydrolase (FAAH) enzyme (Blessing et al., 2015; Jarvis et al., 2017; Manzanares et al., 2006).  The endogenous cannabinoid 2-AG is similarly produced by binding to the cannabinoid receptors and is then inactivated through the process of catalytic hydrolysis; however, differences between AEA and 2-AG exist in the quantity and the region of brain for which biosynthesis of these molecules is controlled (Blessing et al., 2015; Jarvis et al., 2017; Manzanares et al., 2006).

Pharmacokinetics and Administration of Cannabis

The physiological effects of cannabis are dependent on the route of administration.  Cannabis is introduced into the body in several ways, with the most common routes being ingestion through smoking and vaporizing as well as through oral form, including oro-mucosal and sublingual methods (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; MacCallum & Russo, 2018).  Topical and rectal administration are other potential modes of induction into the body ((Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; MacCallum & Russo, 2018).  The formations of cannabis can be administered in a number of ways as well, including in its most natural herbal state or as a resin, as chemically-extracted concentrates in oil or wax form, through edible food, including lozenges and lollipops, and lastly through synthetic forms as prescription medications (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.; MacCallum & Russo, 2018).

Smoking Inhalation

During the smoking of cannabis, the primary psychoactive components of THC are quickly transported from the lungs to the blood (Bridgeman & Abazia, 2017; Jarvis et al., 2017).  Studies of cannabis smoke inhalation indicate the presence of THC in blood plasma approximately 90 seconds after the first inhalation of cannabis smoke (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  Once in the blood plasma, THC peaks rapidly in a matter of three to 10 minutes and is cleared in approximately three hours (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  The psychoactive effects of THC in the body often lasts about one to four hours (Fugh-Burman et al., n.d.).  Therefore, the benefits of smoking are in its efficiency and effectiveness.  In addition, the use of a water pipe to smoke has the added benefits of removing gas-phase toxicants involved in the process of smoking, such as carbon monoxide, acetaldehyde, ammonia, and nitrosamines (Fugh-Berman et al., n.d.).  However, the tar remnants from smoking can still lead to exposure to bronchial irritants and carcinogens that can be detrimental to one’s health (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).

Vaporization Inhalation

Vaporization, another form of cannabis inhalation administration, was founded in the 1970s and has grown in popularity as an alternative method to smoking (Bridgeman & Abazia, 2017).  Vaporization has been shown to be more effective in the delivery of THC when compared to smoking, particularly given the lipophilic nature of cannabis, and provides a more favorable cannabinoid-to-tar ratio than smoking (Fugh-Berman et al., n.d.).  In addition, vaporization is safer and exposes the cannabis user to less harmful byproducts or combustion that is less distressing to the respiratory system (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  However, more complicated and costly equipment is needed to administer cannabis through the process of vaporization (Fugh-Berman et al., n.d.).

Oral Ingestion

Oral cannabinoids are generally made available for administration in several forms, mainly as “edibles”, tinctures, and synthetic forms of prescription cannabinoids (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  The onset of THC through oral ingestion is often delayed, with onset of action occurring within approximately 90 minutes and peaking around one to six hours from ingestion (Bridgeman & Abazia, 2017).  However, given its slow onset, oral ingestion results in longer effects, with most doses lasting anywhere from four to 12 hours (Bridgeman & Abazia, 2017).  This route of administration can be beneficial for individuals with chronic conditions that require higher doses and lacks the pulmonary side effects that are present with methods of inhalation (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  However, delayed onset of action can make titration difficult (Bridgeman & Abazia, 2017). Given the slow rate of metabolism, larger doses may be erroneously taken, resulting in greater likelihood of experiencing and more adverse effects (Fugh-Berman et al., n.d.; Pearson, 2019).

Prescription medications made from synthetic cannabinoids are another common method of oral ingestion (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.). In the United States, FDA-approved medical cannabis options are Dronabinol (Marinol), Nabilone (Cesamet), and Cannabidiol (Exidiolex) (Fugh-Berman et al., n.d.).  Dronabinol, a THC-only product, is generally given in 2.5, 5, or 10 milligram doses and is approved for the treatment of chemotherapy-related nausea and vomiting as well as AIDS-associated anorexia (Fugh-Berman et al., n.d.).  Nabilone, another THC-only medication, is prescribed in 10 milligram doses for chemotherapy-related nausea and vomiting (Fugh-Berman et al., n.d.).  Given the absence of therapeutic CBD compounds that mediate the psychoactive properties of THC, side effects of THC-only products have been shown to include lethargy and dizziness, anxiety and paranoia, seizure risk, and depersonalization (Bridgeman & Abazia, 2017; Pearson, 2019).  Cannabidiol, though, a CBD-derived medication from the Cannabis plant and is approved for the treatment of a severe form of epilepsy, called Dravet Syndrome, and has less adverse side effects as its THC-only counterparts (Fugh-Berman et al., n.d.).

Clinical Implications of Medical Cannabis

Given more definitive findings in recent years of the varying therapeutic effects of cannabinoids, a resurgence in the use of medical cannabis for the management of specific medical conditions has been seen (Manzanares et al., 2006; White, 2019).  Reports from the National Academics of Science, Engineering, and Medicine (2017) have indicated strong findings that medical cannabis is an effective treatment for chronic pain in adults, chemotherapy-induced nausea and vomiting, and has been shown to improve patient-reported spasticity symptoms in people with MS (Fugh-Berman et al., n.d.; Jarvis et al., 2017).

Evidence of the effects of medical cannabis as a treatment modality has also been indicated in the treatment of neuropathic pain, which showed to reduce pain intensity and improve sleep (Fugh-Berman et al., n.d.; White, 2019).  Furthermore, the effects of CBD use have been expansive, with one study showing that the CBD decreased the transmigration of blood leukocytes that subsequently decreased inflammation in patients with MS, leading to improvements in MS-related motor deficits (Fugh-Berman et al., n.d.).

Adverse Effects of Cannabis Use

Despite positive findings in the treatment of medical conditions with cannabis, extensive research around adverse effects of the substance have also indicated significant findings.  Though most research has been conducted with recreational users of cannabis, given the lack of medicinal cannabis research (Bridgeman & Abazia, 2017; Pearson, 2019).  Additionally, the chemical entity of cannabis is still relatively unknown and enforcement around quality of cannabis products is lacking (Bridgeman & Abazia, 2017; Fugh-Berman et al., n.d.).  Therefore, purity, strength, and identity of cannabis compounds continues to be of main concern to many, particularly those that oppose the implementation of medical cannabis treatment (Fugh-Berman et al., n.d.).  In addition, some findings indicate that cannabis may be contaminated with harmful bacteria and pesticides (Fugh-Berman et al., n.d.).

Given the psychoactive properties of THC, evidence of psychosis and other harmful impacts of long-term chronic use has been found, particularly in the onset of schizophrenia (Fischer et al., 2017; Pearson, 2019).  Research around the onset of use of cannabis has also found that ingesting cannabis beginning in adolescence can lead to long-term and irreversible cognitive and physiological impairments, including altered brain development, poor educational outcomes, chronic bronchitis, and diminished life satisfaction (Bridgeman & Abazia, 2017; Pearson, 2019).  However, given the restrictions from the federal government, research on the costs and benefits of medical cannabis use continues to lack the empirical evidence needed to keep up with the growing public demand in order to weigh the costs and benefits associated with side effects (Bridgeman & Abazia, 2017) .

Conclusion

With a turbulent history in the United States and a federal government continuing to regulate its sale and possession, cannabis use for the treatment of medical conditions has been at the center of many political, economic, and social debates.  Made up of hundreds of compounds that can be naturally and chemically altered and manipulated, the opportunities for the use of cannabis abound.  Given the placement of cannabinoid receptors throughout the body as well as the known pharmacological effects of eCBs and phytocannabinoids, there is clear evidence of the therapeutic potential of cannabis as an analgesic, anti-inflammatory, and anti-emetic, among others (Abrams, 2017).  Though adverse effects, particularly, in long-term chronic users have been found, the potential for physician-supervised medical is expansive and requires more extensive research to uncover the full therapeutic potential of cannabis.

References

• Abrams, D. I. (2017). The therapeutic effects of
  
  Cannabis
  
  and cannabinoids: An update from the National Academies of Science, Engineering, and Medicine report.
  
  European Journal of Internal Medicine,
  
  49(2018), 7-11. doi: 10.1016/j.ejim.2018.01.003
• Blessing, E. M., Steenkamp, M. M., Manzanares, J., & Marmar, C. R. (2015). Cannabidiol as a potential treatment for anxiety disorders.
  
  Neurotherapeutics, 12
  
  (4), 825-836. doi:10.1007/s13311-015-0387-1
• Bridgeman, M. B., & Abazia, D. T. (2017). Medicinal cannabis: History, pharmacology, and implications for the acute care setting.
  
  P & T: A Peer-Reviewed Journal for Formulary Management, 42
  
  (3), 180-188.
• Moreira, F. A. & Lutz, B. (2008). The endocannabinoid system: Emotion, learning and addiction.
  
  Addiction Biology,
  
  (2), 196. doi:10.1111/j.1369-1600.2008.00104.x
• Fasinu, P. S., Phillips, S., ElSohly, M. A., & Walker, L. A. (2016). Current status and prospects for cannabidiol preparations as new therapeutic agents.
  
  Pharmacotherapy, 36
  
  (7), 781-796. doi:10.1002/phar.1780
• Fischer, B., Russell, C., Sabioni, P., van, d. B., Le Foll, B., Hall, W., . . . Room, R. (2017). Lower-risk cannabis use guidelines: A comprehensive update of evidence and recommendations.
  
  American Journal of Public Health, 107
  
  (8), e1-e12. doi:10.2105/AJPH.2017.303818
• Fowler, C.J. (2015). The potential of inhibitors of endocannabinoid metabolism as anxiolytic and antidepressive drugs—A practical view.
  
  European Neuropsychopharmacology,
  
  25, 749-762. doi: 10.1016/j.euroneuro.2015.02.005
• Fugh-Berman, A., Wood, S., Kogan, M., Abrams, D., Mathre, M. L., Robie, A., . . . D’Antonio, P. An introduction to the biochemistry and pharmacology of medical cannabis
  
  .
  
  
  Department of Health
  
  . Retrieved from
  
  https://doh.dc.gov/sites/default/files/dc/sites/doh/publication/attachments/Medical%20Cannabis%20An%20Introduction%20to%20the%20Biochemistry%20and%20Pharmacology.pdf
  
• Ibsen, M. S., Connor, M., & Glass, M. (2017).  Cannabinoid CB1 and CB2 receptor signaling and bias.
  
  Cannabis and Cannabinoid Research
  
  , 2.1, 48-60. doi: 10.1089/can.2016.0037
• Jarvis, S., Rassmussen, S., & Winters, B. (2017). Role of the endocannabinoid system and medical cannabis.
  
  The Journal for Nurse Practitioners
  
  , 13(8), 525-531. doi: 10.1016/j.nurspra.2017.05.014
• MacCallum, C. A., & Russo, E. B. (2018). Practical considerations in medical cannabis administration and dosing.
  
  European Journal of Internal Medicine, 49
  
  , 12-19. doi:10.1016/j.ejim.2018.01.004
• Manzanares, J., Julian, M. D., & Carrascosa, A. (2006). Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes.
  
  Current Neuropharmacology, 4
  
  (3), 239-257. doi:10.2174/157015906778019527
• Pearson, M. R. (2019). A meta-analytic investigation of the associations between cannabis use and cannabis-related negative consequences.
  
  Psychology of Addictive Behaviors, 33
  
  (3), 190-196. doi:10.1037/adb0000452; 10.1037/adb0000452.supp (Supplemental)
• Pertwee, R. G. (2006). Cannabinoid pharmacology: the first 66 years.
  
  British Journal of Pharmacology,
  
  147(S1), S163-S171.
• Silote, G. P., Sartim, A., Sales, A., Eskelund, A., Guimarães, F. S., Wegener, G., & Joca, S. (2019). Emerging evidence for the antidepressant effect of cannabidiol and the underlying molecular mechanisms.
  
  Journal of Chemical Neuroanatomy, 98
  
  , 104-116. doi:10.1016/j.jchemneu.2019.04.006State medical marijuana laws. (2019). Retrieved from
  
  http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
  
• State medical marijuana laws. (2019). Retrieved from
  
  http://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx
  
• White, C. M. (2019). A review of human studies assessing cannabidiol’s (CBD) therapeutic actions and potential.
  
  Journal of Clinical Pharmacology, 59
  
  (7), 923-934. doi:10.1002/jcph.1387