By Luke Fortney MD, and Jason Kindschi, DC. Dr. Fortney is an Integrative Family Medicine Physician, Meriter Medical Group, Madison, Wisconsin. Dr. Kindschi is on the Life Sciences – Anatomy & Physiology Faculty at Milwaukee Area Technical College. Dr. Fortney and Dr. Kindschi report no financial relationships relevant to this field of study.
Background: The Historical-Politicalsocial Milieu
Cannabis sativa and indica are fragrant flowering plants native to South Central Asia. Their psychoactive properties have been known and used in some form or another for thousands of years in cultures as diverse as ancient Romania and China. The herb was called ganjika in Sanskrit, and then centuries later marijuana, which is derived from the Mexican word maraguanquo meaning “intoxicating plant.” It has been used for a variety of purposes by various societies across different times, including spiritual rituals as well as for medicinal purposes and recreation.1 A variety of Cannabis ruderalis called hemp (from the Old English word hænep) contains negligible levels of the psychoactive constituents of cannabis. For centuries it has been cultivated and harvested to produce a range of daily products such as food, fabrics, paper, and a building material. Ironically, initial drafts of the American Declaration of Independence are purported to have been written on hemp-fiber paper.2
Today cannabis is a prolific species cultivated worldwide. In the United States, cannabis was commonly used and a part of the U.S. Pharmacopeia and Dispensary until it was removed in 1942. It had been criminalized earlier in 1937 against the advice of the American Medical Association and the pharmaceutical industry.3 Interestingly, the U.S. government instituted the ban in the absence of scientific evidence to support this designation and its subsequent policies. It is contended that anti-marijuana laws and the government’s “reefer madness campaign” from that era were intended to placate racially charged puritans in southwestern states who associated its use with “degenerate Mexicans and migrant workers” along with “crime and deviant behavior.”4,5
It is currently illegal to grow or possess cannabis under the federal Controlled Substances Act (CSA) of 1970 (P.L. 91-513; 21 U.S.C. 801 et seq.) and it is regulated with zero-tolerance by the Drug Enforcement Administration (DEA), which classifies cannabis as an illegal Schedule 1 drug that has “no accepted medical use.” Despite this, the federal government produces medical grade cannabis at the University of Mississippi for research purposes. Nonetheless, there is notable sentiment among marijuana researchers that cannabis research operates “under a paradigm of prohibition.”6 They argue that current federal policy — based almost entirely on long-standing ideology vs legitimate research findings, along with a perceived reluctance by the National Institute on Drug Abuse (NIDA) to support research on marijuana’s medical benefits — continues to erect hurdles in the way of advancing meaningful research and patient care.7
On the social sphere, recreational use of marijuana continues to be widespread in the United States, with many states having enacted legislation that permits medical use of marijuana. In the 2012 election cycle, Colorado and Washington voted to decriminalize recreational use. In total, 18 states and the District of Columbia have passed laws that permit the use of cannabis for medical purposes. Without question, cannabis has proven to be controversial. It is debated among researchers, freedom and civil liberties proponents, policymakers and enforcing agencies, medial patients, and doctors among others.8,9 Proponents of medical marijuana have argued that “patients have a right to all beneficial treatments and to deny them this right violates their basic human rights.”10 Likewise, physicians and the general public are in broad agreement that marijuana shows promise as a valuable therapeutic agent for various medical conditions.11
Tetrahydrocannabinol and Cannabidiol: Physiological Effects of Cannabis
The pharmacodynamic effects of cannabis can vary widely among people and plant strains. What’s more, there are more than 400 different chemicals in a typical marijuana flower/bud, including its most well-known constituents δ-9 tetrahydrocannabinol (THC) and cannabidiol (CBD).12 THC was first isolated as a compound in 1964, and the cannabinoid receptors CB1 and CB2 — both G-protein coupled receptors — were discovered and cloned in the 1990s. This endocannabinoid system has far-reaching modulatory effects throughout the body and is found in particularly high densities in the central and autonomic nervous systems in areas that regulate motor activity, short-term memory, cognition, affect, appetite, sedation, pain, immune function, and inflammation among others.13 In short, it is described by researchers as having a presence in the body from head to toe.
THC is the primary psychoactive compound in cannabis. It inhibits the release of GABA and glutamate by binding to CB1 receptors found on pre-synaptic neurons, which produces feelings of euphoria, an altered sense of time, analgesia, increased appetite, and impaired memory. Data suggest CB1 receptors in the periaqueductal gray of the midbrain and dorsal root ganglion may explain the analgesic properties of cannabis. Likewise, CB1 receptors on sympathetic preganglionic adrenergic neurons have been shown to cause prolonged hypotension and bradycardia. CB2 receptors are found primarily on cells of the immune system, but also in the gut, brain, and vascular endothelium. CBD, on the other hand, is a non-psychoactive compound that is a 5-HT1A receptor agonist with inhibitory effects on the limbic system. CBD is an antagonist to THC, which suggests that therapeutic cannabis varieties with a higher CBD:THC ratio may prove more effective with less adverse effects for some patients. Both chemicals exhibit anti-inflammatory and neuroprotective effects.13,14
The various pharmacokinetics of cannabis are dependent on the particular cannabinoid and its active metabolite. For example, the active metabolite THC-COOH has different effects than its parent molecule THC on the endocannabinoid system. Furthermore, the pharmacokinetics of THC also vary depending on the route of administration. Inhaled THC causes a maximum plasma concentration within minutes (although psychotropic effects begin in seconds), and ultimately reaches maximum levels after 15-30 minutes before tapering down over 2-3 hours in most people. Following oral ingestion, psychotropic effects begin within 30-90 minutes while cannabinoids reach their maximum level after 2-3 hours. Orally ingested cannabinoids also have a longer active duration of 4-12 hours. At doses above the psychotropic threshold, ingestion of cannabis causes “enhanced well-being and relaxation with an intensification of ordinary sensory experiences” in most people. The most common side effects associated with use are dizziness, somnolence, altered mental status, and dry mouth.14 Regular use can lead to dependency in a small fraction of people as well as a mild withdrawal syndrome.15
Surveys show that a majority of the public views marijuana as being benign and non-addicting.16 This sentiment is reflected in the fact that marijuana is the most abused recreational drug in the United States.17 What most people don’t realize is that demand in the United States drives production, which in turn generates considerable cash for various Mexican drug cartels and gangs, which resulted in more than 24,000 deaths from 2006-2010.18
Marijuana imposes other dangers as well. For 9-10% of users it becomes addictive and interferes with interpersonal and occupational advancement.19 A 2002 Dutch study found that risk of psychosis, although small overall, was impressively higher among users compared to non-users (8 of 312 or 2.2%, and 30 of 3652 or 0.8% of users and non-users respectively).20 Furthermore, there is growing concern that the steady increase in the prevalence of frequent use among teenagers — along with a decrease in the age of first use — may induce persistent alterations in brain structure and function. A 2008 review went on to say that there is evidence to suggest that the severity of the effects of cannabis use on cognitive development is dependent on the age when it begins.21 That it has been implicated as a likely aggravator of major psychosis, depression, and anxiety disorders, particularly in young people, is reason for concern.22 A 27-year follow-up study of more than 50,000 Swedes found that the more cannabis individuals used in adolescence, the more likely they were to develop schizophrenia. Although small overall, there was a seven-fold increased chance of schizophrenia among those who used cannabis on more than 50 occasions compared to those who had never used it.23 What’s more, young people are experimenting with “synthetic marijuana,” which is made by dissolving toxic fluorinated synthetic cannabinoids in a solvent that are then applied to various dried plant material and inhaled — commonly known as K2 or spice. These dangerous toxic street cannabinoids have been linked with several cases of acute kidney injury.24
Other potential risks of smoking marijuana include dependency syndrome, increased motor vehicle crashes (MVC), impaired respiratory function, and accelerated cardiovascular disease.25 The most notable acute adverse effects of marijuana are anxiety and panic attacks, as well as increased heart rate and changes in blood pressure.15 Second only to alcohol, cannabinoids are the most commonly detected drug in intoxicated drivers. A meta-analysis of nine studies using a pooled analysis, random-effects model showed a summary odds ratio of 2.66, meaning that marijuana intoxication is associated with a significantly increased risk of MVC.26
The Marijuana Paradox
Smoking, both active and passive, is a well-established cardiopulmonary risk factor. Marijuana smoke, like tobacco, contains thousands of different chemicals.27 Clinically, marijuana smoking can precipitate angina and acute coronary syndrome.28 As such, patients with coronary heart disease (CHD), diabetes (DM), and peripheral arterial disease (PAD) should be warned about the high risk of any form of smoking.29 However, given that CB1 and CB2 receptors play a role in modulation of various cellular elements in vessel walls, a phenomenon known as the “marijuana paradox” shows how modulation of the endocannabinoid system can have seemingly opposing effects. For example, in addition to precipitating angina, cannabis may also have a role in atherosclerosis prevention.28
Along these lines, a case-control study reported at the annual meeting of the American Association of Cancer Research in April 2013 involved 2159 lung cancer patients and 2985 controls. This study showed that daily cannabis smokers were no more likely to develop lung cancer than those who didn’t, whether or not they also smoked cigarettes.30 Regarding this paradoxical finding, Michael Alberts, MD, chief medical officer of the Moffitt Cancer Center explains that conventional wisdom holds that cannabis smoking is not as dangerous as cigarette smoking, and that for some patients, the benefit could outweigh the risks.31
In terms of metabolic syndrome, the marijuana paradox also appears to be at work in that different cannabinoids have opposing effects on appetite and weight. Marijuana is well known for its appetite stimulating effect — popularly called “the munchies” — but it was recently discovered that obesity is paradoxically much lower among cannabis users compared to non-users. A study on the CB1 receptor-agonist Rimonabant concluded that it did in fact help patients lose weight and improve their overall metabolic profile.32
As more states pass legislation legalizing the use of marijuana for both recreation and medical purposes, considerable debate regarding its use, efficacy, and safety continues. Nonetheless, it is now clear that cannabinoids will play a more significant role in health care. The debate is not whether cannabinoids have value and purpose, but rather in what form, when, for what indications, and how they will be regulated. One does not need to look very far to see how the medical marijuana story is likely to unfold. There are historical similarities with the Oriental poppy plant, Papaver somniferum, which is the original source of opium and other opioid analgesics. In both instances, research into these plants and their respective compounds has led to the discovery of widespread endogenous regulatory systems, along with development of subsequent medications.
Development and use of cannabinoid medications is already underway. Whether plant-sourced herbs or synthesized analogue medications, cannabinoids were initially recognized therapeutically for their anticachexic and antiemetic properties.33 Since 1975, more than 100 controlled clinical trials have been conducted on the various medical indications of cannabinoids.14 In 1985, the FDA approved two synthetic cannabinoid derivatives, dronabinol (Marinol, Schedule 3) and nabilone (Cesamet, Schedule 2), taken orally for the treatment of chemotherapy-induced nausea and vomiting (CINV).34 In 1999, the Institute of Medicine acknowledged that there may be some benefit in smoking marijuana to stimulate appetite among AIDS patients suffering from chronic wasting syndrome. The report also acknowledged that it may also be beneficial in treating CINV, as well as for severe pain and spasticity.35 Although cannabinoids are not currently recommended as first-line treatment for CINV, Donald Abrams, MD, chief of oncology at UCSF, argues that medical marijuana should be considered a legitimate treatment option.8 It is a safer alternative to opioids,36 has a quick onset of action, is very effective, and the dose can be easily be self-titrated.34
Nabiximols (Sativex), an oromucosal spray, is a cannabis-derived liquid extract that is approved for medical use in Canada, New Zealand, and in eight European countries for the treatment of spasticity, neuropathic pain, and cancer-related pain and nausea. In 2011, for the first time, this plant-based extract containing equal parts TCH and CBD was approved for clinical use in Germany for the treatment of moderate-to-severe refractory spasticity related to multiple sclerosis. However, it is also commonly used off-label for anorexia, nausea, and neuropathic pain as well.14 It is still not FDA-approved as of 2013, but continues to be evaluated.37
A study of 1746 Californians using marijuana medicinally found that pain, insomnia, and anxiety were the most common conditions patients sought relief from and for which physicians recommended medical use of marijuana.38 There is also evidence that synergistic effects of cannabinoids on the hypothalamus and amygdala may dampen the strength of fear and emotionally traumatic memories through regulation of neuroendocrine and behavioral responses to stress, thereby making it easier for patients with post-traumatic stress disorder to sleep and feel less anxious and depressed.39 Additionally, when used in combination with opioids, cannabinoids lead to greater pain relief and overall reduction in opioid use. Use of cannabinoids in chronic pain patients who use prescription opioids also has been shown to rekindle opioid analgesia in cases where a lower dose had become ineffective. Furthermore, that cannabis has been used medically in the treatment of problematic opioid abuse suggests that appropriate, supervised access to medical marijuana may reduce the personal and social harms associated with opioid addiction.40
Currently, medical marijuana in the United States is obtained most commonly through various dispensaries in states where it is regulated. Increasingly, it is grown “illegally” by patients for personal use. Nonetheless, state-by-state regulation is inconsistent and federal law is contradictory.41 A recent Mayo Clinic Proceedings review of medical marijuana proposes reclassification of marijuana from Schedule 1 to Schedule 2 status11 — similar to opioids and stimulants — which would be a first step toward reconciling federal and state laws as well as permitting stifled research and medical care to move forward.6 Furthermore, the United States and other countries that ban medical marijuana could learn just how “successfully, compassionately — and non-controversially — such a program can be handled by looking at the unique national medicinal cannabis program in Israel” where more than 9000 medicinal cannabis prescriptions are currently active.42 The Israeli Ministry of Health regulates the national program, which along with Canada and the Netherlands, is in compliance with the 1961 United Nations Single Convention on Narcotics, and has consistently been in good standing with the International Narcotics Control Board.42
In the United States in particular, the medical marijuana debate also raises the question, what exactly makes a medicine a medicine? Robert DuPont, the former director of NIDA, asserts that medical marijuana is not actually medicine from the perspective of the FDA, whose role is to evaluate the efficacy and safety of specific pure-drug containing products, but not whole plants.9 What’s more, herbal medicines in general have long been viewed skeptically by allopathic doctors in that they often lack standardization, quality assurance, and regulation, unlike FDA-approved medications. However, an integrative medicine counter-argument contends that there is considerable value for plant-based medicines — including cannabis — which have an important and evolving role in health care.13,41 Rather than seeing herbal and allopathic medicine as dialectically opposed, it is wiser to see them as adjunctive and supportive tools that together can have increased utility and benefit, such as in oncology and palliative care settings.36
It is important to recognize that medical marijuana cannot actually be prescribed in any U.S. state; however, 18 states and the District of Columbia permit, in varying degrees, use of marijuana with a licensed physician recommendation.43 Nonetheless, marijuana use by patients should be approached with caution, noting that there is a small but significant subset of people who will experience adverse effects. That being said, the claims of marijuana’s extreme danger and highly addictive potential are also overstated. In general, for most people — and specifically for a subset of patients with particular conditions who are appropriately screened and counseled in the setting of an established therapeutic relationship with their personal physician — marijuana may be helpful while imposing little risk.44 That being said, all forms of smoking should be actively discouraged, and alternative routes of cannabis delivery — food, tincture, vaporized, sublingual, oral medication — should be used instead where appropriate on a case-by-case basis. It is also very important that physicians remind patients that although marijuana may be useful and safe in some cases, it is still illegal by federal standards. Patients who use medical marijuana depend on practical, up-to-date advice from their personal physicians who can help them navigate this evolving landscape.
Summary Points: Bottom Line on Marijuana