THE REGULATION, BENEFITS AND RISKS OF MARIJUANA USE
Gerald Gianutsos, PhD, JD
Dr. Gianutsos is an Emeritus Associate Professor of Pharmacology at the University of Connecticut School of Pharmacy. He graduated with a B.S. in Pharmacy and M.S. in Pharmacology from St. John’s University. He received a Ph.D. in Pharmacology from the University of Rhode Island and a J.D. degree from the University of Connecticut School of Law. He completed a post-doctoral research fellowship at the Michigan State University School of Medicine. He was a member of the pharmacy faculty at UCONN for almost 40 years, where he taught pharmacology and pharmacy law and authored more than 100 peer-reviewed manuscripts in neuropharmacology with an emphasis on antidepressant and antipsychotic drugs and drug of abuse. He is a three-time recipient of UCONN’s School of pharmacy teacher of the year award and maintains a continuing interest in pharmacy law, especially in areas involving drugs.
Course Overview
Cannabis sativa is an ancient plant used at different points in history as a valuable commercial crop and for its medicinal properties. Its psycho- neurological effects on the mind and body contribute to its therapeutic properties, but they have also led to public health concerns and a perceived danger of marijuana use, which gave rise to federal and state regulations that made the use of marijuana and its component parts illegal. These regulations continue today, but because of emergent evidence that cannabinoids may have potential health benefits in a wide variety of diseases, many states have enacted laws to permit patients to use marijuana for medical purposes. Marijuana's potential health benefits have led to a loosening of governmental regulations over its use. On the other side, evidence continues to arise that conflicts with the view that marijuana’s benefits outweigh the risks of its use. Marijuana’s medicinal uses and its risk for adverse events will be discussed in this course. Given marijuana’s greater acceptance and use, pharmacists and pharmacy technicians need to be able to identify the risks and benefits of using marijuana and recognize the fluid nature of its regulatory oversight.
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Accreditation Statement:
RxCe.com LLC is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education.
Universal Activity Number (UAN): The ACPE Universal Activity Number assigned to this activity is
Pharmacist 0669-0000-22-041-H03-P
Pharmacy Technician 0669-0000-22-042-H03-T
Credits: 1.5 hours of continuing education credit
Type of Activity: Knowledge
Media: Internet Fee Information: $5.99
Estimated time to complete activity: 1.5 hours, including Course Test and course evaluation
Release Date: September 19, 2022
Expiration Date: September 19, 2025
Target Audience: This educational activity is for pharmacists.
How to Earn Credit: From September 19, 2022, through September 19, 2025, participants must:
Read the “learning objectives” and “author and planning team disclosures;”
Study the section entitled “educational activity;” and
Complete the Post-test and Evaluation form. The Post-test will be graded automatically. Following successful completion of the Post-test with a score of 70% or higher, a statement of participation will be made available immediately. (No partial credit will be given.)
Learning Objectives: Upon completion of this educational activity, participants should be able to:
Describe the evolution and current state of federal and state regulations of marijuana use.
Describe the pharmacology of Cannabis and cannabinoids, including the variations associated with the different routes of administration.
Identify the evidence for potential clinical use of marijuana.
Compare the benefits and risks of marijuana use.
Disclosures
The following individuals were involved in the development of this activity: Gerald Gianutsos, PhD, JD, and Susan DePasquale, MSN, PMHNP-BC. There are no financial relationships relevant to this activity to report or disclose by any of the individuals involved in the development of this activity.
ⓒ RxCe.com LLC 2022: All rights reserved. No reproduction of all or part of any content herein is allowed without the prior, written permission of RxCe.com LLC.
Introduction
Cannabis sativa is an ancient plant used at different points in history as a valuable commercial crop and for its medicinal properties. Its psycho- neurological effects on the mind and body contribute to its therapeutic properties, but they have also led to public health concerns and a perceived danger of marijuana use. This conflict has played out in the United States over the recent centuries. Marijuana was readily available in the U.S., during the 19th and early 20th centuries. The view of marijuana as a dangerous drug emerged in the U.S., in the 1930s, spurring federal and state regulations that made the use of marijuana and its component parts illegal. These regulations continue today, but because of emergent evidence that cannabinoids may have potential health benefits in a wide variety of diseases, many states have enacted laws permitting patients to use marijuana for medical purposes. This has led to a loosening of governmental regulations over marijuana use. On the other side, evidence continues to arise that conflicts with the view that marijuana’s benefits outweigh the risks of its use. A history of marijuana and its medicinal uses, as well as its risk for adverse events, will be discussed in this course.
A History of Marijuana Use
Cannabis sativa is one of the oldest known cultivated plants.1,2 It is believed that Cannabis sativa has been grown for at least 12,000 years, initially as a source of textile fiber and food.3,4 Use of the Cannabis plant originated in Central Asia before being introduced into Africa, Europe, and eventually the Americas.3 The earliest known use of Cannabis as a medicine is believed to date to the Neolithic period, around 4000 B.C.1 The earliest documentation of Cannabis’ therapeutic properties dates back to 2737 B.C. It is attributed to the Chinese Emperor Shen Nung, who is considered a father of Chinese Medicine. Cannabis’ therapeutic properties appear in Chinese pharmacopeias believed to be written in the second Century.1,4,5 The plant then traveled from China into other parts of the world, beginning with India, then Egypt, Persia, Syria, and Greece.1
In the 1830s, Sir William Brooke O’Shaughnessy, an Irish physician studying in India, described reports about using hemp tincture as a remedy for rheumatism, cholera, tetanus, and infantile convulsions.1,2,6 Other Western physicians extolled the use of Cannabis extracts and tinctures for pain, migraine, vomiting, spasticity, tremors from Parkinson’s Disease, convulsive disorders, and dysmenorrhea.1,4,5 Queen Victoria reportedly took Cannabis for painful menses, and Austrian Empress Elisabeth took it for cough and possibly also to stimulate appetite.4 By the late 1800s, Cannabis extracts were sold in pharmacies and physician’s offices throughout Europe and the United States to treat various ailments.7 Today, marijuana is once again promoted as a promising therapeutic option for many disorders, although often with limited quantifiable support.
Marijuana Use and Regulation in the United States
The U.S., has had a complicated relationship with Cannabis, alternating between approval and condemnation. Hemp was widely grown in colonial America and Spanish missions in the southwest in the 17th Century.7 Hemp became a commercial crop used to manufacture fabric, rope, paper, and construction products in the U.S., before being replaced by lighter and less expensive fibers such as jute, cotton, and wood pulp.7 Virginia and other colonies encouraged or required farmers, including George Washington and Thomas Jefferson, to grow hemp; it was an important part of commerce in the South.3
Cannabis is also referred to as marijuana. The word marijuana and its cognates (e.g., marihuana) were likely introduced into the American vocabulary in the 19th Century. The word marijuana is considered of Mexican Spanish origins;8 however, Piper (2005) provides an interesting review of the first documented English reference to marijuana in the U.S., which was in 1894. Piper argued that this word might have been introduced by American Indians who called plants with narcotic effects mariguan.8 The Mexican Spanish and American Indian words also had similarities to a Chinese word for hemp brought to the West by Chinese workers in Western Mexico.8 These terms may have already been introduced into Moorish Spain from the earlier
Chinese hemp trade with western Europe, which could give the word marijuana Chinese origins.8
The uses of Cannabis were well established in the U.S., by the 19th Century. Cannabis gained medical importance in the U.S. It was listed in the
U.S. Pharmacopeia between 1850 and 1941 and could be readily obtained at the local pharmacy.7 Extracts and tinctures of Cannabis were used to treat pain, migraine, vomiting, spasticity, tremors of Parkinson’s Disease, and convulsive disorders.2 These applications are being revisited in the 21st Century;6,9 however, this renewed interest came after public opinion turned against marijuana in the early 20th Century. The negative view toward marijuana was fueled partly by economic factors, anti-immigrant fears, and racial bias.3,10 Marijuana was denounced by the nation’s first “Drug Czar” who viewed marijuana as “an addictive drug which produces in its users insanity, criminality, and death.”11 The hostile posture toward marijuana led to federal legislation that severely restricted its use.
The Harrison Narcotic Tax Act of 1914
There was little federal regulation of controlled substances until the Harrison Narcotic Tax Act in 1914, which regulated the production, importation, and distribution of opiates and cocaine by imposing a special tax upon anyone who produced, imported, manufactured, sold, dispensed, distributed, or compounded these substances. The law required physicians and pharmacists who prescribed or dispensed opiates or cocaine to be licensed and pay a fee.12,13 Marijuana was not included in the Act but this law laid the groundwork for regulating certain substance.12
Marihuana Tax Act
Congress passed the Marihuana Tax Act in 1937, which effectively prohibited the sale and possession of marijuana.11,13 This law followed the release one year earlier of the infamous film Reefer Madness, and the release of Marijuana Menace in the same year.11,13 The Marihuana Tax Act was modeled after the Harrison Act.13 It is generally felt that non-medical
concerns, including commercial interests, anti-immigrant and racial bias, exaggerated fear about violence and crime, hysteria about the drug’s alleged contribution to moral decay, and pressure from the Federal Bureau of Narcotics played significant roles in the push for stricter control of marijuana.12-14
At the Congressional hearing on the proposed act, there was no testimony by a health care professional in favor of regulating the use of marijuana. At least 28 preparations containing marijuana were on the market in 1937.13 Only one physician from the American Medical Association appeared at the hearing. He vigorously opposed the act and testified that marijuana was a recognized medicine in good standing.13 A driving force behind the legislation was Henry Anslinger, the first Federal Bureau of Narcotics commissioner. He submitted testimony to Congress about the evils of marijuana use, claiming that it incited violence, depravity, and insanity.12
Congress passed the Act with little discussion.6 Like the Harrison Act, this legislation required persons producing, importing, selling, or otherwise dealing with the drug to pay an occupational tax and to register with the Internal Revenue Service. Transfer of marijuana required a written order form and payment of a transfer tax of $1 an ounce (roughly $1,900 in today’s dollars) when taken medicinally, and $100 an ounce when used for unapproved purposes.6,12,14 The high taxes made marijuana very expensive to obtain legally. Possession without a written order was considered presumptive evidence of noncompliance and subjected the violator to a fine of up to $2000 (equivalent to $38,400 in 2021) and/or imprisonment for up to five years.14 The first person prosecuted under the Act was arrested for selling marijuana the day after the Act was passed. He was sentenced to four years of hard labor.7
Shortly after the passage of the tax act, all states made the possession of marijuana illegal. By this time, 46 of the 48 states, plus the District of Columbia, had passed laws restricting marijuana.12,13 In most states, marijuana was subject to the same penalties as heroin or cocaine.12 California,
which later became the first state to recognize medical marijuana, was the first state to ban Cannabis.15
The Boggs Act
The Boggs Act, passed in 1952, established mandatory sentences for violations of drug-related wrongdoing. A first-time offense for marijuana possession carried a minimum sentence of 2–10 years in prison and a fine of up to $20,000.15
Controlled Substances Act
In 1969, the U.S. Supreme Court declared the Marihuana Act unconstitutional in a case brought by Timothy Leary, the infamous advocate for the use of the psychedelic LSD.16 By then, Congress repealed most of the mandatory penalties for drug-related offenses.7
A year later, the Controlled Substances Act (CSA) was passed by Congress, and marijuana was placed in the most restrictive category, Schedule I.17,18 Marihuana was defined in the CSA as “all parts of the plant Cannabis sativa L., whether growing or not; the seeds thereof; the resin extracted from any part of such plant; and every compound, manufacture, salt, derivative, mixture, or preparation of such plant, its seeds or resin.”19 Therefore, not only was the plant prohibited, but any individual cannabinoid was also a Schedule I substance. (Note that this definition was recently changed for cannabidiol (CBD), as discussed below.) The placement into Schedule I was supposed to be temporary pending a review by the new National Commission on Marihuana and Drug Policy (more commonly known as the Shafer Commission). The Commission’s 1972 report concluded that “neither the marihuana user nor the drug itself can be said to constitute a danger to public safety.”20 It recommended that marijuana possession for personal use not be considered a criminal offense. President Nixon, who continued to view marijuana as dangerous, rejected the advice of his Commission.20
Some factors believed to have spurred the inclusion of marijuana within the CSA included growing concern among middle-class parents that it was a dangerous substance, which could lead to harder drugs and hostility to the drug by then-President Richard Nixon towards the primary users of the drug: minorities and the growing counterculture movement.17,18
There were contrary views, even in the 1970s. In 1977, former President Jimmy Carter said in an address to Congress that “[p]enalties against possession of a drug should not be more damaging to an individual than the use of the drug itself... Nowhere is this more clear than in the laws against possession of marijuana in private for personal use."21 These contrary views were unable to overcome the negative attitudes toward marijuana, which were furthered into the 1980s through the “War on Drugs.”11 Marijuana still sits as a Schedule I drug despite numerous unsuccessful efforts (to date) to change its scheduling.17,18
State Initiatives to Legalize Marijuana
The year 1996 was a watershed year toward legalizing marijuana. In that year, California recognized the potential medical value of Cannabis and permitted its sale and use for medical purposes.12 Under California’s Compassionate Use Act of 1996, California became the first state to allow the use of marijuana for medical purposes when voters approved the Act.22 The Act permits seriously ill residents to use marijuana for medical purposes without fear of criminal liability.22
Since 1996, nearly all states have enacted laws allowing medicinal or recreational use of marijuana to some degree. As of December 2020, some form of medicinal cannabis was legal in 47 states, the District of Columbia, Guam, the United States Virgin Islands, and Puerto Rico.1 For example, Florida has enacted laws allowing medicinal marijuana for specific cases.23 A patient receiving medicinal marijuana treatment must have a qualifying medical condition: cancer, epilepsy, glaucoma, HIV, AIDS, posttraumatic stress disorder, amyotrophic lateral sclerosis, Crohn’s disease, Parkinson’s disease, multiple sclerosis, chronic nonmalignant pain, other similar or terminal
conditions.24 In addition, some states allow the recreational use of marijuana.25
State laws vary with respect to criteria such as qualifying conditions, the amount that can be purchased, registration requirements, age restrictions, non-resident purchases, and the pharmacist’s role. Pharmacists and pharmacy technicians should consult their local laws for guidance. In most cases, marijuana is obtained from a dispensary, although some states permit personal cultivation. Almost all cases, a qualified patient registers with the state and receives an identification card.26 A physician does not “prescribe” marijuana (which is prohibited under Federal Law) but may recommend its use based on the patient’s eligibility.26 Permitted indications range from those with high-quality and low-quality evidence for marijuana efficacy.27
Conflict Between Federal and State Marijuana Laws
While states have enacted medical marijuana laws, they conflict with federal law, which still treats marijuana as a Schedule I substance. The U.S. Supreme Court has ruled that a patient cannot use a defense of medical necessity to circumvent federal restrictions on cultivating marijuana, and the federal government can prosecute patients using marijuana even if the state has a medical marijuana law.28,29
Changing Federal Law
In recent years, national institutes and federal agencies have taken a more relaxed approach towards people who comply with their state’s medical marijuana laws.30-35 Moreover, the FDA has approved some marijuana products for clinical use,25 and recent actions by Congress have sought to revitalize hemp as a commercial product.1,35
The 2018 Farm Bill (Agricultural Improvement Act of 2018) removed many restrictions on CBD,36 but it would be an oversimplification to say it was “legalized.” The bill did not explicitly address the medical use of CBD; instead,
the goal was to encourage the agricultural production of hemp to be used in commercial products.36
The Farm Bill removed “hemp” from control under the CSA. Hemp is very low in THC (0.3% or less).36 Any CBD that fell under this definition of hemp was also removed from scheduling under the CSA. The 2018 bill conformed to the definition of “industrial hemp” under the Agricultural Act of 2014, that defined “hemp” as “the plant Cannabis sativa L. and any part of that plant ... with a delta-9 tetrahydrocannabinol [“THC”] concentration of not more than 0.3 percent on a dry weight basis.”36 Essentially, CBD derived from plants containing not more than 0.3 percent Δ9-THC was no longer a controlled substance; CBD derived from plants containing more than 0.3 percent Δ9-THC was a controlled substance.36,37
However, pharmacists should appreciate that the Farm Bill preserves the FDA’s authority. Cannabinoids promoted as medicines remain under the jurisdiction of the FDA. The FDA’s position is that even if a cannabinoid product meets the definition of "hemp" under the 2018 Farm Bill, it still must comply with the Food Drug and Cosmetic Act (FDCA).38 The approval of Epidiolex® described below is an application of the FDCA.38 The FDA has approved Epidiolex® (cannabidiol), and three synthetic cannabis-related drug products: Marinol (dronabinol), Syndros (dronabinol), and Cesamet (nabilone).39
Pending Congressional Action
The nebulous state of marijuana regulation could be clarified by Congressional action, and Congress may be ready to do just that. The House of Representatives introduced a bill, H.R. 3617, entitled the Marijuana Opportunity Reinvestment and Expungement Act of 2021 (the MORE Act of 2021). This bill would be a significant step toward decriminalizing marijuana.40 The House of Representatives passed H.R. 3617 on April 1, 2022, and it is awaiting action by the Senate.40
The House of Representatives’ bill, H.R. 3617, would replace all federal statutory references of marijuana or marihuana with Cannabis. Highlights of the bill’s provisions include establishing a process to expunge convictions and conduct sentencing review hearings for individuals convicted of federal Cannabis offenses. It would levy an excise tax on Cannabis imported and domestic products and an occupational tax on Cannabis production facilities and export warehouses. The bill would also set up funding within a grant program to provide resources for individuals adversely impacted by the War on Drugs. Small Business Administration loans and services would be made available to entities that are Cannabis-related legitimate businesses or service providers. H.R. 3617 would prohibit the denial of federal public benefits to a person based on certain Cannabis-related conduct or convictions, and it would prohibit the denial of benefits and protections under immigration laws based on the same. Finally, H.R. 3617 would direct the Government Accountability Office to study the societal impact of Cannabis legalization.40
More recently, Republicans in the U.S. House of Representatives introduced legislation entitled the States Reform Act that would decriminalize marijuana and remove most federal restrictions against marijuana and state- licensed marijuana businesses.41 Marijuana would be regulated similarly to alcohol. The Alcohol and Tobacco Tax and Trade Bureau in the Treasury Department would become the primary federal regulatory body for marijuana. Federal regulations would prohibit marijuana use by individuals under 21 years of age, restrict advertising, and expunge the records of people convicted of nonviolent, Cannabis-only related offenses. Physicians would be able to recommend marijuana products to patients in the VA system. A federal excise tax of 3% would be levied on sales. Matters related to the prohibition and regulation of marijuana would be left up to the individual states.41
Given marijuana’s greater acceptance and use, pharmacists and pharmacy technicians need to be able to identify the risks and benefits of using marijuana and recognize the fluid nature of its regulatory oversight. They must also remain cognizant of the conflict between state and federal laws, especially understanding that marijuana remains a Schedule I drug with potential federal criminal consequences. Some leeway appears to be given by
federal authorities to individuals who comply with their state’s laws regarding marijuana use. This makes it imperative that pharmacists and pharmacy technicians know their respective state laws.
Components of Cannabis
The Cannabis plant contains more than 600 different chemical compounds representing 23 different chemical classes, including at least 140 cannabinoids with varying properties.42,43 Cannabinoids are a group of 21- or 22- carbon (some being carboxylated) terpenophenolic compounds which are predominantly found in Cannabis.42,43 The phytochemicals are primarily located in the flowers and leaves of the plant, with very low concentrations in the seeds, stems, and stalk.43
The most abundant and well-known phytocannabinoids found in Cannabis are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol, also known as CBD. The plant produces these in their carboxylic acid forms of Δ9- tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA). Heating (e.g., by smoking or baking), exposure to light, or natural degradation causes decarboxylation to the active form.44
Other less well-known cannabinoids (sometimes called “minor cannabinoids”) have also attracted interest as possible therapeutic agents. These include delta-8 tetrahydrocannabinol (Δ8-THC), cannabinol (CBN), cannabigerol (CBG), tetrahydrocannabivarin (THCV), and cannabichromene (CBC).44,45
Marijuana contains many other classes of compounds in addition to cannabinoids. These may modify the effects of the cannabinoids and contribute to their pharmacological and clinical properties. Terpenes are the largest group, with more than 100 molecules identified in Cannabis.43,45 Terpenes are lipophilic molecules responsible for the distinctive odor and flavor of different varieties of Cannabis and may also have biological activity on cell membranes and neuronal and muscular function.43,45 Phenolic compounds are also found In Cannabis, including nearly 20 identified
flavonoids that contribute to flavor and aroma and may affect biological systems.43,45 Cannabis also contains numerous flavonoid compounds which contribute to its flavor and aroma and which also may have biological activity.43,45
Synthetic Forms
Synthetic Cannabis products are also available. These run the spectrum from FDA-approved therapeutics to dangerous drugs of abuse. The first synthetic cannabinoids were synthesized by the pharmaceutical industry or academic laboratories beginning in the 1940s.42 Most synthetic cannabinoids are pure CB1 or CB2 receptor agonists, and many are synthesized to make non-opioid analgesics.42,45
Dronabinol (Marinol) is a synthetic form of delta-9-THC. It was approved by the FDA in 1985 and is available in an oral dosage form.46 It is approved to relieve nausea and vomiting associated with cancer chemotherapy and to assist with the loss of appetite in patients with HIV. The active ingredient is dissolved in sesame oil to discourage smoking. Dronabinol may be superior to smoked marijuana since the drug may be administered in consistent doses.47 It is currently classified as a Schedule III drug.46
Syndros (C-II), approved in 2016, is a liquified form of dronabinol available as an oral solution that allows the dose to be titrated. It is approved for reducing nausea associated with cancer chemotherapy and the loss of weight associated with AIDS-related anorexia.48
Nabilone (Cesamet; C-II) is a synthetic oral cannabinoid similar to THC and is used to treat nausea and vomiting associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetics. The limited indication is required because of concerns that patients may experience “disturbing psychotomimetic reactions not observed with other antiemetic agents.”49,50 The drug is intended to be used under circumstances that permit close supervision of the patient by a responsible individual.50
Conversely, synthetic drugs acting on CB1 receptors, such as “K2” or “Spice,” are sold as “legal” forms of marijuana and have emerged as dangerous drugs that are misused.51,52 Different structural classes of synthetic cannabinoids have been developed to avoid being classified as controlled substances (i.e., they are “designer drugs”) and avoid forensic identification. Users seek out these drugs for their psychoactive activity and to prevent detection in standardized drug testing.
Illicit synthetic cannabinoids first appeared in Europe in 2005 and in the US in 2008.52 Typically, these drugs are sold as "herbal incense" and are sprayed on mixtures of natural herbs or are used in e-cigarettes to mimic the euphoric effect of Cannabis. They are often falsely labeled as "not for human consumption" to circumvent legal liability. These synthetic substances are much more potent than natural Cannabis; they have greater efficacy than phytocannabinoids and act as full agonists at the cannabinoid receptors.52 These agents have been associated with multiple adverse effects such as psychosis, agitation, autonomic dysregulation, vomiting, and death.52
Pharmacokinetics of Cannabis
Cannabinoids are administered by different routes. The most common routes are inhalation (smoking or vaping) or oral (as a tea or mixed with food) but also include topical, sublingual, oromucosal, or suppository.53-56 The pharmacokinetics can vary as a function of the route of administration.56 The most rapid onset is attained via inhalation, with intoxicating effects of THC occurring within a few minutes, reaching a maximum within 15-30 minutes, and beginning to taper off after two to three hours.56 Inhaled CBD has a plasma concentration-time profile similar to that of THC.56
The bioavailability of THC after inhalation is variable due to inconsistency in intra- and inter-subject inhalational characteristics (e.g., number, duration, and interval of puffs, breath hold time, inhalation volume), the device used to deliver the dose, size of inhaled particles, and site of deposition within the respiratory system.56,57 Some of the inhaled active ingredients are also lost when exhaling. In addition to a rapid onset, inhalation
allows users to titrate their dose, unlike a fixed oral dose.56,57 There is also minimal first-pass metabolism, i.e., minimization of the digestive processes.56
Following oral ingestion of cannabinoids, CNS effects are delayed 30-90 minutes and reach a maximum after two to six hours, with a half-life approaching 20-30 hours.56,57 Oral administration results in extensive first- pass metabolism (digestive processes), generating an active metabolite. Consequently, the high produced by the consumption of edibles can be more pronounced and more prolonged than from smoking but with a delayed onset,56,57 and inexperienced users may not correctly anticipate the delayed effect and long duration of THC when consuming edibles. Cannabidiol is slowly absorbed with high first-pass metabolism after oral ingestion and is greatly influenced by the presence of food; a high-fat meal results in a substantially higher plasma concentration.58
Transdermal administration of cannabinoids also minimizes first-pass metabolism, but absorption is limited by their extreme hydrophobicity, which reduces diffusion across the aqueous layer of the skin.57 In vitro studies with human skin have found that the permeability of CBD is 10-fold higher than that of delta-9-THC, which is consistent with the lower lipophilicity of CBD.57
Cannabidiol is frequently found as a topical preparation. Topical preparations exclude the acidic degradation of CBD to THC, which avoids the psychotropic effects of this degradation “due to the exclusion of digestive processes and a neutral skin environment.”57 This delivery system offers steady CBD plasma levels for extended periods, which makes this route of administration promising in a clinical setting.57
Oromucosal preparations of cannabinoids undergo rapid absorption via the oral mucosa and produce plasma drug concentrations that are higher than oral dosage forms but lower than when inhaled. This route can be helpful when a fast onset is required. However, part of the dose may be swallowed and absorbed orally.57
Cannabinoids are metabolized via cytochrome P450 (CYP 450) isozymes predominantly in the liver, small intestine, brain, and lung (when taken by respiratory route). CYP2C9, CYP2C19, and CYP3A4 metabolize THC. CBD is extensively metabolized by CYP3A4 and 2C19 and to a lesser extent by CYP1A1, CYP1A2, CYP2C9, and CYP2D6.57,58 Pharmacists should note the potential for interactions with other substrates of these enzymes. The main metabolites of Δ9-THC are 11-hydroxy-THC (11-OH-THC) and 11-carboxy-THC (11-COOH-THC). 11-OH-THC is a potent psychoactive metabolite and may account for the prolonged duration of action of oral products.57
Cellular Effects
Cannabinoids act on receptors termed cannabinoid (CB) receptors, members of the large G-protein coupled receptor family, in the brain and other organs of the body. At least two cannabinoid receptors have been identified: CB1, which is found predominantly in the nervous system; and, CB2, which is located mostly in cells and organs that mediate immune functions and other peripheral responses.59,60
Endogenous substances (termed endocannabinoids) such as anandamide and 2-arachidonoylglycerol are the natural ligands for these receptors.59,60 The endocannabinoid system regulates many bodily functions, including emotional behavior, anxiety and depression, neurologic activity, nociception, the immune system, cardiovascular function, reproductive organ function, gastrointestinal motility, and metabolism, and it may be involved in neuroprotection.59,60 The wide range of physiological targets influenced by endocannabinoids has stimulated interest in cannabinoids as therapies for neurological, neurodegenerative, and psychological disorders, as well as pain, immune and inflammatory diseases, GI and metabolic disorders, drug addiction, and cancer.
Phytocannabinoids and synthetic compounds bind to the CB receptors with differing affinity and efficacy.59,60 The mechanistic dissimilarity confers differences in the effects of cannabinoids on the body. Δ9-THC acts as a partial agonist at CB1 and CB2 receptors, and this activity is believed to be
responsible for the characteristic intoxicating effects of Cannabis, such as euphoria, relaxation, and perceptual changes.59,60 Conversely, CBD has a relatively low affinity for CB1 and CB2 receptors, estimated in the low micromolar range.60 It acts as an inverse agonist of the CB2 receptor and a non-competitive negative allosteric modulator of the CB1 receptor at low concentrations and can antagonize the effects of THC.59,60 These mechanisms account for its lack of euphoric properties. However, it may also positively modulate endocannabinoid function.59,60 Although these mechanisms reduce cannabinoid activity, CBD may also produce positive effects by modulating endocannabinoid release.59,60
Despite the physiological importance of the cannabinoid system, many of the therapeutic actions of cannabinoids, especially CBD, involve other non- cannabinoid mechanisms, targeting other neurotransmitter and ion channel receptors (see below).59,60 The mechanisms responsible for both the therapeutic and adverse effects of the phytocannabinoids are not fully understood but the "promiscuous" pharmacology could account for their broad therapeutic spectrum.61,62
Combinations of Cannabis constituents have been hypothesized to produce synergistic activity, referred to as an entourage effect.63 Possible outcomes are a summation or potentiation of activity by active or inactive components, antagonism (such as reducing THC side effects by CBD), or pharmacokinetic and metabolic interactions.63,64 Some proponents of medical marijuana suggest that plant extracts may produce greater efficacy or different effects compared with individual cannabinoids via the “entourage effect.”63 Evidence for such an action is largely anecdotal at this time,64 although a higher potency of herbal CBD compared to purified preparations has been reported in clinical studies.44,64,65
Medical Uses for Marijuana
Cannabis has been promoted as having a benefit for many different disease states. More than a century ago, the United States Pharmacopoeia listed marijuana as a treatment for neuralgia, gout, rheumatism, tetanus,
hydrophobia, epidemic cholera, convulsions, hysteria, mental depression, delirium tremens, insanity, and uterine hemorrhage.5,66
More recently, cannabinoids have been used for many clinical applications, including management of nausea and vomiting, appetite stimulation in patients with HIV infection and AIDS, glaucoma, neurologic disorders (seizure disorders, multiple sclerosis, Parkinson’s disease, Tourette syndrome, and others), sleep disorders, Crohn's Disease, and relief of pain.67,68
Approximately 10% of marijuana users in the U.S. (a little over 1% of the total U.S. population) use the drug for medical purposes.46 As expected, the total is higher in states where medical marijuana is permitted. Generally, studies on the benefits of marijuana as a treatment for various conditions have been inconsistent and based on small sample sizes, often with confounding variables, poor design, different populations, and a lack of consistency in cannabinoid exposure (form, dose, route, frequency).69-72
In a comprehensive review published in 2017, the National Academies of Sciences, Engineering and Medicine evaluated the existing evidence. They concluded that there is conclusive or substantial evidence that Cannabis or cannabinoids are effective in treating chronic pain, reducing chemotherapy- induced nausea and vomiting, and improving patient-reported spasticity associated with multiple sclerosis.46 In addition, there is moderate evidence of cannabinoids improving short-term sleep outcomes associated with obstructive sleep apnea, pain, and multiple sclerosis.
A detailed description of the clinical uses of marijuana is beyond the scope of this lesson, but the interested reader can consult recent reviews for more information.46,69-72 A few major clinical applications will be briefly summarized.
Use of Marijuana to Treat Seizure Disorders
Pre-clinical evidence that marijuana could exert anti-seizure activity has been available for many years, but its strong sedative effect hampered clinical applications.73 Cannabidiol possesses reduced intoxicating activity and has shown great promise as a treatment for seizure disorders in pre-clinical and clinical studies.46,73 Evidence that CBD could exert anti-seizure activity in humans was first described in the 1980s.74
In open-label expanded access programs and randomized placebo- controlled trials, a highly purified oral preparation of CBD showed a significant improvement in seizure frequency in a large number of patients with different types of treatment-refractory epilepsy.46,75 The FDA approved Epidiolex®, a CBD, for the treatment of rare genetic pediatric seizure disorders, Lennox- Gastaut syndrome (LGS) and Dravet syndrome (DS) in 2018 and tuberous sclerosis complex in 2020.76 This is the first (and at this time, only) purified substance obtained from marijuana to receive FDA approval.
Cannabidiol has a weak affinity for cannabinoid receptors, so the anti- seizure effect is likely mediated by other mechanisms involving other receptors, ion channels, and neurotransmitter transporters.73,75 Likely candidates include orphan G protein-coupled receptors (e.g., GPR55), modulation of adenosine, activation of 5HT1A receptors, or modulation of intracellular calcium levels, possibly through the transient receptor potential (TRP) cation channels (e.g., TRPV1, TRPA1, TRPM8).73,75
Use of Marijuana to Treat Pain
The National Academies report (above) concluded that there was strong evidence for cannabinoids as a treatment for pain.46 A study in patients conducted almost 50 years ago found that 10-20 mg of THC reduced pain equivalent to 60-120 mg of codeine.77 Support for the possible analgesic activity of cannabinoids is provided by observations that endocannabinoids modulate pain pathways, and CB1 receptors are found on peripheral sensory nerves.78,79
However, many published reports conclude that the evidence is inconsistent and may depend on the type of pain.77-88 The strongest evidence in support of cannabinoids for pain appears to be for cancer-related pain.85-88 Positive results have also been reported on neuropathic pain, patients with multiple sclerosis, and post-trauma.81,82 A recent literature review found little to no effect in acute pain, headache, and pain associated with spasticity.82 There also may be a narrow therapeutic window for the analgesic properties of Cannabis such that higher doses may introduce adverse effects such as drowsiness, dizziness, and dysphoria.46,81,82 Reduction in pain has also been reported with transdermal CBD-containing gels.56
Generally, research finds more support for reducing pain when THC is combined with CBD than when each is taken alone.89 (Pharmacists should note that an oromucosal spray of Cannabis extract [Sativex®] containing THC and CBD and other minor cannabinoids [aka nabiximols] is available in numerous countries and is in clinical trials in the U.S., for treatment of spasticity due to MS.)90 Another possible advantage of the combination is that CBD may diminish some of the adverse side effects from Δ9-THC.46 Cannabidiol and THC may also be anti-inflammatory.46,89
It has also been proposed that cannabinoids may enhance the anti- nociceptive effects of opioids and reduce the dose of opioids needed for treating pain.91 This could occur through reciprocal interaction between endocannabinoid and opioid nociceptive systems. Cannabinoids produce an increase in synthesis and release of endogenous opioids such as enkephalin and dynorphins, and endogenous cannabinoid systems may play a role in opioid antinociception.91
Clinical studies of cannabinoid/opioid interaction are limited, and they present conflicting results.91-93 There are reports of a decreased need for opioids in some patients using Cannabis for pain. Studies have also reported that states with medical marijuana programs had significantly lower opioid overdose mortality rates than states without them.92,94 Some clinical studies described a considerably lower daily intake of opioids and a slowing of opioid consumption in cancer patients using medical marijuana compared to patients
receiving only opioid medication.5,92,94 One interpretation is that marijuana may enhance the effectiveness of opioids and delay the development of opioid tolerance.95 On the other hand, there are conflicting reports that states with medical marijuana did not have a reduction in opioid overdose mortality rates.93
Use of Marijuana to Treat Cancer
Cannabinoids can play an important role in palliative cancer care because they can reduce nausea and pain while enhancing mood and sleep.86-
88 A possible anti-tumor effect of cannabinoids has also been suggested.87 Cannabinoids have shown anti-tumor properties in cell lines.64,86 Effects seen include cell death by apoptosis; inhibition of cell proliferation, angiogenesis, invasion, and metastasis; and enhanced immune surveillance.64,86 CB1 and CB2 receptor agonists stimulate apoptotic cell death in glioma cells.88 Recent studies have shown that CBD reduces cancer cell viability in many cancer cell types, such as neuroblastoma, glioblastoma, melanoma, leukemia, colorectal, breast, lung, or prostate.88 However, cannabinoids also have immunosuppressive properties, which could be pro-tumorigenic.88
It is important to note that there is no evidence of clinical effectiveness of Cannabis in the treatment or prevention of cancer to date.64,88 This is a frequent issue raised by patients and their families. The preliminary results do not yet provide a basis for recommending nor discouraging Cannabis as an anti-cancer treatment.64
Adverse Effects Associated with Marijuana Use
Marijuana is comparatively safe. Unlike opioids and other CNS depressants, cannabinoids do not produce respiratory depression due to a lack of CB1 receptors in CNS respiratory centers.46 Additionally, there is virtually no risk of a lethal overdose with Cannabis; even regular heavy users are exposed to THC that is orders of magnitude below the theorized human lethal dose of approximately 4 g.46
However, Cannabis is not without adverse effects. The most commonly reported adverse effects of cannabinoids are dizziness and drowsiness.96,97 Other common short-term effects of THC include impaired attention, coordination, and judgment, tachycardia, hypotension, and xerostomia.96,97 Common short-term side effects of CBD use include somnolence, diarrhea, fatigue, and anorexia.96,97
Long-term, high-dose Cannabis use may lead to more severe CNS complications, especially cognitive and memory impairment.98,99 Marijuana may be associated with the development of psychotic disorders, although this relationship is complex and related to many confounding factors, including alcohol use.98,99
The effect on the developing adolescent brain is of particular concern.100,101 Cerebral reorganization and other morphological changes occur during puberty, and many adverse psychological health effects (addiction/dependence, psychosis, cognitive impairment) are amplified when marijuana use begins in adolescence100,101 Evidence also supports that Cannabis use during adolescence and early adulthood may be associated with poor social outcomes, including unemployment, lower income, and lower levels of life and relationship satisfaction100,101 These concerns may be somewhat mitigated by the requirement that users in all states that legalized marijuana to date must be at least 21 years old; however, as with ethanol, these barriers are often easily circumvented.
Pharmacists should also be aware of drug interactions with cannabinoids, particularly pharmacodynamic interactions with other CNS depressants and cardiovascular agents, and pharmacokinetic interactions with drugs metabolized by CYP2C9, CYP2C19, and CYP3A4.57,102
Challenges and Opportunities
As marijuana continues its complicated path as its proponents push for its acceptance, pharmacists and other health care practitioners must confront
complex issues.27,46,103 Patients, caregivers, and others will have questions about the efficacy and safety of marijuana for different conditions.
Pharmacists need to consider that consumers may be using various products (i.e., individual cannabinoids or different combinations) with different formulations (smoked v oral) and doses, often lacking standardization and quality control.57 Patients may use products recommended by a health professional or self-medicate with marijuana to deal with health conditions. They may also be using substances recreationally. The primary source of information for recreational users may be the internet, which provides limited input from a healthcare professional, if at all. Commercially available products are also available in retail outlets beyond pharmacies, creating additional challenges for clinicians.27,104
A recent study from Canada found that the most common uses of Cannabis by patients with legal access were to treat chronic musculoskeletal, arthritic, and neuropathic pain, anxiety and depression, and sleep problems.105 Pharmacists must remain aware of ongoing studies that may clarify inadequate or misleading information and distinguish between high- quality and lesser-quality research.84,86
Supporters and critics of state-level legalization of marijuana make numerous claims.15 Advocates suggest that legalization reduces crime, lowers criminal justice expenditures, improves public health, provides tax revenue, and stimulates the economy. Critics argue that legalization leads to increased use of controlled substances and alcohol, increases crime, diminishes traffic safety, harms public health, and lowers teen educational achievement.15
Research indicates that adolescents who use Cannabis are more likely to use other controlled substances than adolescents who never use Cannabis. However, most users of controlled substances share many genetic and social risk factors leading to substance abuse. Consequently, it is not clear whether Cannabis is a gateway drug that independently increases the risk of using other substances.106
Another growing concern as marijuana availability increases is the effect on driving. Marijuana is the most common illicit drug reported in motor vehicle accidents.107 However, the causal relationship is difficult to ascertain due to wide variations in the use of marijuana.107,108 Studies in an experimental situation indicate that acute intoxication with marijuana affects many cognitive and motor skills relevant to driving, including reaction time, attention, speed of information processing, tracking accuracy, time and distance estimation, motor coordination, and danger perception.108 Adolescents perceive Cannabis as safe to use, but unlike alcohol, marijuana generally leads drivers to overestimate their impairment.71,107,108 Studies have shown a significant correlation between high THC blood concentrations and car crash risk, but most studies do not support such a relationship at lower THC concentrations.71,107,108 However, research has not established a definitive concentration cut-off for impairment, although blood THC concentrations of 1-5 ng/ml have been recommended in different studies.107 Drivers with blood THC concentrations of 5 ng/ml or higher appear to have a risk at least comparable to a blood alcohol concentration of 0.10–0.15%.107,108 Other studies suggest that effects may largely disappear after controlling for other risky driving behaviors.107,108 CBD is sedating and may also impair driving ability, but no study has investigated car crash risks with this substance.107,108
Significantly, the marijuana available today is more potent than in the past. The THC content of commonly cultivated marijuana increased three-fold between 1995-2014, from 4% to 12%, and is considerably higher than the estimated level of 2% before 1990.43,109 These values make it difficult to extrapolate research that uses much lower concentrations of marijuana to “real world” situations.
Marijuana legalization has also significantly benefited states by increasing tax revenue.15 States like Colorado, Washington, Oregon, and California impose substantial excise taxes on medical and recreational marijuana (usually lower for medical), along with standard state sales taxes, local taxes, and licensing fees. California collects almost $50 million per month from recreational marijuana sales, while Colorado and Oregon collect more
than $20 million and $10 million in monthly tax revenues, respectively.15 The proposed federal legislation to decriminalize marijuana (see above) will also impose excise taxes. Thus, there is a financial incentive to legalize marijuana. Healthcare professionals should consider whether Dr. Sanjay Gupta, CNN’s chief medical correspondent, is correct when he says, “it is irresponsible not to provide the best care we can as a medical community, care that could involve marijuana.”110
Summary
The U.S., has had a complicated relationship with Cannabis (marijuana), alternating between approval and condemnation. Federal law evolved after the 1930s, imposing greater regulation on marijuana use and possession. This trend culminated in 1970 with marijuana’s listing as a Schedule I substance. While the states initially followed this path, in 1996, California became the first state to allow the use of marijuana for medical purposes. Since 1996, nearly all states have enacted laws allowing medicinal or recreational use of marijuana to some degree. As of December 2020, some form of medicinal cannabis is legal in 47 states, the District of Columbia, Guam, the United States Virgin Islands, and Puerto Rico.
While states have enacted medical marijuana laws, they conflict with federal law, which still treats marijuana as a Schedule I substance. The federal government can prosecute patients using marijuana even if they comply with the laws of their state. However, in recent years, national institutes and federal agencies have taken a more relaxed approach towards people who comply with their state’s medical marijuana laws.
The most abundant and well-known phytocannabinoids are Δ9- tetrahydrocannabinol (Δ9-THC) and cannabidiol, or CBD. In addition to naturally grown marijuana, synthetic Cannabis products are available. Cannabis has been promoted as having a benefit for many different disease states. More than a century ago, the USP listed marijuana as a treatment for neuralgia, gout, rheumatism, tetanus, hydrophobia, epidemic cholera,
convulsions, hysteria, mental depression, delirium tremens, insanity, and uterine hemorrhage.
Marijuana is comparatively safe. Unlike opioids and other CNS depressants, cannabinoids do not produce respiratory depression due to a lack of CB1 receptors in CNS respiratory centers. Additionally, there is virtually no risk of a lethal overdose with Cannabis; even regular heavy users are exposed to THC that is orders of magnitude below the theorized human lethal dose of approximately 4 g. However, Cannabis is not without adverse effects. The most commonly reported adverse effects of cannabinoids are dizziness and drowsiness.
As federal and state laws regulating marijuana continue to evolve, possibly towards a path of full legalization, pharmacists and other health care practitioners will be confronted by complex issues. Patients, caregivers, and others will have questions about the efficacy and safety of marijuana for medical or recreational use.
Course Test
Under the Controlled Substances Act (CSA), marijuana was
not included as a controlled substance.
listed as a Schedule III drug.
listed as a Schedule V drug.
was placed in the most restrictive category, Schedule I.
Physicians may marijuana to patients eligible under state law.
prescribe
recommend
dispense
authorize
is the only FDA-approved cannabidiol (CBD) used to treat rare genetic pediatric seizure disorders.
Epidiolex®
Dronabinol
Delta-9 tetrahydrocannabinol
Sativex®
Following oral ingestion of cannabinoids such as edibles, CNS effects
are less pronounced than smoking marijuana.
do not last as long as smoking marijuana.
have a delayed onset.
are immediate due to rapid absorption of CBD or THC.
True or False: Orally ingested cannabidiol (CBD) is greatly influenced by the presence of food, and a high fat meal results in a substantially higher plasma concentration.
True
False
Cannabinoids are used to treat cancer in certain settings because of their possible
cell proliferation action.
dyspeptic effects.
inhibition of metastasis.
pro-tumorigenic properties.
Pharmacists should also be aware that cannabinoids interact negatively with
CNS depressants.
drugs metabolized by CYP2C9, CYP2C19 and CYP3A4.
certain cardiovascular agents.
All of the above
The most commonly reported adverse effects of cannabinoids are
the development and exacerbation of psychotic disorders.
tachycardia and hypotension.
xerostomia and anorexia.
dizziness and drowsiness.
If medicinal marijuana is legal under state law, federal laws making marijuana use a crime
do not apply.
do not apply if the patient has a prescription for medical marijuana from a physician.
still apply.
are preempted by state law.
True or False: Long-term, high-dose Cannabis use may lead to cognitive and memory impairment or the development of psychotic disorders.
True
False
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DISCLAIMER
The information provided in this course is general in nature, and it is solely designed to provide participants with continuing education credit(s). This course and materials are not meant to substitute for the independent, professional judgment of any participant regarding that participant’s professional practice, including but not limited to patient assessment, diagnosis, treatment, and/or health management. Medical and pharmacy practices, rules, and laws vary from state to state, and this course does not cover the laws of each state; therefore, participants must consult the laws of their state as they relate to their professional practice.
Healthcare professionals, including pharmacists and pharmacy technicians, must consult with their employer, healthcare facility, hospital, or other organization, for guidelines, protocols, and procedures they are to follow. The information provided in this course does not replace those guidelines, protocols, and procedures but is for academic purposes only, and this course’s limited purpose is for the completion of continuing education credits.
Participants are advised and acknowledge that information related to medications, their administration, dosing, contraindications, adverse reactions, interactions, warnings, precautions, or accepted uses are constantly changing, and any person taking this course understands that such person must make an independent review of medication information prior to any patient assessment, diagnosis, treatment and/or health management. Any discussion of off-label use of any medication, device, or procedure is informational only, and such uses are not endorsed hereby.
Nothing contained in this course represents the opinions, views, judgments, or conclusions of RxCe.com LLC. RxCe.com LLC is not liable or responsible to any person for any inaccuracy, error, or omission with respect to this course, or course material.