Blurred Boundaries: The Therapeutics and Politics of Medical Marijuana
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SPECIAL ARTICLE
Blurred Boundaries: The Therapeutics and
Politics of Medical Marijuana
J. Michael Bostwick, MD
Abstract
For 5 millennia, Cannabis sativa has been used throughout the world medically, recreationally, and spiritually. From the
mid-19th century to the 1930s, American physicians prescribed it for a plethora of indications, until the federal
government started imposing restrictions on its use, culminating in 1970 with the US Congress classifying it as a
Schedule I substance, illegal, and without medical value. Simultaneous with this prohibition, marijuana became the
United States’ most widely used illicit recreational drug, a substance generally regarded as pleasurable and relaxing
without the addictive dangers of opioids or stimulants. Meanwhile, cannabis never lost its cachet in alternative
medicine circles, going mainstream in 1995 when California became the first of 16 states to date to legalize its medical
use, despite the federal ban. Little about cannabis is straightforward. Its main active ingredient, ␦-9-tetrahydrocannab-
inol, was not isolated until 1964, and not until the 1990s were the far-reaching modulatory activities of the endocan-
nabinoid system in the human body appreciated. This system’s elucidation raises the possibility of many promising
pharmaceutical applications, even as draconian federal restrictions that hamstring research show no signs of softening.
Recreational use continues unabated, despite growing evidence of marijuana’s addictive potential, particularly in the
young, and its propensity for inducing and exacerbating psychotic illness in the susceptible. Public approval drives
medical marijuana legalization efforts without the scientific data normally required to justify a new medication’s
introduction. This article explores each of these controversies, with the intent of educating physicians to decide for
themselves whether marijuana is panacea, scourge, or both. PubMed searches were conducted using the following
keywords: medical marijuana, medical cannabis, endocannabinoid system, CB1 receptors, CB2 receptors, THC, cannabidiol,
nabilone, dronabinol, nabiximols, rimonabant, marijuana legislation, marijuana abuse, marijuana dependence, and marijuana
and schizophrenia. Bibliographies were hand searched for additional references relevant to clarifying the relationships
between medical and recreational marijuana use and abuse.
© 2012 Mayo Foundation for Medical Education and Research 䡲 Mayo Clin Proc. 2012;87(2):172-186
Very few drugs, if any, have such a tangled neurobiological function whose manipulation has
history as a medicine. In fact, prejudice, super- significant implications for the development of
For editorial stition, emotionalism, and even ideology have novel pharmacotherapies.4
comment, see managed to lead cannabis to ups and downs As recreational use continues to be endemic in
page 107 concerning both its therapeutic properties and the United States and medical use of smoked canna-
its toxicological and dependence-inducing bis burgeons, it becomes increasingly clear that the
From the Department of
effects. two are not discreet from each other, with implica-
Psychiatry and Psychology, E. A. Carlini1 tions medically for both seasoned and naive users.
Mayo Clinic, Rochester, MN.
Marijuana is unique among illegal drugs in its Even as proponents of legalization contend that
political symbolism, its safety, and its wide use. smoked marijuana is a harmless natural substance
G. J. Annas2 that improves quality of life, a growing body of evi-
dence links it in a small but significant number of
users to addiction and the induction or aggravation
L
ittle about the therapeutics or politics of of psychosis. As laboratory and clinical investigation
medical marijuana seems straightforward. exposes more of the workings of the recently discov-
Despite marijuana’s current classification ered endocannabinoid system and potential phar-
as a Schedule I agent under the federal Controlled macologic applications show increasing promise,
Substances Act, a designation declaring it to have federal law puts a damper on almost any research.
high abuse potential and “no currently accepted As an increasing number of states legalize marijua-
medical use,”3 physicians and the general public na’s medical use, the federal government maintains
alike are in broad agreement that Cannabis sativa its resolute stance that its use for any reason is crim-
shows promise in combating diverse medical ills. inal, a stance that renders prescribers simultane-
As with opium poppies before it, study of a drug- ously law-abiding healers and defiant scofflaws. In
containing plant has resulted in the discovery of what has been called “medicine by popular vote,”5
an endogenous control system at the center of the states formulate medical marijuana statutes
172 Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003 䡲 © 2012 Mayo Foundation for Medical Education and Research
www.mayoclinicproceedings.orgTHERAPEUTICS AND POLITICS OF MEDICAL MARIJUANA
based not on scientific evidence but on political ide- Cannabis-containing remedies were also used for
ology and gamesmanship. pain, whooping cough, asthma, and insomnia and
In each of these respects—recreational vs med- were compounded into extracts, tinctures, ciga-
ical use, benefit vs harm of use, laboratory research rettes, and plasters.13,14 More recently, the Institute
and pharmacologic application vs federal restric- of Medicine issued a report based on a summary of
tions, and state vs federal law— boundaries blur. the peer-reviewed literature addressing the efficacy
Contradictions and paradoxes emerge. This article of therapeutic marijuana use. The 1999 study found
explores each of these areas, with the intent of edu- at least some benefit for smoked marijuana in stim-
cating physicians so that they can decide for them- ulating appetite, particularly in AIDS-related wast-
selves whether marijuana is a panacea, a scourge, ing syndrome, and in combating chemotherapy-in-
or both. PubMed searches were conducted using duced nausea and vomiting, severe pain, and some
the following keywords: medical marijuana, medi- forms of spasticity.15,16
cal cannabis, endocannabinoid system, CB1 receptors, Contemporary Americans who eschew main-
CB2 receptors, THC, cannabidiol, nabilone, dronabinol, stream medical treatments while embracing herbal
nabiximols, rimonabant, marijuana legislation, mari- remedies perpetuate this 19th-century tradition of
juana abuse, marijuana dependence, and marijuana cannabis use. Even if cannabis use lacks the scien-
and schizophrenia. Bibliographies were hand tific legitimacy endowed by the randomized con-
searched for additional references relevant to clari- trolled trials that underpin modern evidence-based
fying the relationships between medical and recre- medicine, these individuals assert that the smoked
ational marijuana use and abuse. herb is highly effective against “a vast array of dis-
eases that are refractory to all other medications”17
WHAT IS MEDICAL MARIJUANA? and requires no further study to prove its medical
worth. Americans who shun prescription drugs but
For 5 millennia, Cannabis sativa has been used
stock up on “natural” compounds in the vitamin
throughout the world medically, recreationally, and
spiritually.6 As a folk medicine marijuana has been section of their local grocery store are prime candi-
“used to treat an endless variety of human miseries,” dates for this long-established folk nostrum, an “or-
although typically under the aegis of strict cultural ganic” means of self-medication.
controls, according to DuPont.7 The first medical With gardening sections in bookstores display-
use probably occurred in Central Asia and later ing robust selections of manuals for cannabis culti-
spread to China and India. The Chinese emperor vation, an uninformed shopper might conclude that
Shen-Nung is known to have prescribed it nearly 5 growing marijuana is as legitimate in the United
millennia ago. Between 2000 and 1400 BC, it trav- States as cultivating roses or zinnias. Anyone with a
eled to India and from there to Egypt, Persia, and credit card has ready access to blueprints for mari-
Syria. Greeks and Romans valued the plant for its juana propagation and culture. The concentration of
ropelike qualities as hemp, although it also had ␦-9-tetrahydrocannabinol (THC), the psychoactive
medical applications. The medieval physician Avi- ingredient in cannabis, ranges from less than 0.2%
cenna included it in his formulary, and Europeans of in fiber-type hemp (so-called ditch weed) to 30% in
the same epoch ate its nutritional seeds and made its the flower buds of highly hybridized sinsemilla.18
fibers into paper, a practice that continued for cen- With the goal of achieving better, more intense
turies. Indeed, the American Declaration of Inde- highs, cannabis cultivators have crossed and re-
pendence was purported to have been drafted on crossed diverse strains with the result that an aver-
hemp-based paper.8,9 age THC content of 2% in 1980 became 4.5% in
Traditional Eastern medicine met Western 1997 and 8.55% by 2006.19,20
medicine when W. B. O’Shaughnessy, an Irish phy- The term medical marijuana is ambiguous in that
sician working in Calcutta in the 1830s, wrote a it can refer to 2 of the 3 forms in which cannabinoids
paper extolling “Indian hemp.”10 The list of indica- occur.18,21 These include (1) endocannabinoids, ar-
tions for which he recommended cannabis—pain, achidonic acid derivatives such as anandamide pro-
vomiting, convulsions, and spasticity—strikingly duced in human tissue like any other endogenous
resembles the conditions for which modern medical neurotransmitters; (2) phytocannabinoids, the hun-
marijuana proponents extol its virtues. As of 1854, dreds of compounds in the C sativa plant, including
the medical use of cannabis received official legiti- the 2 most medically relevant ones, THC and can-
macy by its listing in the US Dispensatory.11 The nabidiol; and (3) synthetic cannabinoids, laborato-
black leather bags of 19th-century US physicians ry-produced congeners of THC and cannabidiol
commonly contained (among many other plant- that form the foundation of the pharmaceutical in-
based medicaments) cannabis tinctures and extracts dustry in cannabinoid-related products.21 For pur-
for ailments ranging from insomnia and headaches poses of this review, medical marijuana will be syn-
to anorexia and sexual dysfunction in both sexes.12 onymous with botanical cannabis, the second option,
Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003 173
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
as distinct from the third option, pharmaceutical can- obvious answer is ‘yes’—after all, this is the basic
nabinoids, which are synthetic cannabinoid-based reason for its recreational use.”
medications in use or under development. Whereas the psychoactive properties of canna-
Botanical cannabis attracts the notoriety and bis were first recognized thousands of years ago,
controversy. Given the far-flung influence of endo- these mind-transcending qualities were valued pri-
cannabinoids throughout the body, it is not surpris- marily as religious adjuncts. In the West before the
ing that botanical cannabis has traditionally been mid-20th century, recreational cannabis use was re-
used to combat so many ills. In modern times, it has stricted to such fringe or marginalized groups as
become an option of last resort for those for whom European intellectuals, rural Brazilian blacks and
available pharmaceuticals have proven ineffective, fishermen, and impoverished Mexicans for whom it
including individuals with intractable nausea and was “the opium of the poor.” Use became increas-
vomiting with cancer chemotherapy or anorexia in ingly popular in African American and immigrant
human immunodeficiency virus disease. This is the Hispanic neighborhoods before 1950. The “explo-
same substance, of course, that delights recreational sion of its consumption for hedonistic purposes” to
users, blurring the boundary between health care the point that up to two-thirds of US young adults,
and pleasure. transcending social class and race, had tried canna-
bis did not occur until the 1970s and 1980s.12 This
RECREATIONAL USE BLENDS INTO MEDICAL explosion happened not only among those getting
USE high for fun but also in those seeking to treat protean
medical conditions.
For recreational users, access to marijuana has
Medical and recreational users differ in how
always been about getting intoxicated. In the 21st
they use the drug. The amount used and goals of
century, cannabis is the most widely used illicit
ingestion diverge.36 The fundamental motivation
drug in the world,22 with the United Nations es-
(symptom relief) of the former does not match the
timating that up to 190 million people consumed
cannabis in 2007.23-25 Alice B. Toklas’s legendary goal (getting high) of the latter.25 Nonetheless, sev-
brownies notwithstanding, smoke inhalation is eral studies have demonstrated significant overlap
the preferred method of ingestion.20 Unlike eaten between medical users and recreational users. In a
botanical cannabis, smoked botanical cannabis af- Canadian study of 104 human immunodeficiency
fords high bioavailability, rapid and predictable on- virus–positive adults, 43% reported botanical can-
set, and easy titration that allows the smoker to max- nabis use in the previous year. Although two-thirds
imize desired psychotropic effects and minimize endorsed medical indications, ranging from appetite
negative ones.26,27 In what Russo calls an “entou- stimulation and sleep induction to antiemesis and
rage effect,” other cannabinoid constituents of the anxiolysis, a full 80% of this group also used it rec-
smoke besides THC may enhance the high28 or re- reationally.37 Another team of Canadian investiga-
duce the toxic effects of unopposed THC.29 Under tors interviewed 50 self-identified medical cannabis
the influence of the inhaled drug, most users expe- users, finding that “typically medical cannabis use
rience “mild euphoria, relaxation, and perceptual followed recreational use and the majority of those
alterations, including time distortion and intensifi- interviewed were long-term and sometimes heavy
cation of ordinary experiences such as eating, recreational users.” Most medical users continued
watching films, listening to music, and engaging in their recreational use.38 One of the “protean” med-
sex.”20 A few experience dysphoria, anxiety, even ical indications is even drug dependence itself. Al-
frank paranoia—symptoms that can also trouble though there is no research to support a substitu-
medical users.30 As cannabis strains are bred that tion strategy, addicts attempting to reduce
amplify THC content and diminish counteracting negative outcomes from alcohol, prescription
cannabidiol, highs become more intense but so do drugs, or illicit drugs, such as opiates, may have
degrees of anxiety that can rise to the level of panic switched to medical cannabis, regarded as a safer
and psychosis, particularly in naive users and unfa- option than the substances on which they were
miliar stressful situations.31-33 formerly dependent.39,40
Marijuana is touted as a kind of social lubricant, Blurring the boundary between medical and
helping users relax and feel more expansive and less recreational use still further, interviews with more
self-conscious. Effects that can limit use in a medical than 4100 Californians revealed that the medically
setting (short-term memory disruption, a sense of ill prefer inhaling their medication. When taken in
slowed time, increased body awareness, reduced pill form, drug effects are harder to control and more
ability to focus, incoordination, and sleepiness) are likely to prove noxious or excessively prolonged.26
exactly the sensations recreational users prize.21,34 Unlike smoked cannabis, swallowed cannabis un-
Cohen35 sums it up thus: “Can the recreational use dergoes first-pass hepatic metabolism, leading to
of marijuana cause cognitive impairment? The most variable and unpredictable amounts of active agent
174 Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003
www.mayoclinicproceedings.orgTHERAPEUTICS AND POLITICS OF MEDICAL MARIJUANA
reaching target tissues. Absorption is more erratic psychoactive adverse effects and ultimately refuse to
and peak concentrations lower.11 Smoked cannabis continue using it.28 Elikkottil et al21 caution about
offers both rapid response and easy titration35 based drawing conclusions that botanical cannabis is only
on the number of inhalations. In the manner of pa- for “potheads,” however, given that randomized
tient-controlled analgesia (the bedside narcotics controlled trials of botanical cannabis in inexperi-
pumps used in medical settings), smokers can dose enced users have not been performed.
themselves repeatedly throughout the day, inhaling
enough THC to get analgesic benefit but not enough
to sustain motor or psychoactive adverse effects that THE RELATIONSHIP BETWEEN PSYCHOSIS AND
will dissipate rapidly, if they occur at all.27,41 Med- MARIJUANA
ical users may actually consume less than recre- Marijuana continues to have the reputation among
ational users, inhaling doses sufficient only to pro- the general public as being benign, non– habit-
duce desired clinical effects for only as long as forming, and incapable of inducing true addic-
needed.35 Vaporizers that heat cannabis enough to tion.39,48 For most users this may be so. Experimen-
release cannabinoids but not the smoke and toxins tation with marijuana has become an adolescent rite
generated with combustion have the potential to re- of passage, with the prevalence of use peaking in the
duce respiratory symptoms and decrease negative late teens and early 20s, then decreasing signifi-
effects on pulmonary function associated with burn- cantly as youths settle into the adult business of es-
ing the drug.42,43 tablishing careers and families. With a lifetime de-
Medical users have the added benefit of breath- pendence risk of 9% in marijuana users vs 32% for
ing in such other marijuana components as canna- nicotine, 23% for heroin, 17% for cocaine, and 15%
bidiol, purported to act synergistically with THC in for alcohol,25 the addiction risk with marijuana is
both increasing benefits and reducing adverse ef- not as high as that for other drugs of abuse. Unlike
fects.44 THC-induced euphoria may also work syn- cocaine dependence, which develops explosively af-
ergistically with the drug’s analgesic effects.21 In ter first use, marijuana dependence comes on insid-
contrast to the usual medical model, the patient iously.49 Marijuana use typically starts at a younger
rather than physician determines the correct dose. age than cocaine use (18 vs 20 years of age). The risk
The physician’s instructions to the patient may be as for new-onset dependence is essentially zero after
vague as telling him or her to smoke as much as the age of 25 years, whereas cocaine dependence
needed.45 continues to accrue until the age of 45 years. Like-
As with the Canadian studies, the California wise, the average age at first alcohol use is the same
study found that medical use often “occurred within as for marijuana, but alcohol users will keep on
a context of chronic use.” That is, those who favored making the transition from social use to dependence
smoked cannabis for medical purposes were kindly for decades after first use.49
disposed toward the drug from previous recre- One in 11 users—1 in 6 for those starting in
ational experience with it and were typically unper- their early teens—is hardly an inconsequential per-
turbed by cognitive and euphoric adverse effects. centage, however.50 Like all addictive drugs, mari-
Indeed, the combination of physical and emotional juana exerts its influence through the midbrain re-
relief botanical cannabis provides may motivate the ward center, triggering dopamine release in the
medically ill to continue using it.26 Further confirm- prefrontal cortex.51 Although its existence was
ing this relationship were the demographics that questioned until recently, a withdrawal syndrome is
emerged from an English study of botanical canna- increasingly appreciated, characterized by irritabil-
bis use in individuals with chronic pain, multiple ity, anxiety, anorexia and weight loss, restlessness,
sclerosis, depression, arthritis, and neuropathy. Bo- disturbed sleep, and craving.52
tanical cannabis users were significantly more likely DuPont7 writes that “marijuana makes users
to be young, male, and recreationally familiar with stupid and lazy,” citing an extreme amotivational
the drug (P⬍.001).46 A recent California study of syndrome characterized by listlessness and apathy
patrons of medical marijuana clinics found similar in heavy smokers, not just when using the drug but
demographics: a sample that was three-fourths all the time. The befuddled, endearingly dissolute
male, three-fifths white, and overwhelmingly famil- stereotype, parodied in “stoner” movies like Cheech
iar with cannabis from recreational use. Although and Chong’s Up in Smoke, is not what happens to
men, whites, and African Americans were overrep- most occasional users who experience only tem-
resented, women, Latinos, and Asian Americans had porary mild perceptual changes accompanying a
disproportionately low representation.47 general sense of well-being and ease with the
Botanical cannabis is clearly not for everyone. world. The disputed amotivational syndrome of
Multiple observers report that patients without rec- heavy use resembles the negative symptom com-
reational experience have difficulty tolerating its plex of schizophrenia.53,54
Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003 175
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Using hospitalization as a proxy for serious psy- strated a dose-response effect, with the OR increas-
chiatric illness, Schubart et al55 identified a dose- ing to 2.09 (95% CI, 1.54-2.84) for more frequent
response relationship, with incidental users having users, defined— depending on the study—as daily,
1.6 times the chance of hospitalization and heavy weekly, or more than 50 times in their lives. A Dutch
users 6.2 times the risk. “The association of cannabis study62 shows how this association plays out in ac-
use with psychiatric inpatient treatment is a clear tual numbers. For 3 years, van Os et al followed up
indication of the association of cannabis use with 3964 psychosis-free individuals, 312 of whom used
mental illness,” they wrote. More specifically and cannabis. During the observation period, 8 of the
more ominously, those with a psychotic predisposi- 312 (2.2%) developed psychotic symptoms, with 7
tion may respond to marijuana with more marked of the 8 (88%) having severe enough symptoms to
perceptual changes into which they have little in- justify receiving a full-fledged diagnosis. Of the
sight, accompanied by elevations in hostility and 3652 nonusers, 30 (0.8%) developed symptoms,
paranoia.56 Schizophrenia has been posited as a hy- with only 3 of the 30 (10%) meeting criteria for a
percannabinoid condition because schizophrenic psychotic disorder. The risk was small in both
patients have significantly elevated cerebrospinal groups but impressively elevated in users vs
fluid levels of anandamide, the most important en- nonusers.
dogenous cannabinoid.57 Cannabis use has been For individuals already diagnosed as having a
implicated as a potential cause, aggravator, or schizophrenic spectrum disorder, ongoing cannabis
masker of major psychiatric symptoms, including use predicts a rockier course. Comparing 24 abus-
psychotic, depressive, and anxiety disorders, par- ing and 69 nonabusing schizophrenic patients who
ticularly in young people.30,58,59 In underscoring were otherwise clinically indistinguishable, Linszen
the potential for psychosis, a longitudinal study of et al63 found 42% of abusers vs only 17% of
more than 50,000 Swedish conscripts has been nonabusers experiencing psychotic relapse during
influential. During a 27-year follow-up period,
the year-long study period (P⫽.03). Moreover,
the more cannabis individuals had used in ado-
when they compared heavy users (⬎1 marijuana
lescence, the more likely they were to develop
cigarette per day) with mild users (ⱕ1 cigarette per
schizophrenia, with those who had used cannabis
day), they found an even more robust correlation,
on more than 50 occasions nearly 7 times more
with 61% of the heavy users vs 18% of the mild
likely to manifest the disease than those who had
users experiencing relapse (P⫽.002). The longer the
never used cannabis.60
period of cannabis use, the higher the risk of relapse.
This association between cannabis and psy-
In a 10-year follow-up of 229 patients after first
chosis notwithstanding, the question of whether
hospitalization for schizophrenia, Foti et al64
cannabis causes psychosis remains unresolved,
demonstrated that the 10% to 18% who contin-
even as evidence mounts that its use worsens the
ued to use cannabis throughout the study period
course of psychotic illness. In an Australian co-
hort, Degenhardt et al61 tested 4 hypotheses re- had a more severe course as measured by the in-
garding the association between cannabis use and tensity of positive psychotic symptoms. The asso-
schizophrenia, including that cannabis use (1) ciation was bidirectional: cannabis smokers had
may cause schizophrenia in some patients, (2) may worse psychosis, and the more intensely psy-
precipitate psychosis in vulnerable individuals, (3) chotic individuals were more likely to smoke
may exacerbate symptoms of schizophrenia, or (4) cannabis.
may be more likely in individuals with schizophre- van Os et al hypothesize that cannabis may exert
nia. They noted that during the last 3 decades of the its negative influence through causing dysregulation
20th century, cannabis use had significantly in- in the endogenous cannabinoid system that (among
creased in Australia without a corresponding in- many other interactions) modulates dopamine and
crease in schizophrenia prevalence, an observa- other neurotransmitter systems within the brain.
tion that gravitated against a simple cause-and- They posit a “preexisting vulnerability to dysregula-
effect relationship between the two. However, tion” that accounts for why some individuals and
they also found that cannabis use precipitated the not others respond to cannabis with psychosis.62
onset of the disease in the vulnerable and exacer- Using contemporary epigenetic terminology, Hen-
bated the course of the illness in those who al- quet et al65 attribute the greater psychosis risk in
ready had it. certain cannabis users to a synergy between gene
In a 2007 meta-analysis pooling 35 longitudi- (inborn susceptibility) and environment (exoge-
nal, population-based studies, Moore et al59 found nous trigger). Moreover, increasing evidence impli-
an elevated odds ratio (OR) of 1.41 (95% confidence cates a vulnerable developmental period—peripu-
interval [CI], 1.20-1.65) for psychosis in individuals berty—when cannabis use is more likely to cause
who had ever used cannabis. They also demon- trouble.
176 Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003
www.mayoclinicproceedings.orgTHERAPEUTICS AND POLITICS OF MEDICAL MARIJUANA
DANGERS OF EARLY USE With regard to cannabis as a “gateway” drug, its
Whereas adult users appear comparatively immune regular or heavy use in adolescence is clearly asso-
to cannabis-induced behavioral and brain morpho- ciated with increased risk for both abuse and depen-
logic changes, the same cannot be said of individuals dence on other illicit drugs.44 Neither causality nor
initiating use during their early teens, when effects directionality has been proven, however. Cannabis
are both more severe and more long-lasting than in use may simply be a marker for deviant behavior,
adults.66 During puberty, a period characterized by with the tendency to advance to harder drugs the
significant cerebral reorganization, particularly of result of their simply being available.39,44,74 In what
the frontal lobes implicated in behavior, the brain is has been called a “reverse gateway,” cannabis use
especially vulnerable to adverse effects from exoge- weekly or more often predisposes adolescent users
nous cannabinoids.58,67 How they interfere with to more than 8 times the risk of eventual tobacco use
this remodeling process during what Schneider67 and progression to nicotine dependence.75
calls a “sensitive period” is unknown, although Schneider66 reminds us that most adolescents
Bossong and Niesink68 propose that exogenous can- who use cannabis do not experience harmful out-
nabis use can induce schizophrenia during late comes. Concerning psychosis specifically, Luzi et
brain maturation through physiologic disruption of al76 emphasize that only 3% of heavy users actually
the endogenous cannabinoid system that modulates develop schizophrenia. Nonetheless, reducing or
glutamate and ␥-aminobutyric acid release in pre- delaying cannabis use could postpone or even pre-
frontal neurocircuitry, an iteration of the hypothesis vent 1 in 6 cases of new-onset psychosis.60,77
of van Os et al. Furthermore, in keeping with the Adolescent cannabis use is also associated with
epigenetic hypothesis of Henquet et al, carriers of a depressive and anxiety disorders that emerge later in
specific polymorphism of the catechol oxidase life.44 In a cohort of Australian girls followed up for
methyltransferase gene (COMT valine 158 allele) are 7 years from the ages of 14 to 15 years, 60% had
especially likely to develop psychotic symptoms or used cannabis by the end of the study and 7% were
full-blown schizophrenia, an effect attenuated or daily users. Although the presence of current de-
eliminated if cannabis use is delayed until after brain pression and anxiety did not predict cannabis use,
maturity.69 gravitating against a self-medication hypothesis,
Short of full-blown schizophrenia, many other Patton et al50 observed a dose-related risk of even-
persistent effects have been observed in heavy (de- tual depression and anxiety. Weekly use was asso-
fined as weekly or more often) pubertal users, in- ciated with nearly double the risk (OR, 1.9; 95% CI,
cluding working memory deficits, reduced atten- 1.1-3.3) of subjects later reporting anxiety or de-
tion, reduced processing speed, anhedonia, abnormal pression, and daily use corresponded with an OR of
social behavior, susceptibility to mood and anxiety 5.6 (95% CI, 2.6-12). The authors were reluctant to
disorders, and greater likelihood of dependence.67,70 attribute the increased risk to cannabis alone, ob-
Kuepper et al71 posit that ongoing cannabis use may serving that social consequences of frequent use, in-
increase psychotic disorder risk by making transient cluding educational failure, unemployment, and
psychotic experiences in adolescent users persist to crime, could account—at least in part—for the
the point of becoming permanent. psychopathology.
A study from 6 European countries comparing Even as Patton et al50 did not find that depres-
the health and legal implications of cannabis initia- sion or anxiety drove teens to smoke marijuana,
tion before the age of 16 years found it associated some recreational users appear to use it in a manner
with higher levels of abuse not only of cannabis but suggestive of antidepressant or anxiolytic medica-
also of other illicit drugs, higher rates of both phys- tions. Teens using cannabis to decrease anxiety fre-
ical injuries and psychosomatic symptoms, aca- quently meet criteria for anxiety disorders before
demic failure, and delinquency.72 Poor academic their cannabis dependence begins.32 Bottorff et al78
achievement, deviant childhood and adolescent be- reported on 20 adolescents who used marijuana reg-
havior, rebelliousness, and parental histories of sub- ularly, finding that these adolescents distinguished
stance abuse characterize those at highest risk of themselves from recreational users in that they
dependence.20,73 Those who started using mari- smoked marijuana not primarily for enjoyment but
juana before the age of 12 years had nearly 5 times rather for its capacity to relieve anxiety and lift
the hospitalization rate of those starting in their later mood, reduce stress, facilitate sleep, and lessen pain.
teens. Moderate use after the age of 18 years was not They titrated their intake, often using several times a
associated with increased rates of mental illness, day and beginning and ending the day with smok-
concluded Schubart et al.55 Protective against de- ing, and frequently using alone. “Unlike the sponta-
pendence is adult age of initiation and low-to-mod- neity typically involved in recreational use,” Bottorff
erate use, particularly when marijuana is ingested et al write, “these youth were thoughtful and pre-
for therapeutic rather than recreational purposes.66 scriptive with their marijuana use, carefully moni-
Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003 177
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
toring and titrating their use to optimize its thera- nies and lacking scientific validation,” Schwartz and
peutic effect.” “Unmet health needs” for them Voth82 state, adding that “a wonder drug it isn’t.” Yet
included access to legitimate treatment for depres- jurisdiction after jurisdiction has permitted the vot-
sion, insomnia, and anxiety. The paradox of mari- ers rather than researchers following standard US
juana both inducing and relieving anxiety is recon- Food and Drug Administration (FDA) protocols to
ciled by understanding that effects on anxiety levels endorse its medical use. “Medicolegal and political
are dose dependent.32 Although deliberate self- issues tend to overshadow the science and the med-
medication bears little resemblance to getting high icine of marijuana use.”83
for the pleasure—and occasionally panic— of it, it So what is already known about the therapeutic
brings its own dangers. Individuals with anxiety dis- potential of cannabis and where might research go
orders who use marijuana, alcohol, or other drugs in were there no proscriptions against studying the
this way are up to 5 times more likely to develop plant?
substance dependence than anxious individuals
who do not self-medicate.3
In sum, marijuana offers the recreational sub- THE ENDOCANNABINOID SYSTEM
stance abuse version of caveat emptor. Although Although cannabis has been part of the world’s
cannabis is an enjoyable diversion for most, it is herbal pharmacopoeia for millennia, next to nothing
linked to self-medication, addiction, or mental ill- about its mechanisms of action was known until the
ness in a few, particularly those who start young.3 last half century. As with all folk medicines, practi-
tioners established the therapeutic benefits and risks
of their plant-derived remedies through careful ob-
DANGERS OF MEDICAL MARIJUANA servation. In this respect, the cannabis story mirrors
Those skeptical of botanical cannabis do not ar- that of the Oriental poppy, Papaver somniferum, the
gue that it is necessarily bad. Rather they contend source of opium, which was appreciated both as a
that the benefits of cannabis—particularly when renowned painkiller and a tantalizing drug of abuse
smoked—remain scientifically unproven, not only for thousands of years before its active agent, mor-
on its own merits but also compared with other phine, was identified in modern times along with
available treatments. They contend that the usual opioid receptors, endogenous opioids, and an inter-
standards for evaluating pharmacotherapies have nal opioid system. “In both instances,” write Baker et
been largely side-stepped.17 They want legitimate al,4 “studies into drug-producing plants led to the
research. In a 2008 position paper, the American discovery of an endogenous control system with a
College of Physicians trod a middle ground between central role in neurobiology.”
praising and demonizing botanical cannabis, stating Modern scientific study of cannabis com-
it is “neither devoid of potentially harmful effects menced with the isolation and structural elucidation
nor universally effective” and calling for “sound sci- of THC in 1964.51 Not until 1990 was the cannabi-
entific study” and “dispassionate scientific analysis” noid receptor with which THC interacts, CB1,
to find the appropriate balance.79 cloned,84 and it was 1992 before anandamide, the
Critics of botanical cannabis are less sanguine endogenous ligand corresponding to THC and
than the American College of Physicians. They as- binding to CB1 receptors, was discovered.85 Since
sert that garden-grown cannabis is neither pure nor then, an additional cannabinoid receptor, CB2, has
refined, standards Americans have come to expect been identified, and the 2 receptors have been found
in their medications. DuPont calls it “a crude drug, a to have disparate distributions and functions in an
complex chemical slush,” composed of well more endocannabinoid system that extends far and wide
than 400 different chemicals from 18 different within the body as a physiologic modulator not only
chemical families, with the smoke containing more of the central nervous system but also of the auto-
than 2000 chemical compounds.7 In the short term, nomic nervous system, immune system, gastrointes-
cannabis can cause increased heart rate, vasodilation tinal tract, reproductive system, cardiovascular sys-
with decreased blood pressure (as outwardly mani- tem, and endocrine network.30,86
fested by bloodshot eyes), and dizziness.4 Although Described as a “ubiquitous network in the ner-
the use of vaporizers can minimize toxic expo- vous system”87 that regulates synaptic neurotrans-
sure,42,43 cannabis smoke contains many of the mission in both excitatory and inhibitory circuits,4
same toxins found in tobacco smoke, a concern not the endocannabinoid system is a finely tuned phys-
for palliative use in the terminally ill but for long- iologic modulator, an “integral part of the [body’s]
term smokers who put themselves at risk for phar- central homeostatic modulatory system”10 acting to
yngitis, rhinitis, asthma, bronchitis, emphysema, regulate neurotransmitter release at the level of the
and lung cancer.11,80,81 “The increasing cries for the synapse.88 It functions in parallel and in conjunc-
release of smoked marijuana to treat a variety of tion with adrenergic, cholinergic, and dopaminergic
medical problems [are] rich in anecdotal testimo- systems in both the central and autonomic nervous
178 Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003
www.mayoclinicproceedings.orgTHERAPEUTICS AND POLITICS OF MEDICAL MARIJUANA
systems, with influence on functions as disparate as in susceptible individuals into cannabis abuse and
blood pressure and bone growth.30,51,84,88 In a spe- dependence.90 Of note, due to the near absence of
cific organ system such as the gut, in which the brainstem CB1 receptors, the drug spares the auto-
endocannabinoid system is increasingly understood nomic nervous system, no matter how much is in-
to have a complex and ubiquitous presence, re- gested, with the result that a lethal overdose in hu-
gional variation in receptor distribution and organ- mans has never been reported. 4,87 They are
specific actions can influence functions as diverse as distributed so widely, however, that activating for
regulation of food intake, visceral sensation, gastro- one purpose can cause indiscriminate activation and
intestinal motility, gastric secretion, intestinal in- a host of unwanted adverse effects throughout the
flammation, and cell proliferation, to list only body, a major challenge for pharmaceutical
some.89 CB1 receptors with their psychoactive po- development.84
tential are found in the central nervous system and
widely distributed throughout the gut.89 CB2 recep-
PROMISING PHARMACEUTICAL APPLICATIONS
tors essentially reside only in the periphery, where
In the rapidly growing field of endocannabinoid
their activity is intrinsic to cellular and humoral re-
pharmacology, the potential for designing pharma-
sponses related to neuroinflammation and pain,86 as
cologic interventions is as broad as the endocan-
well as the critical gastrointestinal functions of di-
nabinoid system’s bodily distribution.91 “Perhaps
gestion and host defense.89
no other signaling system discovered during the
The most common G protein– coupled recep-
past 15 years is raising as many expectations for the
tors in the central nervous system (CB1 receptors)
development of new therapeutic drugs, encompass-
concentrate in specific brain areas that govern plea-
ing such a wide range of potential strategies for treat-
sure, movement, learning and memory, and pain,
ments,” Di Marzo92 writes. Describing the endocan-
including the frontal cortex, basal ganglia, hip-
nabinoid system as “having pleiotropic homeostatic
pocampus, and cerebellum.76 In the mesolimbic re-
function,” he asserts that salutary effects will come
ward center, they reinforce pleasurable activities via from many strategies, including drugs engineered to
anandamide, the endogenous cannabinoid that sub- act as agonists or antagonists through both direct
tly regulates dopamine release. Exogenous plant- and indirect means, as well as agents to increase
derived THC is a sledgehammer compared with synthesis, reduce reuptake, or decrease degradation
anandamide’s delicate chisel, the former causing of endocannabinoids in neuronal synapses.30 Med-
marked disruption of neuronal signaling and circuit ications active as analgesics, muscle relaxants, im-
dynamics in the finely tuned endogenous sys- munosuppressants, anti-inflammatories, appetite
tem56,88 and inducing addiction in the suscepti- modulators, antidepressants, antiemetics, broncho-
ble.51 The presence of CB1 receptors in the cerebel- dilators, neuroleptics, antineoplastics, and antialler-
lum and basal ganglia explains both positive and gens are all possible as a consequence of this “pleio-
negative influences of cannabinoids on motor tone tropic” endocannabinoid system lending itself to
and coordinated movement, including THC-in- manipulation through so many pathways.92 Di
duced discoordination or clumsiness in recreational Marzo conceptualizes the overarching pharmaceuti-
users on the one hand and amelioration of spasticity cal goal as “increasing or decreasing the tone of the
in upper motor neuron diseases such as multiple endocannabinoid system while keeping side effects
sclerosis on the other.87,88 Through their actions at bay.”
in the hippocampus, CB1 receptors modulate More recently, researchers have stated that
mood, and through activity in both the hip- the power of new pharmacologic products will
pocampus and prefrontal cortex, they influence obviate the need for botanical cannabis. Izzo and
many elements of cognition, including concentra- Camilleri93 envision “selective modulation of the
tion, short-term memory processing, attention, and endocannabinoid system in humans using modern
tracking behavior.20,73,87 They influence vegetative pharmacological principles.” Whereas botanical
functions at the hypothalamic level; “the munchies,” cannabis may be justifiable for experienced users
to which recreational marijuana smokers are prone with terminal illness and a tolerance for its psycho-
and for which medical marijuana is prescribed, re- active effects, particularly while awaiting these new
sult from THC stimulation of CB1 receptors that drugs, Kalant28 argues that future advances will re-
govern food intake.89 Nociception is modulated via sult from developing highly selective, pure pharma-
spinal cord dorsal primary afferent tracts, central ceuticals taken orally to bypass the health conse-
components of pain pathways whose manipulation quences of smoke exposure.17,28
by THC gives rise to its vaunted analgesic capacities. Examples of specific strategies include using
CB1 receptors modulate the activity of dopaminer- cannabinoid receptor agonists to increase gut motil-
gic neurons that project to the prefrontal cortex ity in conditions such as ileus and using antagonists
from the brainstem reward center, thereby factoring to decrease motility in inflammatory bowel dis-
Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003 179
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
ease.93,94 Cannabinoid receptor agonists could reducing appetite in obese individuals. Available in
also reduce inflammation peripherally through Europe since 2006, the FDA failed to approve its
CB2 agonist activity.95 Although mechanisms are release in the United States over concerns it can in-
poorly understood, cannabinoid agonists have duce depression and suicidal behavior.56,84,90
shown promise in the laboratory as antineoplastic The 2 US agents are CB1 receptor agonists,
agents, with demonstrated antitumor effects in- based on cannabis’ primary psychoactive compo-
cluding decreased angiogenesis, decreased metasta- nent, THC. FDA approved since 1985,97 dronabinol
sis through interference with cell migration, inhib- (Marinol), a Schedule III controlled substance, is
ited carcinogenesis, and attenuated inflammation.94 synthetic THC indicated for treating chemotherapy-
Cannabinoid receptor antagonists could reverse the induced nausea and vomiting and AIDS-related an-
low blood pressure found in hemorrhagic shock, orexia and wasting. With similar indications,
septic shock, and cirrhotic liver failure.84 nabilone (Cesamet) is a synthetic analog of THC.
The relationship between cannabis use and psy- Dronabinol’s therapeutic effect unfolds gradually for
chotic illness remains unsettled, even as hypothe- 30 to 60 minutes and lasts up to 6 hours. At 60 to 90
sized dysregulation of the endocannabinoid system minutes, nabilone takes longer to act but persists as
in a number of psychiatric disorders has implica- long as 12 hours.14
tions for developing treatments capable of manipu- Even though the antiemetic efficacy of both
lating relevant brain regions.61,90,96 Given the in- dronabinol and nabilone equals or exceeds that of
creased density of CB1 receptors in the prefrontal phenothiazines, their use is limited by the narrow
cortex of schizophrenic patients90 and the potential gap between effective therapeutic doses and doses
role of central CB1 receptor agonists such as THC in that cause such adverse effects as euphoria, dyspho-
the production of schizophreniform illnesses,30 the ria, cognitive clouding, drowsiness, and dizziness
experimental CB1 receptor antagonist SR141716 that are particularly problematic in naive users,
has shown potent antipsychotic activity acting like whether smoking marijuana or taking oral pharma-
an atypical antipsychotic.54 Cannabidiol has also ceuticals.11,44,88,98 The irony, of course, is that the
demonstrated antipsychotic properties without ex- “high” for one class of users is the “acute toxic effect”
trapyramidal adverse effects through poorly under- for another.30 Moreover, because of variable absorp-
stood actions on both cannabinoid and noncannabi- tion and first-pass kinetics, pharmaceutical canna-
noid receptors.30,91 In the cases of both SR141716 binoids achieve unpredictable blood levels, delaying
and cannabidiol, it is unclear whether they exert both onset and cessation of therapeutic action while
their influence directly via the CB1 receptor or indi- making the elusive therapeutic but nontoxic blood
rectly through CB1 modulation of the dopaminergic
level that much harder to achieve. Interest in these
and glutaminergic systems believed to be involved
agents has waned for arresting nausea and emesis
in the cognitive and behavioral impairments of
with the advent of 5-HT3 receptor antagonists like
schizophrenia. Regardless, each shows promise as a
ondansetron that have greater potency, minimal
novel agent for treating psychotic disorders.54
psychotropic effects, and intravenous capabilities.11
Speaking to the broad promise of cannabinoid-
Playing the devil’s advocate, Ware and St Ar-
based pharmaceuticals, Ben Amar11 writes that “for
naud-Trempe99 question why dronabinol or nabil-
each pathology it remains to be determined what
one would ever be preferable to inhaled THC, given
type of cannabinoid and what route of administra-
their adverse effects and delayed onset of action and
tion are most suitable to maximize the beneficial
botanical cannabis’ lower cost and readier availabil-
effect of each preparation and minimize the inci-
ity. Although the delayed onset is problematic when
dence of undesirable reactions.” Further under-
treating acute nausea, these pharmaceutical canna-
standing of the workings of the endocannabinoid
binoids may have a therapeutic edge over other oral
system will continue to shed new light on disease
agents in managing delayed nausea and vomiting or
processes.21 The goals of research should be to iden-
preventing it altogether.17,21,29,100 Wilkins27 and
tify the best strategies for exploiting the endocan-
nabinoid system’s physiologic and pathophysiologic Turcotte et al14 emphasize that pharmaceutical can-
effects and fashion pharmaceuticals accordingly.5 nabinoids should not be first-line therapies when
better tolerated and more effective agents exist. For
an indication such as emesis, dronabinol or
CURRENTLY AVAILABLE PHARMACEUTICALS nabilone is best reserved for cases resistant to stan-
To date, only 4 pharmaceutical cannabinoids have dard therapies.14
been marketed. The first and second (dronabinol Cannabidiol, the other important component
and nabilone) have been available in the United found in botanical cannabis, is distinguished by its
States since 1985 and a third one (nabiximols) in multiple peripheral mechanisms, including interac-
Canada since 2005.36 A fourth (rimonabant) has tion with vanilloid receptors, modulation of adeno-
shown promise treating nicotine dependence and sine signaling, interference with proinflammatory
180 Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003
www.mayoclinicproceedings.orgTHERAPEUTICS AND POLITICS OF MEDICAL MARIJUANA
cytokines, and both immunosuppressant and anti- political gridlock, the Federal Bureau of Narcotics
oxidant activity.33 Cannabidiol lacks psychoactivity over the objection of the American Medical Associ-
and may mitigate the anxiety and paranoia THC can ation pushed for the congressional passage of the
induce, particularly in naive users. Mounting evi- 1937 Marihuana [sic] Tax Act that taxed cannabis at
dence suggests that the 2 cannabinoids work syner- $1 an ounce when taken medicinally, $100 an
gistically through an “entourage effect,” with their ounce when used for unapproved purposes.11
interaction reducing the noxious effects of unop- Musto102 contends that the law was actually meant
posed THC.29,90 Moreover, through nonreceptor to placate xenophobic law enforcement officials and
actions, cannabidiol has shown promise in its own legislators from southwestern and western states
right in the central nervous system as a possible anx- who associated marijuana’s use with “degenerate
iolytic and antipsychotic agent, as well as an anti- Mexicans and migrant workers”, feared as a locus of
convulsant and neuroprotective agent.56,76,91 crime and “deviant behavior.” Pharmaceutical com-
In Canada, an additional agent not yet available panies opposed any regulation.102 In 1942, its re-
in the United States (but currently in phase 3 trials) moval from the US Dispensatory after nearly a cen-
more closely approximates the beneficial delivery tury stripped it of any remaining therapeutic
method of smoked cannabis absent some of the legitimacy.47
risks, including tolerance, withdrawal, and high Not until 1970, however, citing marijuana’s po-
abuse potential.21,25 With indications for cancer tential for abuse and addiction, did the US Congress
pain and neuropathic pain in multiple sclerosis, finally declare it to have no medical value, rendering
nabiximols (Sativex) is a mouth spray that contains illegal a plant that had been used medicinally
both THC and cannabidiol in liquid form to take throughout the world for thousands of years.51,83
advantage of the modulatory interaction between Ironically, given the recent hue and cry over medical
the two.10,29 Administered as an oromucosal spray, marijuana having been legalized without scientific
nabiximols uses a novel delivery method, absorp- input, the US Congress had failed to follow its usual
tion through the buccal mucosa, with the rapid-on- review process dictated by the Controlled Sub-
set advantage of inhaled cannabis and the obvious stances Act that requires scientific evaluation and
benefit of controlled and regulated delivery but testimony before legislative action. It declared can-
without such deleterious effects of smoking as seda- nabis illegal in the absence of such evidence.15
tion and memory impairment.101 With cannabis declared to have “no currently
Rapid uptake notwithstanding, a clinically sig- accepted medical use,” the FDA designated it a
nificant difference between botanical cannabis and Schedule I drug, a categorization reserved for street
nabiximols is the latter’s reduced bioavailability.
drugs with high abuse potential, such as heroin,
With peak plasma THC concentrations nearly 20
quaaludes, lysergic acid diethylamide, and 3,4-
times lower than with smoked cannabis, nabiximols
methylenedioxymethamphetamine.3 This designa-
flattens the steep-slope pharmacokinetic profile
tion has resulted in a near-cessation of scientific re-
found in botanical cannabis, with corresponding re-
search on cannabis in the United States, particularly
ductions in adverse psychotropic effects.25,29 It is
because the only federally authorized source of can-
this pharmacokinetic divergence from botanical
nabis is a strain grown at the University of Missis-
cannabis that reduces the likelihood of nabiximols
sippi and accessible to researchers only by applying
inducing dependence.14,25 The nabiximols story
to the National Institute on Drug Abuse,103 which is
underscores how a pharmaceutical that contains the
reluctant to support medical research and has his-
same active ingredient as smoked cannabis can have
torically focused its efforts (almost) exclusively on
disparate therapeutic effects stemming from diver-
demonstrating the drug’s harmful effects.14 Accord-
gent modes of administration and dissimilar
ing to Ware et al,46,81,99 most cannabis research in
amounts of absorbed THC and cannabidiol.14,36
the United States occurs “under a paradigm of pro-
hibition and the study of risk is not yet balanced by
FEDERAL BARRIERS TO CANNABIS RESEARCH much-needed research on benefits.”
For nearly a century, cannabis was a part of the In challenging the one-sided devaluation of can-
American pharmacopeia,83 but by the 1930s, its nabis as a dangerous substance, Cohen35 empha-
days as a legitimate treatment were numbered. The sizes that medical decision making is not based on
flames of popular fear had been fanned for decades risk alone. “The linchpin for medical decision-mak-
by the popular press102 and by the likes of such ing is not risk—for no treatment is without risk—
high-camp films as the 1936 Reefer Madness, which but the balancing of risks and benefits.” Any rational
hysterically portrayed “marihuana” as a threat to consideration of legalizing medical marijuana
Western civilization through its purported capacity should thus include both sides of the equation. Mar-
to induce user insanity and incite societal mayhem. tin17 writes that the “basic principles of medicine
In a standoff foreshadowing the current medical- should take precedence over political expediency in
Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003 181
www.mayoclinicproceedings.orgMAYO CLINIC PROCEEDINGS
the development of a rational strategy for any ther- hibitions on research are lifted. Ill-informed practi-
apeutic agent, even one as controversial as mari- tioners are thus left to make do with anecdotal
juana.” Marijuana being relegated to Schedule I sta- testimony and case reports—the least rigorous form
tus appears especially irrational when precedence of evidence—to guide their prescribing.10 The cur-
exists for assigning potential drugs of abuse Sched- rent catch-22 is that the cannabis that should be
ule II status when they also possess manifest medical studied— diverse strains hybridized by entrepre-
benefits. Opioids, including morphine, are derived neurial drug dealers—is illegal and the cannabis that
from the sap of P somniferum, the opium poppy. can be legally studied—the decades-old Mississippi
Widely abused in forms ranging from intravenous strain—is essentially kept off-limits.
heroin to oral oxycodone, opioids nonetheless re- It is a judicial fluke that the National Institute on
main in other forms the most potent painkillers in Drug Abuse has provided medical marijuana to a
the legitimate pharmacologic armamentarium. Co- handful of patients (never more than 32, currently
caine, a product of the leaves of the Erythroxylum 4 surviving) as the outcome of the settlement in a law-
coca plant, likewise has ongoing utility as a topical suit pressed in 1976 by a man with cannabis-re-
anesthetic and vasoconstrictor. Closely related sponsive glaucoma. That settlement became the ba-
structurally to methamphetamine, a scourge among sis for the FDA’s Compassionate Investigational New
drug abusers in broad swaths of rural America,104 Drug Study program for patients with marijuana-
psychostimulants such as methylphenidate and responsive conditions. No patient has been en-
dextroamphetamine are treatment mainstays for at- rolled since 1992, when the George H. W. Bush
tention-deficit/hyperactivity disorder. All these drug administration suspended new registration in re-
classes, plus barbiturates and sedative-hypnotics action to a large influx of applications from AIDS
such as benzodiazepines, have high abuse potential patients.106,107
but also important legitimate medical roles. “Their
addicting liability alone has not automatically been STATES’ DEFIANCE OF FEDERAL LAW
allowed to contraindicate their use,” states Cohen.35 Meanwhile, in the legal arena, the federal govern-
Readily available for laboratory scrutiny, the medi- ment pits itself against increasing numbers of
cally active ingredients have been isolated and puri- states—16 plus the District of Columbia—with
fied so that physicians can prescribe them “free of a regulations permitting botanical cannabis use for
hodgepodge of inactive and potentially harmful certain chronically or critically ill patients that
substances.”7 contradict federal law.10 A consequence of the dis-
The involvement of an alphabet soup of federal crepancies between federal and state statutes is that
agencies with divergent missions creates a series of users and purveyors of botanical cannabis for any
potential barriers because several have the power to purpose can be arrested and charged with federal
veto proposed initiatives.105 The FDA, for example, crimes, even in states where possessing small quan-
authorizes research to proceed on safety and effi- tities or growing one’s own stash for medical use is
cacy, the National Institute on Drug Abuse provides legal. In the absence of an overarching federal ap-
the research material, and the Drug Enforcement proach, these states lack consensus on what consti-
Agency grants the investigator the actual license to tutes physician authorization, which patients qual-
perform the research. Any one of these agencies has ify for treatment, and how they can acquire their
the power to halt an initiative in its tracks.15 As botanical cannabis, creating what is essentially a
described earlier in this article, the political climate “regulatory vacuum.”3,15 Possession limits, for ex-
at the federal level has essentially quashed the type ample, range from 1 oz and 6 plants in Alaska and
of research that is routine before commercial intro- Montana to 24 oz and 24 plants in Oregon.108 Some
duction of new drugs. Ironically what Cohen15 calls state laws are remarkably lax. For example, when
“federal intransigence” toward cannabis continues, California became the first American state to legalize
even as knowledge about the substance—most gen- botanical cannabis in 1996, it allowed wide latitude
erated in research laboratories outside the United for its use, permitting physicians to prescribe it not
States in countries, such as Canada, that legalized only for serious medical illnesses but also “for any
medical botanical cannabis in 2006 — has advanced other illness for which marijuana provides relief,”
to the point that the drug and its interactions with including such emotional conditions as depression
the endocannabinoid system can actually be studied and anxiety, a state of affairs that has “maximally
biochemically.11,77 Moreover, the intransigence broaden(ed) the range of allowable indications.”26
perpetuates what Aggarwal et al10 label a “transla- Moreover, no provision of the law defines what con-
tional gap” between “patient-centered medicine” as stitutes a bona fide patient-physician relationship.15
manifested in the public’s wide support and use of An estimated 250,000 to 300,000 Californians have
botanical cannabis and the research-driven scien- garnered physician approval, a number that belies
tific knowledge that cannot accrue until federal pro- botanical cannabis being provided only to the seri-
182 Mayo Clin Proc. 䡲 February 2012;87(2):172-186 䡲 doi:10.1016/j.mayocp.2011.10.003
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