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(p. 256) What Is the Evidence of Marijuana as Medicine? 

(p. 256) What Is the Evidence of Marijuana as Medicine?
Chapter:
(p. 256) What Is the Evidence of Marijuana as Medicine?
Author(s):

Kevin A. Sabet

, David Atkinson

, and Shayda M. Sabet

DOI:
10.1093/med-psych/9780190263072.003.0011
Page of

date: 16 November 2018

Introduction

Since research on marijuana’s potential medicinal properties does not have a long history in Western civilization—as opposed to research on the opium poppy, for instance—the underdeveloped concept of marijuana as medicine today is controversial and often distorted. Medical marijuana in the United States has bypassed the usual process of scientific rigor that is required to make medicine available and has created a political controversy among the American public. The controversy lays, in part, in the question of whether marijuana’s potential benefits outweigh its potential harms. Though some research suggests that components in marijuana can treat nausea from cancer chemotherapy, reduce seizures in epileptic children, assist with muscle spasticity, and may offer pain relief, studies also find (as described in many chapters in this book) that regular and heavy use of whole-plant marijuana is linked to a variety of adverse effects, including mental illness, poor cognitive development, lack of motivation and productivity, and poor academic performance.

Given the potential harmfulness of marijuana, opinion on its use as medicine is strongly divided between the scientific community and the public. According to most opinion polls, the public agrees with medical marijuana when asked (Nelson, 2016). However, virtually every single medical organization stands strongly against state-based medical marijuana programs that permit widespread use.

About half of US states as of 2017 have legalized the use of marijuana for medicinal purposes, in particular, to treat illnesses such as HIV/AIDS, cancer, and glaucoma. Yet, a growing body of literature shows that a very small percentage of medical marijuana patients suffer from serious, life-threatening illnesses. As will be discussed in more detail later in the chapter, over 90% of patients in most (p. 257) medical marijuana states cite chronic pain as the primary purpose for their use (Sabet & Grossman, 2014).

This chapter delineates the history of marijuana’s development as a medicine, gathering the early evidence of its harms and effectiveness. It provides an overview of its medicinal components and the pharmaceutically developed medicines based on such components. The chapter further attempts to analyze the impacts of medical marijuana laws in the United States and the challenges associated with doing so.

History of Medical Marijuana

Though the history of marijuana’s use for therapeutic purposes traces back thousands of years, it was not introduced to Western medicine until the mid-19th century. In 1839, Irish physician William B. O’Shaughnessy introduced the European world to the therapeutic properties of cannabis, which he discovered during his nine years at the Medical College of Calcutta in India. Following his discovery, early applications of various components of marijuana were used to treat ailments such as melancholia and migraines and to act as sleeping aids and anticonvulsants.

An early pharmacopoeia, written by Wood and Bache in 1854 and referenced in Leslie Iversen’s (2007) The Science of Marijuana, offers an insightful view of the perceived medical benefits of marijuana in the 19th century:

Extract of hemp is a powerful narcotic, causing exhilaration, intoxication, delirious hallucinations, and, in its subsequent action drowsiness and stupor, with little effect upon the circulation. It is asserted also to act as a decided aphrodisiac, to increase the appetite, and occasionally to induce the cataleptic state. In morbid states of the system, it has been found to produce sleep, to allay spasm, to compose nervous inquietude, and to relieve pain. In these respects it resembles opium in its operation; but it differs from that narcotic in not diminishing the appetite, checking the secretions, or constipating the bowels. It is much less certain in its effects; but may sometimes be preferably employed, when opium is contraindicated by its nauseating or constipating effects, or its disposition to cause headache, and to check the bronchial secretion. The complaints to which it has been specially recommended are neuralgia, gout, tetanus, hydrophobia, epidemic cholera, convulsions, chorea, hysteria, mental depression, insanity, and uterine hemorrhage. (p. 121)

During this time, Western medicine also witnessed the advent of new synthetic drugs. For example, the active ingredient in the opium poppy, morphine, was identified and isolated, and its salts could be readily formulated for oral use or for injection by hypodermic needle. Soon after, other opioids and oral synthetic medicines, such as aspirin—with defined composition and potency—were also (p. 258) developed. Yet throughout its medical history, individuals never smoked opium for medicinal purposes.

Despite considerable research spanning many decades, the active ingredient in cannabis remained unknown for decades. Because cannabinoids are not water soluble, it was extremely difficult to produce medical products of reliable composition and predictable effect. Patient response was uncertain, and marijuana products gradually fell out of favor with the medical profession. In 1937, the Marijuana Tax Act, which placed a tax on physicians prescribing cannabis, on retail pharmacists selling cannabis, and on the cultivation or manufacturing of medical cannabis, made cannabis-based medicines a much less attractive treatment option. Following the enactment of the tax, Robert Walton, a professor of pharmacology at the University of Mississippi, documented the drug’s decline in popularity, maintaining:

The popularity of the hemp drugs can be attributed partly to the fact that they were introduced before the synthetic hypnotics and analgesics. Chloral hydrate was not introduced until 1869 and was followed in the next 30 years by paraldehyde, sulfonal and the barbitals. Antipyrine and acetanilide, the first of their particular group of analgesics [aspirin-like drugs], were introduced about 1884 [aspirin, not until 1899]. For general sedative and analgesic purposes, the only drugs commonly used at this time were the morphine derivatives and their disadvantages were very well known. In fact, the most attractive feature of the hemp narcotics was probably the fact that they did not exhibit certain of the notorious disadvantages of the opiates. The hemp narcotics do not constipate at all, they more often increase rather than decrease appetite, they do not particularly depress the respiratory center even in large doses, they rarely or never cause pruritus or cutaneous eruption and, most importantly, the liability of developing addiction is very much less than with the opiates. These features were responsible for the rapid rise in popularity of the drug. Several features can be recognised as contributing to the gradual decline of popularity. Cannabis does not usually produce analgesia or relax spastic conditions without producing cortical effects and, in fact, these cortical effects usually predominate. The actual degree of analgesia produced is much less than with the opiates. Most important, the effects are irregular due to marked variations in individual susceptibility and probably also to variable absorption of the gummy resin. (Walton 1938, as quoted in Iversen, 2007, pp. 121–122)

By the 1960s, technology enabled chemists to identify (and synthesize) tetrahydrocannabinol (THC) as the primary psychoactive ingredient of marijuana. At the same time, anecdotal reports of therapeutic benefits from recreational users of marijuana emerged in the 1960s and 1970s. These developments led to increased research interest in developing a medication for cancer chemotherapy-induced nausea and vomiting.

(p. 259) More recently, new techniques have identified other cannabinoids in the plant, allowing for the production of a wide range of medicines with varying cannabinoids or cannabinoid ratios, and different therapeutic synergies and effects. Modern drug delivery methods now permit researchers to develop bioavailable formulations in appropriate dosage forms like oral or oromucosal (e.g., absorbed in the mouth). Had technology been more advanced in the early 1900s, cannabinoid medicines may have developed as opiates did, and there might be a much different medical marijuana controversy – or none at all – today.

The Political Controversy

The case of opium is instructive when discussing marijuana and its possible medical benefit. In the 1800s, a clear path for medicalizing the opium poppy plant was established. That is, opium was processed into purified forms to produce medicines like morphine, but it was also frequently abused, particularly with hypodermic needles. Though some derivatives were promising, a diacetyl derivative called heroin created more benefits for pain relief than possibly imagined from its marketed role as a cough suppressant. However, cannabis did not follow these paths—medical research on the drug did not start in earnest until the mid-20th century—and thus, today we are left with a political controversy.

Today the issue seems to be distorted, with medical marijuana earning a place in the modern lexicon. The all too narrow references to smoking the marijuana plant versus the more scientifically accurate medical cannabinoids further reinforce this distortion. Marijuana legalization proponents have taken advantage of this misleading view of medicine. For years, proponents of legalization have attempted to use medical marijuana as a stepping-stone to broader liberalization of the drug. Keith Stroup, the founder of the National Organization for the Reform of Marijuana Laws (NORML), said in 1979, “We [NORML] are trying to get marijuana reclassified medically. If we do that (we’ll do it in at least 20 states this year for chemotherapy patients) we’ll be using the issue as a red herring to give marijuana a good name. That’s our way of getting to them.” (“NORML Chairman Keith Stroup Talks on Pot Issues,” 1979).

Though NORML would not succeed in legalizing marijuana for medical purposes for another 15 years, the long-term messaging strategy seems to have paid off. In 1996, the Compassionate Use Act passed in California, allowing people with qualifying medical conditions to legally obtain and grow marijuana. In time, the director of NORML, Allen St. Pierre flatly stated, “In California, marijuana has also been de facto legalized under the guise of medical marijuana” (St. Pierre, 2009).

Since 1996, about two dozen additional states and the District of Columbia have also legalized the use of marijuana for medical purposes, and there is considerable variability among them in terms of regulation and eligible ailments or disorders (Bestrashniy & Winters, 2015). Table 10.1 provides a summary of all medical marijuana laws in the United States (National Council of State (p. 260) (p. 261) (p. 262) (p. 263) (p. 264) (p. 265) Legislatures, 2017). Seven of the 23 states allow for-profit medical marijuana dispensaries to operate, 3 states place qualifying conditions under the discretion of physicians, and 13 states delineate 10 or more qualifying conditions.

Table 10.1 State Medical Marijuana/Cannabis Program Laws

State

Statutory Language (Year)

Patient Registry or ID cards

Allows Dispensaries

Specifies Conditions

Recognizes Patients from Other States

State Allows for Retail Sales/Adult Use

Alaska

Measure 8 (1998) SB 94 (1899) Statute Title 17, Chapter 37

Yes

No

Yes

Yes, for AZ; approved conditions, but not for dispensary purchases

Ballot Measure 2 (2014) Not yet fully operational/regulated production or sales

Arizona

Proposition 203 (2010)

Yes

Yes

Yes

Yes

Arkansas

Issue 6 (2016) Details pending

Pending

Pending

Pending

Pending

California

Proposition 215 (1996) SB 420 (2003)

Yes

Yes (cooperatives and collectives)

No

No

Proposition 64 (2016)

Colorado Medical program info Adult- use info

Amendment 20 (2000)

Yes

Yes

Yes

No

Amendment 64 (2012) Task Force Implementation Recommendations (2013) Analysis of CO Amendment 64 (2013) Colorado Marijuana Sales and Tax Reports 2014 “Edibles” regulation measure FAQ about CO cannabis laws by the Denver Post

Connecticut

HB 5389 (2012)

Yes

Yes

Yes

Delaware

SB 17 (2011)

Yes

Yes

Yes

Yes, for DE; approved conditions.

District of Columbia

Initiative 59 (1998) L18-2010 (2010)

Yes

Yes

Yes

Initiative 71 (2014)

Florida

Amendment 2 (2016) Details pending

Pending

Pending

Pending

Pending

Guam

Proposal 14A Approved in Nov. 2014, not yet operational. Draft rules released in July 2015

Yes

Yes

Yes

No

Hawaii

SB 862 (2000)

Yes

No

Yes

No

lllinois

HB 1 (2013) Eff. 1/1/2014 Rules

Yes

Yes

Yes

No

Maine

Question 2 (1999) LD 611 (2002) Question 5 (2009) LD 1811 (2010) LD 1296 (2011)

Yes

Yes

Yes

Yes, but not for dispensary purchases

Question 1 (2016)

Maryland

HB 702 (2003) SB 308 (2011) HB 180/SB 580 (2013) HB 1101-Chapter 403 (2013) SB 923 (signed 4/14/14) HB 881-similar to SB 923

Yes

Yes

Yes

No

Massachusetts

Question 3 (2012) Regulations (2013)

Yes

Yes

Yes

No

Question 4 (2016)

Michigan

Proposal 1 (2008)

Yes

Not in state law, but localities may create ordinances to allow them and regulate them

Yes

Yes, for legal protection of posession, but not for dispensary purchases

Minnesota

SF 2471, Chapter 311 (2014)

Yes

Yes, limited, liquid extract products only

Yes

No

Montana

Initiative 148 (2004) SB 423 (2011) Initiative 182 (2016)

Yes

New details pending

No**

New details pending

Yes

New details pending

No

New details pending

Nevada

Question 9 (2000) NRS 453A NAC 453A

Yes

No

Yes

Yes, if the other state’s program are “substantially similar”; patients must fill out Nevada paperwork

Question 2 (2016)

New Hampshire

HB 573 (2013)

Yes

Yes

Yes

Yes, with a note from their home state, but they cannot purchase through dispensaries

New Jersey

SB 119 (2009) Program information

Yes

Yes

Yes

No

New Mexico

SB 523 (2007) Medical Cannabis Program

Yes

Yes

Yes

No

New York

A6357 (2014) Signed by governor 7/15/14

Yes

Ingested doses may not contain more than 10 mg of THC, Product may not be combusted (smoked)

Yes

No

North Dakota

Measure 5 (2016) Final details pending

Pending

Pending

Pending

Pending

Ohio

HB 523 (2010) Approved by legislature, signed by governor 6/8/16, not yet operational

Yes

Oregon

Oregon Medical Marijuana Act (1998) SB 161 (2007)

Yes

No

Yes

No

Measure 91 (2014)

Pennysylvania

SB 3 (2016) Signed by governor 4/17/16, not yet operational

Yes

Yes

Yes

Puerto Rico

Public Health Department Regulation 155 (2016), not yet operational

Cannot be smoked

Rhode Island

SB 791(2007) SB 185(2009)

Yes

Yes

Yes

Yes

Vermont

SB 76 (2004) SB 7 (2007) SB 17 (2011)

Yes

Yes

Yes

No

Washington

Initiative 692 (1998) SB 5798 (2010) SB 5073 (2011)

No

Yes, approved as of Nov. 2012, stores opened in July, 2014

Yes

No

Initiative 502 (2012) WAC marijuana rules: Chapter 314-55 WAC

FAQ about WA cannabis laws by the Seattle Times

Who Uses Medical Marijuana and Why?

As noted in Table 10.1, the medical use of unrefined marijuana is currently legalized in nearly half of the American states and the District of Columbia; also, there are a number of countries across the globe, including Canada and Australia, that permit medical marijuana. Today, there are thousands of medical marijuana dispensaries across the United States and hundreds of thousands of medical marijuana cardholders. Though the initial campaigns to pass medical marijuana laws in the United States have typically been associated with cancer, HIV/AIDS, and glaucoma patients, today, relatively little is known about the real conditions afflicting medical marijuana cardholders. Still, the few studies that exist find that only a small minority of medical marijuana users report serious, life-threatening illnesses.

Most previous research on who uses medical marijuana and why is limited to California, where legislation passed in 1996 permitting the use of marijuana for “cancer, anorexia, AIDS, chronic pain, spasticity, glaucoma, arthritis, migraine, or any other illness for which marijuana provides relief” (Compassionate Use Act of 1996; emphasis added). In 2007, the Harm Reduction Journal published a study that examined of 4,117 medical marijuana users in California between 2001 and mid-2007 (O’Connell & Bou-Matar, 2007). The authors found that during this period, 77% of medical marijuana users were male with a median age of 31 years, and nearly 70% of all users were White—not representative of the American adult population. Moreover, 88% of all users first used marijuana before the age of 19 and almost 90% report near daily use (O’Connell & Bou-Matar, 2007). In a study of a series of 623 psychiatric patients, Nussbaum, Thurstone, McGarry, Walker, and Sabel (2015) found that possession of medical marijuana cards was associated with being more likely to use marijuana over 20 times in the past month. Furthermore, the study identified 282 individuals who report using marijuana, and 133 who have bought or received medical marijuana from a cardholder. Forty-one percent of cardholders in this population reported ever having shared or sold their medical marijuana (Nussbaum et al., 2015).

A recent study by Lankenau et al. (2017) reveals that in the past 90 days medical marijuana patients were using the drug during an average of 76.4 days and spent an average of $565 on marijuana during that 90-day period; 22.6% reported reselling the dispensary products to someone else during the past 90 days.

Another study analyzed a sample of 1,746 medical marijuana users within nine medical marijuana assessment clinics (i.e., clinics that charged $100 to $125 for an assessment of eligibility for medical marijuana but did not dispense marijuana) in California in mid-2006 (Reinarman, Nunberg, Lanthier, & Heddleston, 2011). Similar to the findings from O’Connell and Bou-Matar (2007), Reinarman (p. 266) et al. reported that nearly three fourths of all patients were male and 62% were White. Sixty-seven percent of patients reported using marijuana daily, and 53% reported use at least twice a day. The study also found that nearly 83% of patients self-report that pain relief is the primary reason for using medical marijuana. Nunberg, Kilmer, Pacula, and Burgdorf’s (2011) further analysis of the data found that the most frequently diagnosed conditions were musculoskeletal and neuropathic chronic pain such as back pain and arthritis, while HIV/AIDS, cancer, and glaucoma combined comprised of only 4.4% of diagnoses.

A problem inherent in these reports is that there is an overabundance of illnesses that can only be demonstrated by subjective report. Without objective criteria, it is difficult to assess which individuals are using marijuana for their stated medical conditions, since incentive exists to report a medical need in states where the drug is illegal for recreational use or taxed at different rates for medical and recreational use.

Oregon passed medical marijuana legislation in 1998 for patients diagnosed with qualifying conditions such as cancer, glaucoma, Alzheimer’s disease, HIV/AIDS, and posttraumatic stress disorder (PTSD). As of 2015, there were over 72,000 medical marijuana patients in Oregon. State records have found that 92.8% of patients reported using medical marijuana to treat severe pain, while only 8.1% are diagnosed with the original qualifying conditions: cancer, glaucoma, HIV/AIDS, or Alzheimer’s disease (Oregon Health Authority, 2015). According to the Oregon Health Authority’s 2015 report on Oregon’s Medical Marijuana Program, 23 physicians (1.4% of all physicians associated with Oregon’s Medical Marijuana Program) were responsible for 78% of all patient registrations (Oregon Health Authority, 2015). In Colorado, there are 113,585 active medical marijuana patients, signed for by only 226 physicians (Colorado Department of Health and Environment, 2015). Of these patients, 99.8% reported severe pain as the primary condition for seeking medical marijuana, while less than 5% also reported having cancer, glaucoma, or HIV/AIDS (Colorado Department of Health and Environment, 2015).

An analysis of over 200,000 medical marijuana patients from seven different states found that 91% of users report using marijuana primarily to alleviate severe or chronic pain (Sabet & Grossman, 2014). Consistent with Nunberg et al. (2011), Reinarman et al. (2011), and O’Connell and Bou-Matar (2007), Sabet and Grossman found that a very small percentage of their sample are cancer, glaucoma, or HIV/AIDS patients (3.2, 1.3, and 1.4%, respectively).

Treating Chronic Pain

As previously noted, the majority of medical marijuana users cite pain as the main reason for its use. When examining this literature, there are issues of whether cannabis is inhaled to treat the pain, the potency of the product, and whether acute or chronic pain was treated. The clinical trials reviewed in the recent report by the National Academies of Sciences, Engineering, and Medicine (p. 267) (2017) all had a fairly short follow-up, and the clinical laboratory studies showed simply the short-term relief of pain, rather than a sustained reduction in pain, which limits the ability to determine whether cannabis is efficacious for chronic pain. The report, and press related to it, often confused whole-plant cannabis with components within cannabis, frustrating the head of the National Institute on Drug Abuse in a remarkably candid blogpost (Volkow, 2017). It should be noted that the long-term efficacy data supporting the use of opioids for pain in these conditions are also lacking, and efficacy for chronic pain is limited by the practical difficulties in continuing placebo-controlled studies for a long period of time.

Of note regarding the debate of smoked versus non-smoked cannabis is the recent publication by Andreae et al. (2015), in which the authors pooled patient data from multiple randomized controlled trials. Their main conclusion was a significant effect for smoked cannabis. Yet this method differs from a conventional meta-analysis, which examines the effect sizes of each individual study. The decision by Andreae et al. to pool individual patient data increases the statistical power to determine whether the treatment is effective, but, by doing so, it adds potential confounds as studies with varying parameters are combined. The authors noted that the studies in the review varied with respect to the duration of marijuana use (it varied from a few days to a few weeks), the length of follow-up assessments, and difficulties determining whether subjects knew which treatment they had been allocated to (i.e., unblinding; when an experienced marijuana user would likely know if he or she were in a placebo condition, even if the design were double-blind) and thus could be susceptible to the placebo effect.

To ensure validity of the studies showing that cannabis may be an effective and sufficiently safe treatment option for chronic pain, the treatment should not just be for acute pain, and if inhaled cannabis is used, the safer, noninhaled cannabinoid preparations should be tested as a comparison. If studies show efficacy, it would be important for state medical marijuana programs to approximate the controls used in the studies to ensure that users are in accordance with what the science may show to be effective. Unfortunately, the robust controls in these studies are typically very different from those afforded by medical marijuana programs, including limits on frequency, quantity, and using a known concentration of THC in the marijuana. In addition, findings from clinical laboratory studies may not generalize in the face of rigorous clinical trials. For example, Wilsey et al. (2016) demonstrated in a laboratory experiment that marijuana was associated with pain reduction in the lab, an effect that is well-known for cannabis. But the study does not add to our knowledge of whether this is an effective medical treatment for chronic pain in the clinical setting requiring day-to-day pain relief. Frequently, substances lose their effect when used over days and weeks as the body adapts to the “new normal” of having the drug in its system.

Clinical studies should also address whether there are any benefits to inhaled cannabis as opposed to orally administered purified forms, because the additional addiction risk incurred through the oral route of administration along with (p. 268) other intoxication effects and variabilities in dosing are significant concerns for the patient using medical marijuana. Moreover, there is the issue of side effects. For example, as noted by Wallace, Marcotte, Umlauf, Gouaux, and Atkinson (2015) impairment in neuropsychological task performance was associated with marijuana dosage levels.

Furthermore, whereas authors report that medical marijuana has reduced opioid use, there is a difficulty in determining whether this effect is directly due to cannabis or simultaneous increasingly strict laws against opioids that happened to coincide with medical cannabis. The Michigan study (Boehnke et al., 2016) did not look at the changes in opioid use of a control group and used only one marijuana dispensary in that state, leaving questions of generalizability. Bradford and Bradford (2016) used all prescriptions filled by Medicare Part D enrollees from 2010 to 2013 and found that use of prescription drugs for which cannabis could serve as a therapeutic alternative dropped significantly subsequent to the implementation of medical marijuana laws. This finding is most interesting and could signal a means by which patients eschew opioid abuse. But these findings would have been strengthened if the authors had also examined whether possible changes in opioid access laws and standards had been considered in the analysis.

Marijuana’s Adverse Effects

The first rule of all physicians is primum non nocer. That is, whatever treatment a doctor prescribes to a patient, first and foremost, that treatment must not do anything that the doctor has good reason to believe will cause a net increase of harm to the patient. This principle is at the heart of the medical marijuana debate on the political, health and social fronts, the most contentious aspect of which regards the degree of potential harm associated with the drug’s use.

Marijuana’s adverse mood reactions may include anxiety and paranoia, panic, depression, dysphoria, and hallucination. These reactions are more likely to be observed in new or heavy marijuana users. For example, a 2015 article published in the Lancet suggests that regular use of high-potency THC (often referred to as “skunk-like” and containing 14 to 15% THC) is associated with 24% of new cases of psychotic disorder in South London (Di Forti et al., 2015).

The Institute of Medicine’s report (Joy, Watson & Benson, 1999), as well as the follow-up report by the National Academies of Sciences, Engineering, and Medicine (2017), thoroughly examined both the psychological and physiological risks of marijuana. Like that of many other drugs, the regular use of marijuana produces chronic adverse effects such as tolerance, physical dependence, and withdrawal symptoms (Budney, Hughs, Moore, & Vandrey, 2004; Chung & Winters, this volume). With respect to its other health effects, at the time of the IOM report in 1999, the effects of marijuana were mainly evidenced by statistical associations; yet subsequent research, which is presented in numerous chapters in this volume, provides more evidence of marijuana playing a causal role.

(p. 269) For the purposes of this chapter, we discuss a health issue pertinent to the medical marijuana issue: childhood exposure. Perhaps due to a media-driven enthusiasm for high-cannabidiol [CBD]/low-THC oil, many parents are turning to CBD-oil for their epileptic children. One difficulty with outcomes of observational studies done in the context of media hype is the potential of the placebo effect to bias open-label research. The question was raised in an open-label study (Press, Knupp & Chapman, 2015) finding that parents who came to Colorado from out-of-state were more likely to report response to marijuana preparations. Of the eight responders who had EEG data, none showed improvement in electroencephalogram. Porter and Jacobson (2013) reported that some children treated with high CBD oil were getting up to 0.8 mg/kg of THC. Since a “typical” joint contains 29 mg of THC (Hunault et al., 2008), this means that even 36 kg (79 pound) kids would be getting one joint’s worth of THC every day. Given the substantial harms that have been linked to daily, or near-daily, marijuana use, it seems that this is a very important consideration when maintaining CBD purity. Furthermore, the addition of THC to CBD could lead to the untrained eye mistaking improvements in spasticity or locomotor activity after THC administration for a genuine reduction in epileptic seizures. There is also potential concern that THC would be used for the amelioration of behavior problems, because exhausted parents might see the reductions in locomotor activity as therapeutic benefits—while the action raises an ethical concern regarding tranquilizing a disruptive child instead of using behavioral modifications.

Groups such as MAMMA (Mothers Advocating Medical Marijuana for Autism) have made striking claims of efficacy, but it remains to be seen how the drug affects these youth in the short and long-terms. Given the drug’s adverse effects on reinforcement learning (Oleson & Cheer, 2012) and social functioning (Platt, Kamboj, Morgan, & Curran, 2010), extreme caution is needed prior to giving the drug to individuals with autism, who rely on the evidence-based treatment with behavioral modifications and social skills training for their psychotherapeutic treatment. The sedating effects of cannabis also raise the danger that the drug could be simply used to reduce these children’s undesirable behaviors rather than improve their developmental growth.

Medicinal Properties of Cannabis: What Does the Science Say?

The marijuana plant constitutes approximately ten groups of closely related cannabinoids, which have a variety of effects on the brain. Recent advances in science have identified two cannabinoid receptors in the brain, CB1 and CB2. CB1 receptors mediate the psychoactive effects of THC, while the CB2 receptors are expressed mainly in the immune system and other areas outside the brain (Felder & Glass, 1998; Munro, Thomas & Abu-Shaar, 1993; Pertwee, 1999, 2006), but they are also present in special cells that nourish and promote neuronal function, called microglial cells. These cells are thought to have some potential (p. 270) role in substance use disorders and other psychiatric disorders (Cutando et al., 2013). While the role of CB2 receptors remains somewhat mysterious, the role of the type 1 receptors is much clearer.

CB1 receptors are abundantly located throughout the brain and regulate numerous functions such as brain development, memory and cognition, motivational systems, appetite, immunological functions, reproduction, movement coordination, and pain regulation, though the extent and direction of each effect depends on the dosage of marijuana administered (Joy, Watson, & Benson, 1999). The original function of these receptors was, of course, not to be acted upon by THC but to respond to chemical messages in the brain. The natural activators of these receptors are called endocannabinoids, and they activate the cannabinoid receptors much less potently than THC or synthetic cannabinoids do. Chemicals that activate receptors are frequently called agonists, and those that block the receptors are called antagonists.

The modulation of the endocannabinoid system in ways that are more sophisticated than simple CB1 agonist action represents an enormous therapeutic opportunity (Picone & Kendall, 2015). There is hope in the future to affect regulators of the endocannabinoid system such as fatty acid amyl hydrolase, monoacylglycerol lipase (Tuo et al., 2017) for a more targeted improvement in therapeutic symptoms that does not disrupt endocannabinoid signaling. Certain drugs that act at sites related to the CB1 receptor, termed allosteric modulators, that do not fully agonize the CB1 receptor, also hold significant promise (Nguyen, Li, Thomas, Wiley, & Kenakin, 2016).

There are a number of marijuana-based medicines legally available that do not require smoking or inhaling the raw plant, and most current research on the efficacy of cannabinoids is not focused on crude marijuana extract but on the individual components of the plant that may have medical value. It should go without saying that smoking would not be an accepted therapeutic delivery system for reasons of dosage control, cognitive side effects, enhanced reinforcement leading to increased medicine self-administration, cardiac effects, and the acute and chronic respiratory effects on the lungs. Most drug delivery systems, with the exceptions of drugs like bronchodilators and nitroglycerine, are designed to deliver steady blood levels over many hours, whereas smoking produces rapid peaks.

Whole Plant Marijuana

Advocates of using the entire marijuana plant or whole-plant extracts frequently invoke the concept of entourage effects, whereby the mixture of all of the cannabinoid chemicals together would produce new therapeutic effects not seen with the components alone. Combining other components judiciously with CBD may add to clinical benefits. Also, additional cannabinoid compounds contributing to therapeutic benefits of medical marijuana is biologically plausible, but they have not been proven to contribute in a clinically meaningful way. Potential (p. 271) downsides to adding these chemicals exist, such as a lack of therapeutic specificity and a multiplication of potential side effects with different compounds. As to whether the whole plant is superior to the individual components, there is limited research. One study compared purified components to whole-plant extract, and it showed that THC actually outperformed the whole plant extract (Zajicek et al., 2005), and another study showed no benefit of the whole plant extract over purified components, but neither treatment had stronger effects than the placebo in that study (Strasser et al., 2006).

Though many maintain that marijuana’s whole plant extract is superior to its individual chemicals, use of the former is associated with potential risks. First, the inherent inconsistency of a plant will vary with the genetic endowment of its parents and varies greatly with the conditions of growth. Unlike purified extracts of THC and cannabidiol that are negative in the Ames test, whole plant extract has been shown to be carcinogenic (Wehner, van Rensburg, & Thiel, 1980), and there is great incertitude regarding the long-term toxicity of each of the many additional chemicals in the plant. Two studies point to the effects of smoke condensate in animals, one in female rats (Murthy et al., 1985), and one in Swiss Albino mice (Hoffman, Brunneman, Gori, & Wynder, 1975).

Matching the dose of THC in whole-plant extract with a purified pharmaceutical extract is difficult due to plant variability, and matching doses with the smoked plant is especially difficult due to the different concentrations (varying 24–462 μ‎g/L with the same dose of the drug smoked by a dozen different individuals) that individual users achieve (Hunault et al., 2008).

Several studies have tested whole plant marijuana for pain relief, but these studies have not used an active comparator of oral THC to demonstrate that the therapeutic benefits are superior when inhaled, which would be necessary to justify the increased risk of smoked plant. Studies of inhaled THC have also not shown superiority to the higher doses (Wilsey et al., 2016), The well-controlled conditions of these studies are also not analogous to the way in which ad lib cannabis is being recommended in American medical marijuana programs, and the benefits relatives to harms are much more difficult to maximize without these controls.

THC

Dronabinol (also known as Marinol® and Syndros) is a laboratory-synthesized THC capsule approved in 1985 in the United States for treatment of nausea and vomiting associated with cancer chemotherapy. By 1992, the Food and Drug Administration (FDA) also approved it for appetite stimulation for AIDS patients. Currently, it is the only cannabis-based drug approved for distribution in the United States. Its most common side effects include anxiety, confusion, depersonalization, dizziness, euphoria, dysphoria, and somnolence, though clinical trials suggest that lowering its dosage can significantly alleviate these effects (Joy et al., 1999).

(p. 272) Nabilone (also known as Cesamet), also based on THC, is used for nausea and vomiting related to cancer chemotherapy, but it has significant side effects such as dizziness and vertigo (Ward & Holmes, 1985) that have limited its use. Recently, nabilone has risen in popularity as a potential treatment for PTSD after benefits were suggested by an open-label trial (Fraser, 2009) and a preliminary randomized double-blind trial (Jetley, Heber, Fraser, & Boisvert, 2015). More data are sure to arrive regarding the use and effects of nabilone, and it will be important to investigate its relative efficacy and side effect frequency compared to other cannabinoids and standard treatments for PTSD.

CBD

CBD is one of the main components of marijuana that has been investigated for medical use and has been investigated for FDA approval. In the mid-2000s, researchers and activists began to educate interested patients and others about the therapeutic potential of CBD, which had been selectively bred-out of high-THC marijuana in the United States. Indeed, not long ago many individuals in the United States believed that CBD was an inert compound. There were also anecdotal reports of some adults with epilepsy who discovered that inhaled marijuana seemed to prevent or reduce their seizures. As more and more scientific research demonstrated that CBD had a variety of therapeutic effects, interest in the use of CBD in epilepsy grew.

Cannabidiol has been widely held to be the component of marijuana with better anti-seizure efficacy and certainly has evidenced a much better safety profile (Devinsky et al., 2014), since THC is a toxin to the developing child. For this reason, proper medical management would involve the maximization of the therapeutic potential of cannabidiol. Some have reported that the addition of THC to a CBD treatment could further improve the treatment of seizures, but it would seem advantageous to maintain independent dosing of CBD and THC to minimize potential harms of THC administration by keeping the dose as low as possible. Assuming an actual benefit to the addition of THC, slowly titrating THC would allow the physician to optimize the risk/benefit ratio in the partially protective presence of cannabidiol.

Since the mid-2000s, several pharmaceutical companies have been intensively researching CBD as treatment for medical conditions, including epilepsy. Several companies are currently developing CBD-based medications. One such product is the highly-purified CBD product, Epidiolex. Pediatric neurologists around the country, concerned that the desperate families of their pediatric patients were seeking access to artisanal CBD preparations of unknown quality and potency, began to seek FDA and US Drug Enforcement Agency (DEA) approval of expanded access or compassionate access investigational new drug programs to treat their patients with intractable epilepsy with Epidiolex. Approximately 20 such investigational new drug programs, covering over 400 children, have been approved by the FDA as of 2015 and many have secured DEA research (p. 273) registrations. One open-label study was reported by Devinsky et al. (2016) at the American Academy of Neurology, and it showed that in 137 out of 213 study completers, cannabidiol led to a mean reduction of seizures by 54%. GW Pharmaceuticals is also conducting four placebo-controlled clinical trials in children with two types of intractable epilepsy. Phase three studies released in 2016 found that Epidiolex achieved a median reduction in monthly convulsive seizures of 39% compared with a reduction on placebo of 13%, which was highly statistically significant (p = 0.01). Sativex (nabiximols), an orally administered 1:1 CBD–THC marijuana extract is currently in use in Canada and across Europe to treat neuropathic pain, as well as spasticity and other symptoms of multiple sclerosis (MS). Sativex is now approved for MS spasticity in 27 countries and is completing Phase 3 trials in almost 60 research sites in the United States in advanced cancer patients with significant pain.

The CNN program hosted by Dr. Sanjay Gupta in August 2013 (Gupta, 2013) reported the case of a toddler with horrible, life-threatening, intractable epilepsy. According to Dr. Gupta, her condition was greatly improved by a CBD-rich preparation produced by purveyors in Colorado. Though many were dismayed at how Dr. Gupta’s program interchangeably used THC and CBD and further confused the issue of recreational and medical marijuana (especially since the program was called “Weed”), the program resulted in enormous interest in CBD from families of children with epilepsy.

As desperate parents sought high CBD products wherever they could purchase them, a number of dispensaries and other opportunistic vendors began to sell these products. However, the labeled potency and composition of these products are often inaccurate and uneven, depending on the marijuana strain from which they come, the methods of manufacture used to prepare them, and the quality of the testing facility/procedures—leading the FDA to issue its first-ever warnings against medical marijuana companies (“2016 Warning Letters and Test Results for Cannabidiol-Related Products,” n.d.). At many stages in the cultivation and manufacturing process, lack of standardization can result in higher levels of THC and lower levels of CBD—as well as the varying levels of dangerous microbes or pesticides—in the final preparation. For example, growing from seed rather than clones; differences in the cultivation, harvesting, and drying conditions; uneven decarboxylation; and use of toxic extraction chemicals, such as butane or non-pharmaceutical ethanol.

Manufacturers and other purveyors of CBD products make many therapeutic claims that bring those products within the scope of the Food, Drug, and Cosmetic Act. For manufacturers of other products such as pharmaceutical products, dietary supplements, and even foods, the FDA reviews all sources of promotional statements (including websites, Facebook, Twitter, and other online media sources) that could be interpreted as making improper therapeutic claims. Claims are often made for a wide variety of medical conditions and risks are rarely mentioned. In a survey administered by the journal Epilepsia, a minority of epileptologists and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data, and 48% (p. 274) would advise using medical marijuana in severe cases of epilepsy (Mathern, Beninsig, & Nehlig, 2014). By comparison, nearly all patients and the public said there were sufficient safety (96%) and efficacy (95%) data, and 98% would recommend medical marijuana in cases of severe epilepsy. General physicians, basic researchers, nurses, and allied health professions sided more with patients, agreeing that there are sufficient safety (70%) and efficacy (71%) data, and 83% would advise using marijuana in severe cases. A majority (78%) said there should be pharmacologic-grade compounds containing CBD, and there were no differences between specialists, general medical personal, and patients and the public. The huge gap between what the public thinks and what medical doctors believe is emblematic of the medical marijuana debate generally. Despite not producing euphoria or addiction, use of cannabidiol with a developing brain still carries concerns. The development of axons and proper synapses is dependent upon the growth of small projections termed filopodia, whose growth can be inhibited by cannabidiol’s disruption of G protein-coupled receptor 55 signaling (Cherif et al., 2015), and the practical consequences of this on brain development are unknown.

Some studies find that CBD can counteract some of the adverse effects of THC (Morgan, Freeman, Schafer, & Curran, 2010). However, research finds that it does not do so by blocking the CB1 receptors, but rather by modifying these receptors and acting at a different site (Laprairie, Bagher, Kelly, & Denovan-Wright, 2015). The interactions between CBD and THC are very complex, and involve actions of CBD at other sites.

Dosage Issues of THC and CBD

An urgent and critically important concern regarding the combined use of THC and CBD is the fact that the dosing ranges for therapeutic benefits are quite different, and the THC: CBD ratios found in the plants do not approximate the difference in the drugs therapeutic doses. The therapeutic doses of THC for FDA-approved indications range from 2 to 20 mg of THC per day, while the dose of cannabidiol that is theorized to be effective for treating seizures is between 200 and 600 mg/day, and perhaps higher, making the therapeutic dosing of THC and CBD at a minimum to be a 1:10 THC:CBD ratio (max of 20 mg of THC/day, and a minimum of 200 mg of CBD/day). Because the ratio of THC:CBD is at least 1:1 in most plants, and can be as high as 20:1, it makes it very difficult to find a strain of C. indica or C. sativa that would meet these requirements. Also, it makes sense to give clinicians the ability to individually titrate doses of THC and CBD, rather than be at the mercy of whatever the plan produces. As it stands now, clinicians who do not have access to pure, or near-pure, cannabidiol are locked into giving a much higher dose of THC than is medically indicated if they are titrating cannabidiol up to its therapeutic dose.

Also, it is very important to disentangle the effects of high-dose CBD from the effects of high-dose THC. THC has more developmentally neurotoxic effects (p. 275) and can acutely produce a good deal of sedation and euphoria that might color subjective reports of efficacy, as well as measures of seizure efficacy based on motor activity, as is the case of parental-reported seizure frequency. Limiting the amount of THC is also important when considering the 1938 statements of Walton (p. 152) who reported that medical use was practically limited due to “cortical” effects often predominating over the other physical effects at typical marijuana doses, which is echoed in the modern MS literature, reporting significant cognitive impairment among individuals with MS who use cannabis (Honarmand, Tierney, O’Connor, & Feinstein, 2011).

Other Cannabinoids

While considerably less researched, tetrahydrocannabivarin (THCV) is another component of marijuana with potentially important effects. THCV is an antagonist of the CB1 and receptor (Pertwee et al., 2007; Thomas et al., 2005), which means that it is highly unlikely that co-administering it would add to the therapeutic benefit of THC, but would probably counteract it. However, there is a possibility that this drug would have therapeutic potential for other indications, because it is a neutral antagonist of the CB1 receptor. This is opposed to rimonabant, which is an inverse agonist, meaning rimonabant destabilizes the endocannabinoid system by doing the opposite of what THC does. The neutral antagonist could be potentially therapeutic. It is also likely to be a partial agonist of CB2 (Pertwee, 2008), which could have therapeutic potential to affect that system, which is thought to be more important to diseases outside the central nervous system.

Another chemical component of marijuana with possible antiepileptic pharmacologic effect is cannabidivarin (Hill et al., 2012, 2013). Though it has not demonstrated a unique mechanism of action compared to CBD and THC on TRPV3 and TRPV4 channels (De Petrocellis et al., 2012), it’s antiepileptic effect is not CB1 dependent (Hill et al., 2013). It remains to be researched more extensively before its potential medical role is elucidated.

Evidence of Marijuana and Its Components’ Effectiveness as Medicine

The Journal of the American Medical Association recently published a meta-analysis that reviewed the medicinal benefits and adverse effects of using different cannabinoid drugs (Whiting et al., 2015). The authors’ analysis of 79 randomized medical trials examines the impact of using cannabinoids on nausea or vomiting from chemotherapy, appetite stimulation for HIV/AIDS patients, chronic pain, spasticity or paraplegia due to MS, anxiety disorder, sleep disorder, glaucoma, and psychosis, as well as any adverse effects such as dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination.

(p. 276) Though the study’s findings suggest that the use of cannabinoids is associated with certain improved benefits compared with placebos or comparators, few of its results are statistically significant. Specifically, treatment of nausea/vomiting, appetite stimulation, treatment of chronic pain or spasticity, glaucoma, or psychosis all yielded no improvements or statistically insignificant ones (Whiting et al., 2015). For marijuana to be effective for glaucoma, the person would need to smoke every three hours (Tomida et al., 2006), something not practical and highly dangerous if the user neglected to follow the regimen because glaucoma treatment requires continuous reduction of intraocular pressure. The positive benefits were limited to anxiety and sleep disorders; the meta-analysis finds that cannabidiol, compared to placebo, is associated with a greater improvement in anxiety symptoms as well as sleep disorders. However, the researchers judged many of the trials included in the analysis are at high risk of bias and thus should be interpreted with caution (Whiting et al., 2015).

Regarding adverse effects of marijuana use in these therapeutic studies, an analysis of 62 trials finds that there is a statistically significant increased risk of short-term adverse effects such as balance problems, confusion, disorientation, euphoria, and hallucination associated with the drug’s use (Whiting et al., 2015, p. 2466).

Sallan, Cronin, Zelen, and Zinberg (1980) compared prochlorperazine and THC for nausea and found that among these patients, there was a subjective preference for THC in the users, when both reduced nausea to seemingly equal levels. However, there are now many medications that are preferred to prochlorperazine for nausea, and these may outperform THC with greater breadth of treatment acceptance and fewer cognitive side effects. When a group of oncologists listed their preferred medications for nausea, they listed THC in ninth place among treatments and sixth out nine as a potential treatment for severe nausea (Schwartz & Beveridge, 1994). The emergence of cannabis-induced hyperemesis syndrome (Kim, Anderson, Saghafi, Heard, & Monte, 2015) suggests that it is very important to talk to patients who are using cannabis for nausea and vomiting about whether the drug is actually causing the problem, rather than relieving it.

A study of oral cannabis extract by Strasser et al. (2006) found that oral cannabis extract for cancer-related cachexia and wasting does not have any improvements in symptoms or quality of life compared with a placebo or THC extract. In fact, there were no differences in any outcome measure of the groups at any of the time measures.

In the unending quest to obtain a greater THC potency, plants are being bred and grown in conditions that maximize the conversion of the precursor material CBD to THC. While many medical marijuana strains show a lower THC:CBD ratio, some scientific evidence suggests the importance of giving THC and CBD together. A study comparing THC:CBD extract to THC alone showed that the combined treatment was associated with better improvement in pain, although it produced more nausea (Johnson et al., 2010). Whereas it is associated with a reduction in the intensity of the high (Morgan et al., 2010), this difference is not observed in all laboratory measures (Hindocha et al., 2015; Karschner et al., 2011).

(p. 277) Wade, Collin, Stott, and Duncombe (2010) and Novotna et al. (2011) demonstrated that Sativex (nabiximols) led to reduction in spasticity, and more recent open-label observational studies have supported the findings of efficacy and tolerability of nabiximols (Serpell, Notcutt, & Collin, 2013; Trojano & Vila, 2015). Corey-Bloom et al. (2012) showed efficacy of smoked marijuana for spasticity, but there was danger of unblinding, as it would be easy for the individual to know which treatment arm they had been allocated to based on the rather noticeable effects cannabis has on the user. This study also showed adverse cognitive effects, as have been found in other studies (Honarmand et al., 2011). Not all studies have seen cognitive problems, but there have been other correlations observed, such as a correlation between THC concentration and psychopathologic symptoms (Aragona et al., 2009).

The promise of cannabinoids in neuropathic pain is somewhat dampened by the mixed results of Langford et al. (2013), showing equivocal results. A very high placebo response in the first phase of the study was possibly responsible for hiding the positive benefits of nabiximols, but in the second phase of the study, which was a study following to discontinuation/treatment failure, the group given nabiximols performed better than placebo. An earlier study in diabetic peripheral neuropathy showed that cannabis was ineffective, but the authors suggested that depression was a confounding variable in their sample (Selvarajah, Gandhi, Emery, & Tesfaye, 2010).

Abrams showed some reduction of neuropathic pain in the short term with smoked cannabis, but the treatment also induced hyperalgesia (Abrams et al., 2007), a condition of increased pain sensitivity, as has been shown in other studies (Kraft et al., 2008). Opioids have been well-established to cause hyperalgesia and is a major limiting factor in their long-term therapeutic use (Yi & Pryzbylkowski, 2015), and this is a potentially important under-investigated parameter of long-term cannabinoid use (Kraft et al., 2008). A dose-dependent effect of THC on capsaicin-induced hyperalgesia has been suggested in the literature, with low doses of THC (2% THC joints) improving hyperalgesia, and high doses (8% THC joints) worsening it (Wallace et al., 2007). The smoked form of the medication also presents other problems.

Moore (2005) showed that long-term use of marijuana was associated with lung functioning; beyond the chronic cough, the study also found persistent bronchitis. Although as Tashkin (this volume) notes, the link between marijuana use and lung health is confounded by other variables and causal links are difficult to make.

Self-Regulated Dosing of Marijuana

Further research is needed to examine the potential effects and side effects of self-regulated dosing of marijuana, as is the practice in medical marijuana states in the United States (vs. doctor-controlled and doctor-prescribed dosing of THC). Due to lax medical marijuana law regulations, it is not a valid assumption (p. 278) to assume that benefits and levels of harm seen in controlled scientific studies will translate to benefits and levels of harm seen in an environment where patients control their own dosing and frequency of use of a substance that is habit-forming. Individuals left to use and dose on their own will often exceed the safety guidelines for medical marijuana and may miss therapeutic benefits seen at moderate doses that are potentially eclipsed at higher doses.

Difficulties in Placebo Control of Marijuana Studies

There are methodological challenges when medical marijuana studies use self-report measures. The first is that beyond the placebo effect of taking a medication that the user believes might help, there is an effect of intoxication on subjective reporting of all events. During a state of euphoria, neutral events are more likely to be rated positively, because of the neurobiologic alterations of the brain under the influence of THC. Activation of the ventral tegmental area and nucleus accumbens shell underlies the reinforcing properties of THC, and placebo effects have been shown to activate the nucleus accumbens as well. This means that subjective reports will be colored, typically toward the more positive during intoxication. Impairment of insight and awareness of errors has been shown with marijuana users (Hester, Nestor, & Garavan, 2009), and this may lead to underreporting of adverse effects of the drug on cognitive and behavioral performance. Pharmacologic studies of psychiatric medications rely on the blinded status of participants (not knowing which arm of the treatment study they have been allocated to), who are unaware of their medication states, to eliminate placebo effects. Participants in studies can sometimes accurately guess whether they have received active drug or placebo, and the use of cannabis and cannabinoids that take effect immediately raises a significant risk to double-blind studies, as users will often be able to tell that they are using a psychoactive cannabinoid (Lutge, Gray, & Siegfried, 2013).

It is very difficult to design a study in which an active marijuana user is unable to determine whether he or she had received marijuana or placebo—particularly when we are considering studies of smoked or vaporized cannabis that act rapidly on the central nervous system. For this reason, subjective reports of improvement are suspect if not corroborated by blinded raters’ assessments of the individual’s behaviors. Better potential exists for successful blinding with slow-release, oral forms of cannabis and cannabinoids that also probably have fewer central nervous system effects and greater therapeutic indices, meaning there is a larger margin for error between the dose that is medically effective and the dose that is dangerously toxic. Again, this highlights one of the major problems with medical marijuana. The question should not be whether inhaled whole-plant marijuana can positively affect any disease outcome; it is whether there is any value added to administering the smoked form of the drug to otherwise available oral forms.

(p. 279) Do Medical Marijuana Laws Increase Use?

Many studies seek to understand the relationship between approving norms of marijuana in a community and positive attitudes toward it and prevalence of its use, particularly among adolescents (Chilenski, Greenberg, & Feinberg, 2010; Hasin et al., 2015; Lipperman-Kreda, Grube, & Paschall, 2010; Stolzenberg, D’Alessio, & Dariano, 2016). While in many of the articles it has been stated as a conclusion that medical marijuana laws have not increased the use by adolescents, it is important to remember that this is very difficult to disprove, and failure to detect a difference does not prove a noneffect. The method of investigation has often been to determine whether the law enacted by the state changes adolescent use in that same state by controlling for pre-existing prevalence. While local laws would be expected to affect availability, changes in perception of harm are highly unlikely to stop at state borders. In assuming that they will do so, this approach ignores the realities of mass media culture, which brings the discussion of medical marijuana law changes in any state at a national level. Adolescents’ perception of harm has gone down, and state-by-state data need to be analyzed to see how different forms of medicalization, commercialization, and legalization affect drug availability in that particular state. Not all medical marijuana laws are created equal, and those that increase cannabis supply by creating a commercial market might be expected to have a higher impact, as shown by Pacula, Powell, Heaton, and Sevigny (2015). Analysis of individual factors and features of each medical marijuana law is critical for determining the effects of the law on a population. For this reason, it has been suggested that we use a taxonomy of medical marijuana regimes to analyze their effects on the population more effectively (Chapman, Spetz, Lin, Chan, & Schmidt, 2016).

A common question people ask is whether marijuana use rates are sensitive to changes in policy? Theory suggests that passage of medical marijuana policies can increase demand for marijuana in at least three ways: (a) through changes in perceived harms, risks, or disapproval of the drug; (b) through changes in the ability to access marijuana; and (c) changes in the supply or production of marijuana that ultimately reduce its price (Pacula & Sevigny, 2013).

Challenges in Analyzing the Effects of Marijuana Laws

An added difficulty of measuring the effects of marijuana laws on perceived harms is that the message of less harm is often delivered most forcefully during the phase of campaigning for legislative change—that is, prior to the vote. Also, an electoral victory may change perceptions of social acceptance of a drug prior to the actual implementation of the law. Measuring local effects of marijuana laws is difficult because messages communicated in the marijuana debate often do not stay confined to locale where the law was being debated—due to much of the conversation being through national media. Likewise, there is difficulty (p. 280) measuring the effects of marijuana laws on supply and availability of marijuana because licitly produced drug in a looser medical marijuana laws state will often illicitly cross state lines, as has been reported by Rocky Mountain High Density Trafficking Area (2014) reports. Another potential bias is that legal changes to marijuana and medical marijuana laws may simply be a reflection of greater acceptance of the drug, and studies would need to account for the expected continued rate of change before and after a medical marijuana law was passed. Certainly, the issue is complicated and requires better studies.

Since there has been a generalized reduction in the rates of many different adolescent risk-taking behaviors (e.g., sexual behavior, smoking, drinking, other drug use), it is important to analyze any change in marijuana use in regards to the general trend for other drug use, teen pregnancy, and motor vehicle accidents. Also, the Internet and social media have greatly changed teen culture, and more people than ever are staying connected by Internet as opposed to real-life contacts. This new phenomenon might explain some of the changes in drug using patterns. The rewarding effects of social media may be a substitute for some youth to the effects of using drugs, a possibility that has even intrigued Nora Volkow, the director of the National Institute on Drug Abuse (Richtel, 2017). But we appreciate that mathematically modeling the contribution of online activities is very challenging.

Early Evidence on the Effects of Medical Marijuana Laws

According to the 2014 National Survey on Drug Use and Health (NSDUH), the perceived risk of regularly (i.e., once or twice a week) using marijuana among Americans of all ages has been steadily declining, from approximately 51% in 2002 to 34% in 2014—a statistically significant difference in rates between the two years (Lipari, Kroutil, & Pemberton, 2015). Moreover, the 2014 Monitoring the Future survey data show that 23% of eighth graders associate risks and harm with marijuana use, compared to 29% in 2000 (Johnston, O’Malley, Miech, Bachman, & Schulenberg, 2014). Other studies have sought to examine the relationship between the availability of marijuana and prevalence of its use, yet the results remain mixed (Kim et al., 2016; Lucas & Walsh, 2017; Pardo, 2016).

Other correlations with medical marijuana laws have been found that are somewhat surprising, such as the effect on education based on medical marijuana law exposure (Plunk et al., 2016). It is important to analyze data such as these further, as was done by the authors of a study showing a correlation of medical marijuana laws and reduced fatality rates (Santaella-Tenorio et al., 2017). The authors noted that the heterogeneity of effects based on medical marijuana laws within states suggested that the reduction in traffic accidents was mediated by other factors. It is also important to analyze findings regarding traffic fatalities within the lens of decreasing rates of traffic fatalities over time (p. 281) (NHTSA, 2016) for the entire nation and to examine effects of changes in ride-sharing availability and driving under the influence enforcement.

Harper et al. (2012) questioned the validity of Wall et al.’s (2011) conclusion that states that legalized medical marijuana had higher rates of adolescent marijuana use, declaring that it is “unable to validly isolate the causal effect of interest, which is the estimated difference in marijuana use that we would observe if we randomly assigned some states to pass a law” (p. 208). (An important note: Wall et al. use 2002–2008 NSDUH data while Harper et al. use 2002–2009 data, adding an additional year of data to their sample.) To account for this, Harper et al. used a difference-in-difference model to analyze the same data, estimating within-state changes in marijuana use, before and after medical marijuana legislation. They concluded that past-month marijuana use among adolescents actually decreased by 0.53 percentage points MML states with medical marijuana laws, though their findings was consistent with Wall et al. that the perception of marijuana’s great risk decreased among youth in states with medical marijuana laws (Harper et al., 2012). Harper et al.’s analysis is problematic given that the estimated causal effect of marijuana was determined by changes observed in only 5 of the 16 states with medical marijuana laws. A further technical problem in the analysis is that difference-in-difference estimators are suited to a case-crossover design where all 50 states crossed over, rather than the analysis of 5 nonrandomly selected states among a group of 50. Furthermore, two of the five states used in their sample had abnormally high use rates in the year prior to legalization and removal of either of the states from the analysis would have yielded null results (Wall et al., 2012).

An analysis of combined state- and national-level Youth Risk Behavior Survey Surveillance between 1993 and 2011 found that medical marijuana legalization is associated with a decrease in the probability of past-month marijuana use among 12 to 17 year olds by 2.1 percentage points, though the study’s sample does not include Washington State and Oregon—two states with medical marijuana laws during the study period (Anderson, Hansen, & Rees, 2012). Conversely, an all-50-states analysis, the National Epidemiologic Survey on Alcohol and Related Conditions found a higher rate of marijuana use and a higher rate of dependence in all 50 states (Cerda, Wall, Keys, Calea, & Hasin, 2012). The survey also failed to find a difference in cannabis use disorders using NSDUH dat, but still demonstrated higher rates of use in those states (Cerda et al., 2012).

Schuermeyer et al. (2014) showed a difference in perceived risk for all age groups, greater availability for those age 26 and older, and a trend toward increased rates of abuse and dependence after the onset of commercialization in Colorado. Over the past decade, while medical marijuana use has been widely discussed and debated, we have seen reductions of perceived risk from 2002 to 2012, with especially great reductions in risk from 2008 to 2012 (Pacek, Mauro, & Martins, 2015). While one cannot say for certain how much medicalization has led to this decreased risk, the decreased perception of harm has correlated with increased daily and nondaily use (Pacek et al., 2015). The conversation has (p. 282) taken place on the national stage, and common sense would assume to lead one to think that conversations in the national stage might affect an individual’s perception of harm even outside of communities that have considered and enacted legislation.

A 2016 study published in the International Journal of Drug Policy (Stolzenberg et al., 2016) found that medical marijuana laws amplify youth marijuana use. The study, which utilized the largest national sample of drug users available, used five measurement periods calibrated in two-year intervals (2002–2003 to 2010–2011). The authors remarked,

[Our] research design is advantageous in that it affords us the ability not only to assess the effect of the implementation of medical marijuana laws on juvenile drug use, but also to consider other state-specific factors that may explain variation in drug use that cannot be accounted for using a single time series. (p. 1)

Stolzenberg et al. also found that other salient predictors of juvenile marijuana use include perceived availability of marijuana, percent of juveniles skipping school, severity of perceived punishment for marijuana possession, alcohol consumption, percent of respondents with a father residing in household, and percent of families in the state receiving public assistance.

An analysis of the Monitoring the Future surveys, which contain annual representative data of 8th-, 10th-, and 12th-grade students in the United States between 1991 and 2014, finds that past-month marijuana use is more prevalent among all three grades in states with medical marijuana laws than states without such laws (Hasin et al., 2015). However, the researchers also reported that the risk of marijuana use in medical marijuana states before passing medical marijuana laws did not differ significantly from their risks after the law was passed. The study, published in Lancet Psychiatry, attracted considerable attention. However, key findings were omitted from the media reports. For example, the study found that 10th and 12th grade use in Colorado increased significantly after medical marijuana. This finding suggests that medical marijuana laws and their implementation vary drastically across the United States. Colorado has a large, well-established, commercialized medical marijuana program, often heralded as an example by legalization advocates. It is important to control for these vast differences and to look at what happened in states with more established laws and laws that allow for commercialization.

A similar study was conducted by Pacula et al. (2015) in which the authors evaluated the impact of differential medical marijuana provisions—such as allowing home cultivation, commercialization, or requiring users to register as cardholders—on youth and adult use rates. They postulated that medical marijuana laws that increase the availability of the drug reduce the costs associated with consuming it, such as search costs, legal risks, perceptions of associated health risks, and its price, and thus, as basic economic theory predicts, demand for the drug increases.

(p. 283) Wen, Hockenberry, and Cummings (2015) pooled nine years of cross-sectional data from a restricted-access version of the NSDUH data set, 2004 to 2012, and reported there were increases in (a) the probability of current marijuana use, regular marijuana use, and marijuana abuse/dependence among those ages 21 years and above and (b) in marijuana use initiation among those ages 12 to 20 years.

Using data from the Treatment Episode Data Set and the National Longitudinal Survey of Youth 1997, Pacula et al. (2015) reported that states that allow the existence of medical marijuana dispensaries are associated with a 15% increase in treatment admissions, though the associations between home cultivation and cardholder registration requirements do not yield significant results. Moreover, the authors found that legal protection of medical marijuana dispensaries is associated with a 2% increase in past-month marijuana use and that laws allowing home cultivation are associated with an increase in past-month use by 1.8% and raise the probability of heavy use (defined as using marijuana more than 20 times in the last 30 days) by 1%.

Location of Dispensaries

The location and density of marijuana dispensaries is also related to marijuana use prevalence. A study published in September 2015, analyzing panel data of marijuana-related hospitalizations in California between 2001 and 2012, finds that each additional dispensary per square mile is associated with a 6.8% increase in the number of marijuana-related hospitalizations (Mair, Freisthler, Ponicki, & Gaidus, 2015). With regards to the changing price of marijuana, evidence suggests that the availability and legality of medical marijuana are associated with a 9.8% decrease in the price of high-quality marijuana (Anderson, Hansen, & Rees, 2013). A 2015 study finds that exposure to medical marijuana advertising has effects on youth by increasing their intentions to use (D’Amico, Miles, & Tucker, 2015). Monte, Zane, and Heard (2015) reported that there were more medical marijuana dispensaries than McDonald’s or Starbucks (Monte, Zane, & Heard, 2015).

Methodological Issues

Implementation of medical marijuana laws takes years, so what is needed is an analysis of the longer-term effects of these laws and their accompanying commercialization/regulation efforts. Colorado, for example, passed medical marijuana laws in 2000 but did not experience major changes until 2009, when commercialization began to flourish (Ghosh et al., 2015). Some studies only report a limited range of use frequency variables. For example, the Lancet study (Hasin et al., 2015) only reported past-year and past-30-day use and inexplicably did not include heavier (weekly or daily) use; such heavy use was the variables most associated with changes in marijuana laws in Pacula et al. (2015). Also, any (p. 284) Monitoring the Future study that reports the 12th grade data is not going to reflect nationally representative of 18- and 19-year-olds given the relatively high rates of school dropout rates in many regions of the country.

Effect of Medical Marijuana Laws on Other Substance Use

The reduction of opioid use in medical cannabis using individuals is frequently cited as a reason for allowing medical marijuana, and it is based on patients’ self-reports of substitution of cannabis for opioids (Lucas & Walsh, 2017). An oft-cited statistic is that harmful opioid use went down in states with medical marijuana laws (Kim et al., 2016), but this was an effect inferred from a reduction only seen in 21- to 40-year-old males based on fatal overdose toxicity, when the data were aggregated across states, which does make it difficult to analyze whether concomitant changes in state-level opioid policy has mediated any of the decrease. There remain significant barriers to making causal assumption because there have been significant changes in state and federal policy regarding opioids recently, which have been found to reduce opioid use, particularly prescription monitoring programs (Pardo, 2016). There have not been any analyses that have examined the combined contribution of reduction in opioid use from prescription monitoring and medical marijuana and crackdowns on pill mills (clinics with very high rates of opioid prescribing) that would be expected to have a more direct effect on opioid use. Choi (2014) reported that alcohol abuse/dependence rates are sensitive to medical marijuana laws; these rates increased after marijuana legalization, suggesting the two drugs might be complements and not substitutes as is often assumed. Also, a similar increase in nicotine use has been observed after marijuana legalization (Choi, Dave, & Sabia, 2016).

Conclusion

The term medical marijuana implies that the whole marijuana plant is a safe and effective medicine established by scientific inquiry. It is easy to see how the term medical opium could have led to similar confusion in the past, and, today, it is important to clarify the debate to inform people that different constituent components of the cannabis plant, called cannabinoids, have different effects on different diseases, and many of the potential effects remain less well-established than others. The cannabinoid system is a potentially powerful system to modulate, and much investigation into this area is needed.

Medical marijuana’s marketing to society, and the emphasis of potential positive benefits may have affected youth use. Moreover, the amplification of THC concentration since legalization and medical commercialization has led to a less-safe and less-standardized product because of protected indoor growing. Supply of marijuana is greater in these areas, and ill-effects of commercialization are not (p. 285) acted upon due to the powerful financial interests of recently legitimized medical marijuana growers allowing them to resist appropriate regulation. Recently, an attempt to collect signatures for a ballot initiative to require warning labels in Colorado was stifled by the industry paying the signature-collecting corporations not to collect signatures that were necessary for the referendum to head to a ballot (“Big Marijuana Trashes Democratic Process,” 2016).

Some benefits of THC and CBD have been found in a handful of controlled clinical trials for a very limited number of health problems. Following on this success, dramatic claims for success and accusations of conspiratorial silencing of marijuana’s benefits have led to an explosion in advertised benefits of medical marijuana, with frequently very little data backing up the claims, including claims seen in petri dishes that have been refuted in living organisms, as is the case of cancer. Effects of impure CBD preparations could lead many families to report effects of the preparation that are actually due to tranquilization secondary to THC intoxication. With a therapeutic dose range of 200 to 600 mg for CBD, even a residual 20:1 CBD:THC ratio could intoxicate a young person at a dose of 10 to 30 mg of THC.

When we look at the unintended effects of medical marijuana laws on health outcomes, an important caveat is that we must not assume that the effects of legalization and medicalization do not cross state lines. Youth and adults are well aware of the messages being transmitted in Colorado, California, and other states through the national media. We have seen marijuana being trafficked out of Colorado and California, and provisions allowing retail dispensaries have been associated with a subsequent increase in marijuana potency (Sevigny, Pacula, & Heaton, 2014). Due to illegal trafficking of legally produced marijuana in Colorado and California, it remains to be seen whether this will also increase the supply of high-potency THC across the country. Finally, another policy dimension that becomes incredibly complicated to study is the effect of domestic marijuana production on the rates of importation of cocaine, methamphetamine, and heroin. There is evidence for crop substitution in Mexico, with illegal traffickers switching from cannabis to opioids (Miroff, 2015).

The effects of medicalization have not been studied in depth, despite legalization and medicalization proponents claims that such policy changes would aid research. For example, money earmarked for research in California was not spent studying the effects of the legalized medical marijuana in humans. Unartful legislative drafting has not specified a practical monitoring mechanism for the drug, and the effects of legalization on testing have not been shown. The fast-tracking of research and collecting of data are highly important. None of the states that allow marijuana and extracts to be used as medicine have implemented adequate data collection tools. Part of this deficiency may be due to state governments not possessing the regulatory apparatus and expertise of the federal government, which are needed to ensure that measures are put in place to determine the efficacy and safety of pharmaceutical products. It has only been recently, and only with marijuana, that states have taken on the regulatory role of determining safety and efficacy of a pharmaceutical product. Furthermore, (p. 286) authors of the bills for regulation have not included experts in all of the relevant fields to legalization. The effects of medicalization that remain unexplored are those involving the substitution of medical marijuana for other treatments, the effect of regular marijuana use on compliance with other prescribed medical regimens, the adherence of medical marijuana patients to their prescribed regimens of marijuana, and the potential confounds of unblinding caused by the noticeable physical effects of marijuana.

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