User login
CASE
Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.
As Mr. S’s physician, how do you respond?
Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.1 Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,2 leading to legalization in most of the United States.
As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.
The pharmacology of cannabis
Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.3 Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.4
The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.5
Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.
The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB1 and CB2, found throughout the body: CB1, predominantly in the central and peripheral nervous system, and CB2 in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB1 and CB2.
[polldaddy:10402702]
Continue to: Botanical or synthetic?
Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.
Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used
A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.8
Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.4
Physiologic effects. THC is a partial agonist of CB1 and CB2 receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB1 receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.7 THC exerts its psychotropic effects at CB1 sites in the central nervous system; CBD can antagonize these THC effects at CB1 receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB2 receptors.9
Continue to: THC has tremendously...
THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.
Clinical implications and indications
Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:
- For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
- What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?
Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.10 The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.
Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.
There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).
Continue to: The primary conclusion...
The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.
HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:
- In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.11
- In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.10
Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.9 In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.
CASE
Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB1 and CB2 as potential targets for antiemetic treatment.
Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.
Continue to: Based on recent observational data...
Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.
A legal system at oddsover the status of medical Cannabis
The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.
At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).12 The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.13 Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I14; ie, the substance
- has high potential for abuse,
- has no accepted therapeutic medical use in the United States, and
- lacks acceptable safety for use under medical supervision.
Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.15
In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”15
Continue to: The bill was referred to the Senate...
The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.
On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.16,17
At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures18 (www.ncsl.org) designates a program “comprehensive” if it
- includes protection from criminal penalties for using marijuana for a medical purpose,
- allows access to marijuana through home cultivation, dispensaries, or other system,
- permits a variety of strains, including those more potent than what is labeled “low-THC,” and
- allows smoking or vaporization of marijuana products, plant-based material, or extract.
An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.18
Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.
Continue to: Physician shield
Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.19 In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.
CASE
Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.
How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.
Common concerns
Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,18 and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).20
Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.21
Continue to: Large cross-sectional...
Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.
“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.
Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.24 Although patients often report the use of medical Cannabis to treat anxiety,25 panic attacks are often associated with Cannabis use.26
While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.27
We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.
Continue to: Overconsumption of edibles
Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.28
Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).29 These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.30
CASE
Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.
How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.30
Cannabis use disorder in the context of medical marijuana
Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.31 Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.31 Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.
Continue to: A recent study...
A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.32 Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.32
A paucity of pediatric data
The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.
The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.33 The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.34
Recognized risk: Not supporting medical Cannabis
As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:
Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.35
Continue to: Limiting patients to other medications
Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.36
Resigning patients to obtain Cannabis from an illegal source. This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:
- Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.37
- Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.38
CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; Lara.weinstein@jefferson.edu.
1. College of Family Physicians of Canada. Authorizing Dried Cannabis for Chronic Pain or Anxiety: Preliminary Guidance from the College of Family Physicians of Canada. Mississauga, Ontario: College of Family Physicians of Canada; 2014. www.cfpc.ca/uploadedFiles/Resources/_PDFs/Authorizing%20Dried%20Cannabis%20for%20Chronic%20Pain%20or%20Anxiety.pdf. Accessed July 10, 2019.
2. Hartig H, Geiger AW. About six-in-ten Americans support marijuana legalization. Pew Research Center Web site. www.pewresearch.org/fact-tank/2018/10/08/americans-support-marijuana-legalization/. Published October 8, 2018. Accessed July 10, 2019.
3. Li H-L. An archaeological and historical account of cannabis in China. Econ Bot. 1974:28:437-448.
4. Zuardi AW. History of cannabis as a medicine: a review. Braz J Psychiatry. 2006;28:153-157.
5. Marijuana strains and infused products. Leafly Web site. www.leafly.com/start-exploring. Accessed July 10, 2019.
6. Fraguas-Sánchez AI, Torres-Suárez AI. Medical use of cannabinoids. Drugs. 2018;78:1665-1703.
7. Maurya N, Velmurugan BK. Therapeutic applications of cannabinoids. Chem Biol Interact. 2018;293:77-88.
8. Kelkar AH, Smith NA, Martial A, et al. An outbreak of synthetic cannabinoid-associated coagulopathy in Illinois. N Engl J Med. 2018;379:1216-1223.
9. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215.
10. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456-2473.
11. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2008;34:672-680.
12. US Department of Justice, Drug Enforcement Administration, Diversion Control Division. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I—Control and Enforcement. Part A—Introductory Provisions. §801. Congressional findings and declarations: controlled substances. www.deadiversion.usdoj.gov/21cfr/21usc/801.htm. Accessed July 10, 2019.
13. Yeh BT. The Controlled Substances Act: regulatory requirements. Congressional Research Service 7-5700. https://fas.org/sgp/crs/misc/RL34635.pdf. Published December 13, 2012. Accessed July 10, 2019.
14. US Department of Justice, Drug Enforcement Administration, Diversion Control Division. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I—Control and Enforcement. Part B—Authority to Control; Standards and Schedules. §812. Schedules of controlled substances. www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. Accessed July 10, 2019.
15. United States Senate. The STATES Act. Senator Elizabeth Warren and Senator Cory Gardner. 2018. www.warren.senate.gov/imo/media/doc/STATES%20Act%20One%20Pager.pdf. Accessed July 10, 2019.
16. Strengthening the Tenth Amendment Through Entrusting States (STATES) Act of 2019, HR 2093. 116th Cong, 1st Session (2019). www.congress.gov/bill/116th-congress/house-bill/2093/text. Accessed July 20, 2019.
17. Strengthening the Tenth Amendment Through Entrusting States (STATES) Act of 2019, S 1028. 116th Cong, 1st Session (2019). www.congress.gov/bill/116th-congress/senate-bill/1028/all-info?r=3&s=6. Accessed August 8, 2019.
18. State medical marijuana laws. National Conference of State Legislatures Web site. www.ncsl.org/research/health/state-medical-marijuana-laws.aspx#3. Published July 2, 2019. Accessed July 10, 2019.
19. Conant v Walters. 309 F.3d 629 (9th cir. 2002).
20. American Society of Addiction Medicine. The role of the physician in “medical” marijuana. www.asam.org/docs/publicy-policy-statements/1role_of_phys_in_med_mj_9-10.pdf?sfvrsn=0. Published September 2010. Accessed July 12, 2019.
21. What are marijuana’s effects on lung health? National Institute on Drug Abuse Web site. www.drugabuse.gov/publications/research-reports/marijuana/what-are-marijuanas-effects-lung-health. Updated July 2019. Accessed July 10, 2019.
22. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10:239-247.
23. Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium. Int J Cancer. 2015;136:894-903.
24. Getting medical marijuana. Commonwealth of Pennsylvania Web site. www.pa.gov/guides/pennsylvania-medical-marijuana-program/. Accessed July 20, 2019.
25. Kosiba JD, Maisto SA, Ditre JW. Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: systematic review and meta-analysis. Soc Sci Med. 2019;233:181-192.
26. Crippa JA, Zuardi AW, Martín-Santos R, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24:515-523.
27. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319-328.
28. Barrus DG, Capogrossi KL, Cates S, et al. Tasty THC: Promises and Challenges of Cannabis Edibles. Publication No. OP-0035-1611. Research Triangle Park, NC: RTI Press; 2016. www.rti.org/sites/default/files/resources/rti-publication-file-6ff047d7-3fa4-41ad-90ed-9fb11663bc89.pdf. Accessed July 10, 2019.
29. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12-19.
30. MacCoun RJ, Mello MM. Half-baked—the retail promotion of marijuana edibles. N Engl J Med. 2015;372:989-991.
31. Cannabis use disorder [305.20, 304.30]. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington, DC: American Psychiatric Association; 2013:509-516.
32. Williams AR, Santaella-Tenorio J, Mauro CM, et al. Loose regulation of medical marijuana programs associated with higher rates of adult marijuana use but not cannabis use disorder. Addiction. 2017;112:1985-1991.
33. American Academy of Pediatrics Committee on Substance Abuse, American Academy of Pediatrics Committee on Adolescents. The impact of marijuana policies on youth: clinical, research, and legal update. Pediatrics. 2015;135:584-587.
34. Wong SS, Wilens TE. Medical cannabinoids in children and adolescents: a systematic review. Pediatrics. 2017;140. pii: e20171818.
35. Drug Enforcement Administration. Drugs of abuse: a DEA resource guide. www.dea.gov/sites/default/files/drug_of_abuse.pdf. Published 2017. Accessed July 10, 2019.
36. National Academies of Science, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press; 2017. www.nap.edu/read/24625/chapter/12017:2017-2019. Published 2017. Accessed July 10, 2019.
37. Emerging trend and alerts. National Institute on Drug Abuse Web site. www.drugabuse.gov/drugs-abuse/emerging-trends-alerts. Accessed July 10, 2019.
38. Drug Policy Alliance. From prohibition to progress: a status report on marijuana legalization. www.drugpolicy.org/sites/default/files/dpa_marijuana_legalization_report_feb14_2018_0.pdf. Published January 2018. Accessed July 10, 2019.
CASE
Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.
As Mr. S’s physician, how do you respond?
Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.1 Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,2 leading to legalization in most of the United States.
As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.
The pharmacology of cannabis
Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.3 Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.4
The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.5
Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.
The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB1 and CB2, found throughout the body: CB1, predominantly in the central and peripheral nervous system, and CB2 in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB1 and CB2.
[polldaddy:10402702]
Continue to: Botanical or synthetic?
Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.
Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used
A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.8
Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.4
Physiologic effects. THC is a partial agonist of CB1 and CB2 receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB1 receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.7 THC exerts its psychotropic effects at CB1 sites in the central nervous system; CBD can antagonize these THC effects at CB1 receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB2 receptors.9
Continue to: THC has tremendously...
THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.
Clinical implications and indications
Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:
- For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
- What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?
Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.10 The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.
Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.
There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).
Continue to: The primary conclusion...
The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.
HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:
- In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.11
- In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.10
Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.9 In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.
CASE
Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB1 and CB2 as potential targets for antiemetic treatment.
Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.
Continue to: Based on recent observational data...
Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.
A legal system at oddsover the status of medical Cannabis
The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.
At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).12 The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.13 Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I14; ie, the substance
- has high potential for abuse,
- has no accepted therapeutic medical use in the United States, and
- lacks acceptable safety for use under medical supervision.
Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.15
In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”15
Continue to: The bill was referred to the Senate...
The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.
On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.16,17
At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures18 (www.ncsl.org) designates a program “comprehensive” if it
- includes protection from criminal penalties for using marijuana for a medical purpose,
- allows access to marijuana through home cultivation, dispensaries, or other system,
- permits a variety of strains, including those more potent than what is labeled “low-THC,” and
- allows smoking or vaporization of marijuana products, plant-based material, or extract.
An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.18
Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.
Continue to: Physician shield
Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.19 In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.
CASE
Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.
How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.
Common concerns
Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,18 and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).20
Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.21
Continue to: Large cross-sectional...
Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.
“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.
Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.24 Although patients often report the use of medical Cannabis to treat anxiety,25 panic attacks are often associated with Cannabis use.26
While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.27
We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.
Continue to: Overconsumption of edibles
Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.28
Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).29 These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.30
CASE
Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.
How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.30
Cannabis use disorder in the context of medical marijuana
Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.31 Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.31 Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.
Continue to: A recent study...
A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.32 Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.32
A paucity of pediatric data
The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.
The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.33 The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.34
Recognized risk: Not supporting medical Cannabis
As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:
Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.35
Continue to: Limiting patients to other medications
Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.36
Resigning patients to obtain Cannabis from an illegal source. This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:
- Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.37
- Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.38
CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; Lara.weinstein@jefferson.edu.
CASE
Barry S, a 45-year-old man with a new diagnosis of non-Hodgkin’s lymphoma, recently started induction chemotherapy. He has struggled with nausea, profound gustatory changes, and poor appetite; various antiemetics have provided only minimal relief. He tells you that he is hesitant to try “yet another pill” but has heard and read that marijuana (genus Cannabis) is used to alleviate disruptive chemotherapy-induced adverse effects. He asks if this is a treatment you’d recommend for him.
As Mr. S’s physician, how do you respond?
Understandably, some family physicians are hesitant to recommend an unregulated, federally illegal substance characterized by conflicting or absent evidence of safety and effectiveness.1 Nevertheless, throughout history and in the current court of public opinion, medical Cannabis has overwhelming support,2 leading to legalization in most of the United States.
As with many traditionally accepted therapies (whether they are or are not supported by substantial evidence), physicians are expected to provide individualized guidance regarding minimizing risk and maximizing benefit of the therapeutic use of Cannabis. The rapidly growing scientific and commercial fields of medical Cannabis guarantee that information on this topic will constantly be changing—and will often be contradictory. In this article, we review the most common concerns about medical Cannabis and provide up-to-date evidence on its use.
The pharmacology of cannabis
Cannabis sativa was among the earliest plants cultivated by man, with the first evidence of its use in China, approximately 4000 BC, to make twine and rope from its fibers.3 Records of medicinal Cannabis date back to the world’s oldest pharmacopoeia, a written summary of what was known about herbal medicine through the late 16th century.4
The 2 principal species of Cannabis are sativa and indica. There is no good medical evidence to separate the impacts of either strain; however, a staggering amount of lay information exists about the reported differing effects of each strain.5
Chemical constituents. Phytocannabinoids derived from C sativa are the plant’s best-known proteins, constituting a complex lipid-signaling network involved in numerous physiological processes. There are more than 100 known phytocannabinoids, the most well-recognized being Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Additional sources of cannabinoids include endogenous cannabinoids, or endocannabinoids, and synthetic cannabinoids.
The endocannabinoid system, comprising cannabinoid receptors, endocannabinoids, and their specific enzymes, is a potential therapeutic target for a variety of pathologic processes.6,7 The 2 most well-studied targets for cannabinoids in the human body are the cannabinoid receptors CB1 and CB2, found throughout the body: CB1, predominantly in the central and peripheral nervous system, and CB2 in a more limited distribution in the immune and hematopoietic systems. Other pathways activated or antagonized by THC and CBD exist, but are less well-mapped than CB1 and CB2.
[polldaddy:10402702]
Continue to: Botanical or synthetic?
Botanical or synthetic? It is important to distinguish between synthetic and plant-based cannabinoids, for you and your patients' benefit. Pharmaceutical (synthetic) THC is just that: THC alone. Whole-plant Cannabis, on the other hand, has hundreds of additional chemicals—most notably, phytocannabinoids and terpenoids. Data on the mechanisms of action and interactions of these additional chemicals are limited.
Although clinical trials have been undertaken with synthetic cannabinoids, there is increasing understanding and interest in the medical community of whole-plant Cannabis as a distinct entity. For example, nabiximols is a novel development in plant-based Cannabis products. Available as an oromucosal spray, a dose provides THC and CBD at 2.7 mg/100 mcL. Nabiximols is not approved by the US Food and Drug Administration (FDA) but is widely used
A third class of Cannabis comprises nonregulated synthetic cannabinoids that have no medically recognized benefit. They are solely a drug of abuse; common names include “K2” and “Spice.” These cannabinoids are outside of the scope of our discussion, but patients and providers should be aware of these cannabinoids because they are street-available. Unsuspecting patients might not know the difference between abusive and therapeutic formulations.8
Delivery and strength. Common forms of plant-based Cannabis include leaf that is smoked or vaporized, oral tincture, pill, and oil concentrate that can be vaporized. All forms come in a range of THC:CBD ratios—from as high as 90% THC content to 0% THC and all CBD-based content. Patients who are naïve to Cannabis might be concerned about formulations with a high THC concentration because of the psychoactive effects of this substance. Given the minimal CNS activity of CBD, a tolerable therapeutic starting point often is a THC:CBD ratio of 1:1, which contains a lower percentage of THC.4
Physiologic effects. THC is a partial agonist of CB1 and CB2 receptors; CBD functions as an antagonist at both receptors. The primary effects of THC result from activation of CB1 receptors, which exist in various areas of the cerebrum and cerebellum, as well as in the spinal cord.7 THC exerts its psychotropic effects at CB1 sites in the central nervous system; CBD can antagonize these THC effects at CB1 receptors. CBD also has anti-inflammatory and other effects that are mediated through peripherally distributed CB2 receptors.9
Continue to: THC has tremendously...
THC has tremendously complex capacity for activation and inhibition within various neuronal circuits, resulting in effects on mood, appetite, and movement.1,7 Adverse effects associated with Cannabis are wide-ranging: Most commonly, nausea, drowsiness, fatigue, dry mouth, and dizziness are reported alongside cognitive effects. Rarely, tachycardia, hypotension, hyperemesis, and depression can be seen.
Clinical implications and indications
Clinical indications for legal medical Cannabis vary by state; typically, indications include human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS), cachexia, cancer, glaucoma, epilepsy and other seizure disorders, severe and chronic pain, spasticity from neurodegenerative disorders, and irritable bowel syndrome and Crohn’s disease, as well as a wide range of less-universal diagnoses. A patient may have a so-called qualifying diagnosis (ie, having the potential to allow the patient to be certified to purchase and use Cannabis) in one state but not have the same standing in a neighboring state, posing a complex legal issue. Given the significant complexities of performing medical research with plant-based Cannabis in the United States, little research has been done. The result? Policymakers are grappling with questions that only scientific research can answer:
- For which conditions does Cannabis provide medicinal benefit equal to or superior to alternatives?
- What are the appropriate dosages (or CBD:THC ratios), formulations (plant-derived or synthetic), and routes of administration (smoked, ingested, or topical) for various conditions?
Bird’s-eye view of clinical research. A meta-analysis of isolated synthetic and plant-based cannabinoids for medical use was published in 2015.10 The analysis included more than 6000 patients in 79 trials, most of which assessed whether dronabinol or nabilone (both synthetic isolates) were effective compared to placebo or alternative non-Cannabis-based therapy. The studies examined chemotherapy-induced nausea and vomiting, appetite stimulation in HIV and AIDS, chronic pain, spasticity, depression and anxiety, sleep disorders, and psychosis.
Twenty-eight studies assessed chemotherapy-induced nausea and vomiting. All of these studies indicated a greater benefit from cannabinoids than from alternative antiemetic regimens and placebo; however, that finding did not reach statistical significance across all studies.
There was moderate evidence to suggest the use of Cannabis for neuropathic and nonneuropathic cancer-related pain. However, there is an increased short-term risk of adverse events with synthetic isolates dronabinol (when used for pain) and nabilone (when used for nausea and vomiting).
Continue to: The primary conclusion...
The primary conclusion of the meta-analysis is that further study is required because little evidence exists on the effects and the adverse events of plant-based Cannabis.
HIV infection. Data on Cannabis for the treatment of refractory neuropathy and appetite stimulation in HIV infection is mixed.10,11 Smoked Cannabis for medically refractory neuropathy was examined in several trials:
- In a randomized crossover trial, researchers found statistically significant subjective improvement in neuropathic pain, with minimal intolerable adverse effects, in the 28 HIV-infected participants who completed the trial.11
- In another study,Cannabis ingested in various forms resulted in appetite stimulation in late-stage HIV infection but did not produce statistically significant weight gain.10
Pediatric epilepsy. Research on pediatric patients who have epilepsy characterized by refractory seizures has shown that the impact of Cannabis on their disease is promising. Specifically, CBD has shown tremendous potential impact: Patients experienced a statistically significant reduction in the number of seizures.9 In 2018, the FDA approved the first plant-based derivative of Cannabis: an oral cannabidiol (marketed as Epidiolex [Greenwich Biosciences, Inc.]) for the treatment of intractable seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, rare and severe forms of epilepsy. Epidiolex is the first FDA-approved drug that contains a purified drug substance derived from marijuana.
CASE
Mr. S’s diagnosis of cancer is broadly included in the list of Cannabis-qualifying illnesses in all 34 states that certify patients for medical Cannabis. He qualifies both because (1) he is a cancer patient and (2) he has not found relief from chemotherapy-induced nausea and vomiting with several targeted therapies, including 5-hydroxytryptamine-receptor antagonists, steroids, and antipsychotics. Evidence supports CB1 and CB2 as potential targets for antiemetic treatment.
Given Mr. S’s consequent anorexia, his frustration with taking an increasing number of medications, and possible adverse effects of additional therapy, Cannabis is a reasonable course of action to treat nausea and vomiting. He would be able to use oral tincture or vaporization of oil to further limit his pill burden—likely, with a THC:CBD ratio of 1:1 or similar.
Continue to: Based on recent observational data...
Based on recent observational data from New York Cannabis dispensaries, cancer patients pursing Cannabis to treat chemotherapy-induced symptoms report that (1) either products with a high concentration of THC or products that contain THC and CBD in a 1:1 ratio are most effective and (2) products in 1:1 ratio of THC and CBD are most tolerable.
A legal system at oddsover the status of medical Cannabis
The core legal issue underlying medical Cannabis is a contradiction between federal and state laws.
At the federal level. The federal government regulates the lawful production, possession, and distribution of controlled substances through the Controlled Substances Act (CSA).12 The CSA is the basis for categorizing certain plants, drugs, and chemicals into 5 schedules, based on the substance’s medical use, potential for abuse, and safety or dependence liability.13 Under the CSA, marijuana (along with substances such as heroin and methamphetamine) is categorized as Schedule I14; ie, the substance
- has high potential for abuse,
- has no accepted therapeutic medical use in the United States, and
- lacks acceptable safety for use under medical supervision.
Despite waxing and waning efforts to protect states from federal prosecution, any use of a Schedule-1 substance violates federal law.15
In June 2018, a bipartisan group of federal lawmakers introduced a bill designed to amend the CSA and guarantee the rights of states and territories to self-determine marijuana regulation. The bill established a so-called STATES (Strengthening the Tenth Amendment Through Entrusting States) Act that “amends the Controlled Substances Act (21 U.S.C. § 801 et seq.) so that—as states and tribes comply with a few basic protections—its provisions no longer apply to any person acting in compliance with state or tribal laws relating to the manufacture, production, possession, distribution, dispensation, administration, or delivery of marijuana.”15
Continue to: The bill was referred to the Senate...
The bill was referred to the Senate and House Judiciary Committees but, ultimately, the STATES Act was blocked from debate in 2018.
On April 4, 2019, the Act was reintroduced in the House (H.R. 2093) and Senate (S. 1028) of the 116th Congress. Although there is bipartisan support for this bill, the timeline for moving it forward is unclear.16,17
At the state level. Thirty-four states have comprehensive public medical marijuana and Cannabis programs. The National Conference of State Legislatures18 (www.ncsl.org) designates a program “comprehensive” if it
- includes protection from criminal penalties for using marijuana for a medical purpose,
- allows access to marijuana through home cultivation, dispensaries, or other system,
- permits a variety of strains, including those more potent than what is labeled “low-THC,” and
- allows smoking or vaporization of marijuana products, plant-based material, or extract.
An additional 14 states allow for “low-THC, high-CBD” products for medical reasons, in limited situations, or as a legal defense. Regulation in these states varies widely, however: Some states allow industrialized hemp products only; others do not provide for any in-state production.18
Last, many states have some form of so-called “affirmative-defense” statutes that allow people charged with marijuana possession to mention use of marijuana for medical purposes as a possible defense.
Continue to: Physician shield
Physician shield. Despite inconsistent and evolving state and federal laws, physicians are protected, based on the Conant v Walters decision, from prosecution or revocation of their prescriptive authority for the professional “recommendation” of the use of medical marijuana.19 In 2002, the US Ninth Circuit Court of Appeals upheld the permanent injunction, based on a physician’s First Amendment right to discuss medical marijuana with patients.
CASE
Mr. S is amenable to trial of Cannabis to relieve nausea and anorexia. He asks you if he is allowed to use Cannabis at work, were he to return to an office-based desk job—even part-time—during treatment for cancer.
How would you answer Mr. S? Patients are legally protected from workplace penalties and dismissal for using and consuming Cannabis in states with a medical Cannabis law (including the state in which Mr. S resides). However, all employers have some variability in corporate policy, especially if a person works in a federally supported or regulated occupation. It’s always helpful to advise patients who will be using medical Cannabis to be proactive and speak with a human resources or employee health department staff member before beginning a course of medical Cannabis. Additionally, Cannabis with any amount of THC has the ability to alter focus, concentration, and perceptions of time. Thus, if a patient using medical Cannabis with THC asks about driving to work, he should be given the same advice one would offer about driving after consuming alcohol or ingesting opioids.
Common concerns
Ignorance of legal status. Theoretically, the Conant v Walters decision protects physicians from investigation for recommending medical Cannabis even in states where it is illegal. However, you should adhere closely to procedures set out by your state. The National Council of State Legislatures provides up-to-date information on each state’s procedures and programs,18 and the American Society of Addiction Medicine (www.asam.org) has established standards of professionalism for physicians who discuss medical Cannabis with patients (TABLE).20
Exposure to smoke. Cannabis smoke carries many of the same carcinogens found in tobacco smoke; furthermore, use of Cannabis and tobacco are highly correlated, confounding many population-based studies. The manner of inhalation of Cannabis can result in significantly higher levels of tar and carbon dioxide than with tobacco smoking. Because the effects of Cannabis last longer, however, people who smoke Cannabis may smoke it less often than tobacco smokers smoke tobacco.21
Continue to: Large cross-sectional...
Large cross-sectional and longitudinal studies have not found a link between Cannabis smoking and long-term pulmonary consequences, such as chronic obstructive pulmonary disease and lung cancer.22,23 The technology of Cannabis delivery systems has progressed far more rapidly than the clinical evidence for or against such technology.
“Vaping” is an informal term for inhalation of aerosolized Cannabis components and water vapor. Vaporizers do not heat Cannabis to the point of combustion; therefore, they provide less exposure to smoke-related toxicants while providing similar time of onset.
Neuropsychiatric adverse effects. Data regarding the relationship between Cannabis use and psychiatric disorders are incompletely understood, in conflict, and related to cannabinoid type. Consider Pennsylvania’s addition of anxiety disorder as a “serious medical condition” covered under the Pennsylvania Medical Marijuana Act.24 Although patients often report the use of medical Cannabis to treat anxiety,25 panic attacks are often associated with Cannabis use.26
While there is a clear association between Cannabis use and psychotic disorder, a causal link has yet to be unequivocally established. However, the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily.27
We recommend, therefore, that physicians screen patients for serious mental health concerns before recommending or certifying them to use medical Cannabis.
Continue to: Overconsumption of edibles
Overconsumption of edibles. Cannabis edibles (ie, food products infused with Cannabis extract) are distinct from inhaled Cannabis in regard to onset, duration, and potential for adverse effects. Cannabis edibles might be more popular than inhaled products among older medical Cannabis users.28
Edible Cannabis has a reported onset of 1 to 3 hours (compared to 5-10 minutes with inhaled Cannabis) and a duration of effect of 6 to 8 hours (compared with 2-4 hours for inhaled products).29 These qualities might render Cannabis edibles preferable to inhaled formulations for controlling chronic symptoms and conditions. However, delayed onset of edible products and wide variation in the concentration of THC also increase the risk of overconsumption, which can lead to overdose and self-limited Cannabis-induced psychosis. We recommend providing patient education about the effects of the physiologically active therapeutic compounds tetrahydrocannabinol and cannabidiol, to prevent overconsumption of high-THC products.30
CASE
Mr. S returns to your office after a trial of Cannabis as vaporized oil and reports some relief of nausea and a mild increase in appetite, but no weight gain. He is concerned about overconsumption or overdose, and asks you what the risks of these problems are.
How should you counsel Mr. S? Explain that ingestion of Cannabis has a prolonged onset of action; vaporization has a more rapid onset of action; therefore, he could more easily self-regulate ingestion with the vehicle he has chosen. In states where edible Cannabis products are legal, education is necessary so that patients know how much of the edible to consume and how long they will wait to feel the full impact of the effects of THC.30
Cannabis use disorder in the context of medical marijuana
Cannabis use disorder (CUD) incorporates general diagnostic features of a substance use disorder, including behavioral, cognitive, and physiologic symptoms such as cravings, tolerance, and withdrawal, in the setting of persistent use despite significant substance-related problems.31 Features of Cannabis withdrawal syndrome include irritability, anger or aggression, anxiety, depressed mood, restlessness, sleep difficulty, and decreased appetite or weight loss.31 Cannabis use disorder can develop in people who use medical Cannabis; however, physiologic symptoms of tolerance and withdrawal can also develop in the setting of appropriate medical use and do not, in isolation, represent CUD.
Continue to: A recent study...
A recent study considered nationwide cross-sectional survey data from the US National Survey of Drug Use and Health to examine the relationship between medical marijuana laws and CUD.32 Study findings did not show an increase in the prevalence of CUD or marijuana use among adults in states with a legalized medical marijuana program. Importantly, when researchers looked at marijuana use among adolescents and young adults, they found no increase in measured outcomes (eg, active [ie, past-month] marijuana use, heavy [> 300 d/yr] use, and a diagnosis of CUD) after medical marijuana laws were passed.32
A paucity of pediatric data
The adolescent brain might be more vulnerable to the adverse long-term effects of Cannabis; there is potential significant harm associated with Cannabis in children and adolescence. However, accurate data concerning risk and benefit are limited.
The most recent policy statement of the American Academy of Pediatrics (AAP) reflects this paucity of data.33 The AAP opposes the use of medical Cannabis outside regulation by the FDA, although the organization allows for consideration of compassionate use of medical Cannabis for children who have life-threatening or severely disabling conditions. The AAP does support (1) additional research into pharmaceutical cannabinoids and (2) changing Cannabis from Schedule I to Schedule II to facilitate this process. Since the publication of the policy statement, Pediatrics, the official journal of the AAP, has published a review of medical cannabinoids and found (1) strong evidence for benefit in chemotherapy-induced nausea and vomiting and (2) accumulating evidence of benefit in epilepsy.34
Recognized risk: Not supporting medical Cannabis
As with all medical decisions, the risks and benefits of certifying patients for medical Cannabis must be balanced against the risks and benefits of not doing so. The risks that accompany failure to certify a patient for medical marijuana fall into 3 categories:
Blocking access to a substance that has potential therapeutic benefit. More data regarding the potential benefits and risks of medical Cannabis will, undoubtedly, dispel some of the uncertainty regarding the decision to certify a patient for medical Cannabis. When you recommend medical Cannabis and certify patients for its use, you do so with the certainty that the Cannabis safety index (ie, risk of overdose or serious adverse effects) is exceedingly low.35
Continue to: Limiting patients to other medications
Limiting patients to other medications that, potentially, carry a risk of more or greater harmful effects. An example is the decision to prescribe an opioid for chronic pain instead of certifying a patient for medical Cannabis. For certain other conditions, including chemotherapy-induced nausea and vomiting, FDA-approved pharmaceuticals might have more reported serious adverse events and interactions than medical Cannabis.36
Resigning patients to obtain Cannabis from an illegal source. This speaks to harm reduction and social justice, because obtaining Cannabis from an illegal source carries health and legal risks:
- Increased health risks result from lacing or cutting botanical or synthetic Cannabis products with potentially toxic substances. Cocaine, the rodenticide brodifacoum, methamphetamine, and phencyclidine are all known, or have been reported, to be added to botanical and synthetic Cannabis.37
- Legal repercussions of Cannabis possession are disproportionately racially based, with a significantly higher arrest rate among people of color, even in states where medical Cannabis has been legalized.38
CORRESPONDENCE
Lara Carson Weinstein, MD, MPH, DrPH, Department of Family and Community Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, 1015 Walnut Street, Suite 401, Philadelphia, PA 19107; Lara.weinstein@jefferson.edu.
1. College of Family Physicians of Canada. Authorizing Dried Cannabis for Chronic Pain or Anxiety: Preliminary Guidance from the College of Family Physicians of Canada. Mississauga, Ontario: College of Family Physicians of Canada; 2014. www.cfpc.ca/uploadedFiles/Resources/_PDFs/Authorizing%20Dried%20Cannabis%20for%20Chronic%20Pain%20or%20Anxiety.pdf. Accessed July 10, 2019.
2. Hartig H, Geiger AW. About six-in-ten Americans support marijuana legalization. Pew Research Center Web site. www.pewresearch.org/fact-tank/2018/10/08/americans-support-marijuana-legalization/. Published October 8, 2018. Accessed July 10, 2019.
3. Li H-L. An archaeological and historical account of cannabis in China. Econ Bot. 1974:28:437-448.
4. Zuardi AW. History of cannabis as a medicine: a review. Braz J Psychiatry. 2006;28:153-157.
5. Marijuana strains and infused products. Leafly Web site. www.leafly.com/start-exploring. Accessed July 10, 2019.
6. Fraguas-Sánchez AI, Torres-Suárez AI. Medical use of cannabinoids. Drugs. 2018;78:1665-1703.
7. Maurya N, Velmurugan BK. Therapeutic applications of cannabinoids. Chem Biol Interact. 2018;293:77-88.
8. Kelkar AH, Smith NA, Martial A, et al. An outbreak of synthetic cannabinoid-associated coagulopathy in Illinois. N Engl J Med. 2018;379:1216-1223.
9. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215.
10. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456-2473.
11. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2008;34:672-680.
12. US Department of Justice, Drug Enforcement Administration, Diversion Control Division. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I—Control and Enforcement. Part A—Introductory Provisions. §801. Congressional findings and declarations: controlled substances. www.deadiversion.usdoj.gov/21cfr/21usc/801.htm. Accessed July 10, 2019.
13. Yeh BT. The Controlled Substances Act: regulatory requirements. Congressional Research Service 7-5700. https://fas.org/sgp/crs/misc/RL34635.pdf. Published December 13, 2012. Accessed July 10, 2019.
14. US Department of Justice, Drug Enforcement Administration, Diversion Control Division. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I—Control and Enforcement. Part B—Authority to Control; Standards and Schedules. §812. Schedules of controlled substances. www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. Accessed July 10, 2019.
15. United States Senate. The STATES Act. Senator Elizabeth Warren and Senator Cory Gardner. 2018. www.warren.senate.gov/imo/media/doc/STATES%20Act%20One%20Pager.pdf. Accessed July 10, 2019.
16. Strengthening the Tenth Amendment Through Entrusting States (STATES) Act of 2019, HR 2093. 116th Cong, 1st Session (2019). www.congress.gov/bill/116th-congress/house-bill/2093/text. Accessed July 20, 2019.
17. Strengthening the Tenth Amendment Through Entrusting States (STATES) Act of 2019, S 1028. 116th Cong, 1st Session (2019). www.congress.gov/bill/116th-congress/senate-bill/1028/all-info?r=3&s=6. Accessed August 8, 2019.
18. State medical marijuana laws. National Conference of State Legislatures Web site. www.ncsl.org/research/health/state-medical-marijuana-laws.aspx#3. Published July 2, 2019. Accessed July 10, 2019.
19. Conant v Walters. 309 F.3d 629 (9th cir. 2002).
20. American Society of Addiction Medicine. The role of the physician in “medical” marijuana. www.asam.org/docs/publicy-policy-statements/1role_of_phys_in_med_mj_9-10.pdf?sfvrsn=0. Published September 2010. Accessed July 12, 2019.
21. What are marijuana’s effects on lung health? National Institute on Drug Abuse Web site. www.drugabuse.gov/publications/research-reports/marijuana/what-are-marijuanas-effects-lung-health. Updated July 2019. Accessed July 10, 2019.
22. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10:239-247.
23. Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium. Int J Cancer. 2015;136:894-903.
24. Getting medical marijuana. Commonwealth of Pennsylvania Web site. www.pa.gov/guides/pennsylvania-medical-marijuana-program/. Accessed July 20, 2019.
25. Kosiba JD, Maisto SA, Ditre JW. Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: systematic review and meta-analysis. Soc Sci Med. 2019;233:181-192.
26. Crippa JA, Zuardi AW, Martín-Santos R, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24:515-523.
27. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319-328.
28. Barrus DG, Capogrossi KL, Cates S, et al. Tasty THC: Promises and Challenges of Cannabis Edibles. Publication No. OP-0035-1611. Research Triangle Park, NC: RTI Press; 2016. www.rti.org/sites/default/files/resources/rti-publication-file-6ff047d7-3fa4-41ad-90ed-9fb11663bc89.pdf. Accessed July 10, 2019.
29. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12-19.
30. MacCoun RJ, Mello MM. Half-baked—the retail promotion of marijuana edibles. N Engl J Med. 2015;372:989-991.
31. Cannabis use disorder [305.20, 304.30]. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington, DC: American Psychiatric Association; 2013:509-516.
32. Williams AR, Santaella-Tenorio J, Mauro CM, et al. Loose regulation of medical marijuana programs associated with higher rates of adult marijuana use but not cannabis use disorder. Addiction. 2017;112:1985-1991.
33. American Academy of Pediatrics Committee on Substance Abuse, American Academy of Pediatrics Committee on Adolescents. The impact of marijuana policies on youth: clinical, research, and legal update. Pediatrics. 2015;135:584-587.
34. Wong SS, Wilens TE. Medical cannabinoids in children and adolescents: a systematic review. Pediatrics. 2017;140. pii: e20171818.
35. Drug Enforcement Administration. Drugs of abuse: a DEA resource guide. www.dea.gov/sites/default/files/drug_of_abuse.pdf. Published 2017. Accessed July 10, 2019.
36. National Academies of Science, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press; 2017. www.nap.edu/read/24625/chapter/12017:2017-2019. Published 2017. Accessed July 10, 2019.
37. Emerging trend and alerts. National Institute on Drug Abuse Web site. www.drugabuse.gov/drugs-abuse/emerging-trends-alerts. Accessed July 10, 2019.
38. Drug Policy Alliance. From prohibition to progress: a status report on marijuana legalization. www.drugpolicy.org/sites/default/files/dpa_marijuana_legalization_report_feb14_2018_0.pdf. Published January 2018. Accessed July 10, 2019.
1. College of Family Physicians of Canada. Authorizing Dried Cannabis for Chronic Pain or Anxiety: Preliminary Guidance from the College of Family Physicians of Canada. Mississauga, Ontario: College of Family Physicians of Canada; 2014. www.cfpc.ca/uploadedFiles/Resources/_PDFs/Authorizing%20Dried%20Cannabis%20for%20Chronic%20Pain%20or%20Anxiety.pdf. Accessed July 10, 2019.
2. Hartig H, Geiger AW. About six-in-ten Americans support marijuana legalization. Pew Research Center Web site. www.pewresearch.org/fact-tank/2018/10/08/americans-support-marijuana-legalization/. Published October 8, 2018. Accessed July 10, 2019.
3. Li H-L. An archaeological and historical account of cannabis in China. Econ Bot. 1974:28:437-448.
4. Zuardi AW. History of cannabis as a medicine: a review. Braz J Psychiatry. 2006;28:153-157.
5. Marijuana strains and infused products. Leafly Web site. www.leafly.com/start-exploring. Accessed July 10, 2019.
6. Fraguas-Sánchez AI, Torres-Suárez AI. Medical use of cannabinoids. Drugs. 2018;78:1665-1703.
7. Maurya N, Velmurugan BK. Therapeutic applications of cannabinoids. Chem Biol Interact. 2018;293:77-88.
8. Kelkar AH, Smith NA, Martial A, et al. An outbreak of synthetic cannabinoid-associated coagulopathy in Illinois. N Engl J Med. 2018;379:1216-1223.
9. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153:199-215.
10. Whiting PF, Wolff RF, Deshpande S, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313:2456-2473.
11. Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2008;34:672-680.
12. US Department of Justice, Drug Enforcement Administration, Diversion Control Division. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I—Control and Enforcement. Part A—Introductory Provisions. §801. Congressional findings and declarations: controlled substances. www.deadiversion.usdoj.gov/21cfr/21usc/801.htm. Accessed July 10, 2019.
13. Yeh BT. The Controlled Substances Act: regulatory requirements. Congressional Research Service 7-5700. https://fas.org/sgp/crs/misc/RL34635.pdf. Published December 13, 2012. Accessed July 10, 2019.
14. US Department of Justice, Drug Enforcement Administration, Diversion Control Division. Title 21 United States Code (USC) Controlled Substances Act. Subchapter I—Control and Enforcement. Part B—Authority to Control; Standards and Schedules. §812. Schedules of controlled substances. www.deadiversion.usdoj.gov/21cfr/21usc/812.htm. Accessed July 10, 2019.
15. United States Senate. The STATES Act. Senator Elizabeth Warren and Senator Cory Gardner. 2018. www.warren.senate.gov/imo/media/doc/STATES%20Act%20One%20Pager.pdf. Accessed July 10, 2019.
16. Strengthening the Tenth Amendment Through Entrusting States (STATES) Act of 2019, HR 2093. 116th Cong, 1st Session (2019). www.congress.gov/bill/116th-congress/house-bill/2093/text. Accessed July 20, 2019.
17. Strengthening the Tenth Amendment Through Entrusting States (STATES) Act of 2019, S 1028. 116th Cong, 1st Session (2019). www.congress.gov/bill/116th-congress/senate-bill/1028/all-info?r=3&s=6. Accessed August 8, 2019.
18. State medical marijuana laws. National Conference of State Legislatures Web site. www.ncsl.org/research/health/state-medical-marijuana-laws.aspx#3. Published July 2, 2019. Accessed July 10, 2019.
19. Conant v Walters. 309 F.3d 629 (9th cir. 2002).
20. American Society of Addiction Medicine. The role of the physician in “medical” marijuana. www.asam.org/docs/publicy-policy-statements/1role_of_phys_in_med_mj_9-10.pdf?sfvrsn=0. Published September 2010. Accessed July 12, 2019.
21. What are marijuana’s effects on lung health? National Institute on Drug Abuse Web site. www.drugabuse.gov/publications/research-reports/marijuana/what-are-marijuanas-effects-lung-health. Updated July 2019. Accessed July 10, 2019.
22. Tashkin DP. Effects of marijuana smoking on the lung. Ann Am Thorac Soc. 2013;10:239-247.
23. Zhang LR, Morgenstern H, Greenland S, et al. Cannabis smoking and lung cancer risk: pooled analysis in the International Lung Cancer Consortium. Int J Cancer. 2015;136:894-903.
24. Getting medical marijuana. Commonwealth of Pennsylvania Web site. www.pa.gov/guides/pennsylvania-medical-marijuana-program/. Accessed July 20, 2019.
25. Kosiba JD, Maisto SA, Ditre JW. Patient-reported use of medical cannabis for pain, anxiety, and depression symptoms: systematic review and meta-analysis. Soc Sci Med. 2019;233:181-192.
26. Crippa JA, Zuardi AW, Martín-Santos R, et al. Cannabis and anxiety: a critical review of the evidence. Hum Psychopharmacol. 2009;24:515-523.
27. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319-328.
28. Barrus DG, Capogrossi KL, Cates S, et al. Tasty THC: Promises and Challenges of Cannabis Edibles. Publication No. OP-0035-1611. Research Triangle Park, NC: RTI Press; 2016. www.rti.org/sites/default/files/resources/rti-publication-file-6ff047d7-3fa4-41ad-90ed-9fb11663bc89.pdf. Accessed July 10, 2019.
29. MacCallum CA, Russo EB. Practical considerations in medical cannabis administration and dosing. Eur J Intern Med. 2018;49:12-19.
30. MacCoun RJ, Mello MM. Half-baked—the retail promotion of marijuana edibles. N Engl J Med. 2015;372:989-991.
31. Cannabis use disorder [305.20, 304.30]. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Washington, DC: American Psychiatric Association; 2013:509-516.
32. Williams AR, Santaella-Tenorio J, Mauro CM, et al. Loose regulation of medical marijuana programs associated with higher rates of adult marijuana use but not cannabis use disorder. Addiction. 2017;112:1985-1991.
33. American Academy of Pediatrics Committee on Substance Abuse, American Academy of Pediatrics Committee on Adolescents. The impact of marijuana policies on youth: clinical, research, and legal update. Pediatrics. 2015;135:584-587.
34. Wong SS, Wilens TE. Medical cannabinoids in children and adolescents: a systematic review. Pediatrics. 2017;140. pii: e20171818.
35. Drug Enforcement Administration. Drugs of abuse: a DEA resource guide. www.dea.gov/sites/default/files/drug_of_abuse.pdf. Published 2017. Accessed July 10, 2019.
36. National Academies of Science, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. Washington, DC: The National Academies Press; 2017. www.nap.edu/read/24625/chapter/12017:2017-2019. Published 2017. Accessed July 10, 2019.
37. Emerging trend and alerts. National Institute on Drug Abuse Web site. www.drugabuse.gov/drugs-abuse/emerging-trends-alerts. Accessed July 10, 2019.
38. Drug Policy Alliance. From prohibition to progress: a status report on marijuana legalization. www.drugpolicy.org/sites/default/files/dpa_marijuana_legalization_report_feb14_2018_0.pdf. Published January 2018. Accessed July 10, 2019.
PRACTICE RECOMMENDATIONS
› Educate patients about the effects of the physiologically active therapeutic compounds in Cannabis; this is critical to prevent overconsumption of products with high levels of tetrahydrocannabinol. B
› Screen patients for serious mental health concerns before recommending or certifying medical Cannabis; this is essential because the rate of psychiatric hospitalization is increased in bipolar disorder and schizophrenia patients who use Cannabis heavily. B
› You can recommend medical Cannabis and certify patients for its use with the certainty that the risk of overdose or serious adverse effects is exceedingly low. A
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
