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O’Shaughnessy’s • Summer 2009 —7—

Cannabinoids and Cancer


Evidence from cell culture systems and animal models indicates
that THC and other cannabinoids may inhibit the growth of some tumors
by the modulation of signaling pathways.
By Donald I. Abrams and Manuel Guzman
Although long-recognized for its Synthetic delta-9-THC in sesame oil
medicinal values and widely used by
millions throughout the world, marijuana
Key Concepts was first licensed and approved in 1986
for the treatment of chemotherapy-asso-
receives little attention in the standard • Cannabis has been used in medicine for thousands of years prior to ciated nausea and vomiting. Clinical tri-
literature because of its status as a con- achieving its current status as an illicit substance. als done at the time determined that
trolled substance and classification in the • Cannabinoids, the active components of Cannabis sativa, mimic the dronabinol was as effective, if not more
United States as a Schedule I agent with effects of the endogenous cannabinoids (the so-called endocannabinoids), so, than the available antiemetic agents.9
a high potential for abuse and no known activating specific cannabinoid receptors, particularly CB1 found predomi- The potent class of serotonin receptor an-
medical use. Data on the potential effec- nantly in the central nervous system and CB2 found in cells involved with tagonists which have subsequently revo-
tiveness of medicinal cannabis is diffi- immune function. lutionized the ability to administer
cult to find due to the limited numbers Delta-9-tetrahydrocannabinol, the main psychoactive cannabinoid in the emetogenic chemotherapy had not yet
of clinical trials that have been conducted plant, has been available as a prescription medication approved for chemo- come to market.
to date. therapy-induced nausea and vomiting and treatment of anorexia associated Dronabinol was investigated for its
As a botanical, cannabis shares those with the AIDS wasting syndrome. ability to stimulate weight gain in pa-
difficulties encountered in the study of • In addition to treatment of nausea and anorexia, cannabinoids may be tients with the AIDS wasting syndrome
plants that are grown in many climates of benefit in the treatment of cancer-related pain, possibly in a synergistic in the late 1980s. Results from a num-
and environments from diverse genetic fashion with opioid analgesics. ber of trials suggested that although pa-
strains and harvested under variable con- • Cannabinoids have been shown to be of benefit in the treatment of tients reported an improvement in appe-
ditions. However, the potential benefits HIV-related peripheral neuropathy suggesting that they may be worthy of tite, no statistically significant weight
of medicinal cannabis have not been lost study in patients with chemotherapy-related neuropathic symptoms. gain was appreciated.10-11 In one trial
on a large number of people living with • Cannabinoids have a favorable drug safety profile, medical use pre- evaluating megestrol acetate and
cancer, some of whom have been quite dominantly limited by their psychoactive effects and their limited dronabinol alone and together, the can-
vocal in attributing their ability to com- bioavailability. nabinoid seemed to negate some of the
plete their prescribed course of chemo- • There is no conclusive evidence that chronic cannabis use leads to the weight increase seen in those only re-
therapy to the anti-emetic effects of development of any malignancies; some preclinical studies actually sug- ceiving the hormone.12
smoked cannabis. gest a protective effect.
In the practice of integrative oncol- • Cannabinoids inhibit tumor growth in laboratory animal models by CANNABINOID CHEMISTRY
ogy, the provider is frequently faced with modulation of key cell-signaling pathways, inducing direct growth arrest AND BIOLOGIC EFFECTS
situations where being able to recom- and tumor cell death, as well as by inhibiting tumor angiogenesis and me-
mend medicinal cannabis seems like the tastasis. Cannabinoids are a group of 21 car-
right thing to do. A growing body of pre- • Cannabinoids appear to be selective antitumor compounds as they kill bon terpenophenolic compounds pro-
clinical evidence suggests that cannabis tumor cells without affecting their non-transformed counterparts. duced uniquely by Cannabis sativa and
may not only be effective for symptom • More basic and clinical research is needed to ascertain not only the Cannabis indica species. 13-14 With the
management, but may have a direct anti- role of cannabinoids in palliative cancer care, but to delineate their role as discovery of endogenous cannabinoids
tumor effect as well. This article will potential anti-cancer agents with activity at a number of sites by way of and to distinguish them from pharma-
review the role of cannabinoids in can- multiple mechanisms of action. ceutical compounds, the plant com-
cer. pounds may also be referred to as
until 1962, who testified in Congress that cluded that it was a safe substance with phytocannabinoids.
CANNABIS AS MEDICINE: “Marijuana is the most violence-causing no addictive potential that had medici- Although delta-9-THC is the primary
A BRIEF HISTORY drug in the history of mankind.” The Act nal benefits. Despite the fact that it wasactive ingredient in cannabis, there are
imposed a levy of $1 an ounce for me- deemed to have no medical use, mari- a number of non-THC cannabinoids and
Use of cannabis as medicine dates dicinal use and $100 an ounce for recre- juana was distributed to patients by the non-cannabinoid compounds that also
back at least 2000 years.1-4 Widely em- ational use, which in 1937 dollars was a United States government on a case-by- have biologic activity. Cannabinol, can-
ployed on the Indian subcontinent, can- prohibitive cost. case basis by way of a Compassionate nabidiol, cannabichromene, cannabi-
nabis was introduced into Western medi- By using the Mexican name for the Use Investigational New Drug (IND) gerol, tetrahydrocannabivarin and delta-
cine in the 1840s by W.B. O’Shaugh- plant and associating it with nefarious program established in 1978. 8-THC are just some of the additional
nessy, a surgeon who learned of its me- South-of the-Border activities, the pro- In the late 1980s and early 1990s, cannabinoids that have been identified.
dicinal benefits first hand while work- ponents fooled many physicians. The Act many people living with human immu- It is postulated that the secondary
ing in the British East Indies Company. was singly opposed by the American nodeficiency virus-1 (HIV) developed a compounds may enhance the beneficial
Promoted for reported analgesic, seda- Medical Association, who felt that ob- wasting syndrome as a pre-terminal effects of delta-9-THC, for example by
tive, anti-inflammatory, antispasmodic jective evidence that cannabis was harm- event.5 The wasting syndrome, charac- modulating the THC-induced anxiety,
and anticonvulsant properties, cannabis ful was lacking and that its passage terized by anorexia, weight loss of anticholinergic or immunosuppressive
was said to be the treatment of choice would impede further research into its greater than 10 percent body weight, and effects. In addition, cannabis-associated
for Queen Victoria’s dysmen-norhea. In medical utility. In 1942, cannabis was frequently, fever and diarrhea, created terpenoids and flavonoids may increase
the early 1900s, medicines that were in- removed from the U.S. Pharmacopoeia. hordes of cachectic individuals in search cerebral blood flow, enhance cortical
dicated for each of cannabis’ purported Mayor Fiorello LaGuardia of New of any potential therapeutic intervention.activity, kill respiratory pathogens and
activities were introduced into the West- York commissioned an investigation into Many turned to smoking marijuana.6-8 provide anti-inflammatory activity.
ern armamentarium, making its use less the reality of the potential risks and ben- Fearful that there might be a run on The neurobiology of the cannabinoids
widespread. efits of cannabis that reported in 1944 the Compassionate Use program, the continued on next page
Physicians in the United States were that the substance was not associated Bush administration shut
the main opponents to the introduction with any increased risk of criminal ac- it down in 1992, the same
of the Marihuana Tax Act by the Trea- tivity, addiction or insanity as had been year that dronabinol
sury Department in 1937. The legisla- claimed. The LaGuardia Commission (delta-9-tetrahydrocan-
tion was masterminded by Harry Report, as well as subsequent similar nabinol, Marinol(r)) was
Anslinger, director of the Federal Bureau investigations that have been commis- approved for treatment of
of Narcotics from its inception in 1931 sioned nearly every decade since, went anorexia associated with
largely ignored. the AIDS wasting syn-
Donald I. Abrams, MD, is Chief of He- In 1970 with the initiation of the Con- drome.
matology-Oncology at San Francisco General trolled Substances Act, marijuana was Delta-9-tetrahydro-
Hospital; Director of Clinical Programs at the classified as a Schedule I drug. Where cannabinol is one of the
Osher Center for Integrative Medicine; and both Schedule I and Schedule II sub- approximately 70 cannab-
Professor of Clinical Medicine at the Univer- stances have a high potential for abuse, inoids found in the can-
sity of California San Francisco. Schedule I drugs are distinguished by nabis plant and is felt to be
Manuel Guzman, PhD, is Professor of Bio-
having no accepted medical use. Other the main psychoactive
chemistry and Molecular Biology at the
School of Biology, Complutense University,
Schedule I substances include heroin, component. Overall, the
Madrid, Spain. This article appears in “Inte- LSD, mescaline, methylqualone and, plant contains about 400 CANNABINOIDS are a group of 21-carbon terpeno-
grative Oncology,” edited by Dr. Abrams and most recently, gammahydroxybutyrate compounds derived from phenolic compounds. Delta-9-tetrahydrocannabinol
Andrew Weil, MD, and published by Oxford (GHB). its secondary metabolism, (THC) is the most potent of the phytocannabinoids
University Press (2009). O’Shaughnessy’s In 1973, President Nixon’s investiga- many of which may con- produced by the Cannabis species. The cannabinoids
thanks the authors an d Oxford University tion into the risks and benefits of mari- tribute to its medicinal ef- complex with two receptors, CB1 and CB2, to produce
Press, Inc, for permission to publish it. juana, the Shafer Commission, con- fect. physiologic effects.
—8— O’Shaughnessy’s • Summer 2009

Cannabinoids and Cancer from previous page

ENDOGENOUS CANNABINOIDS, anandamide (AEA) and 2-arachidonoylglycerol SIGNALING PATHWAYS COUPLED TO THE CB1 CANNABINOID RECEPTOR
(2-AG), function as neurotransmitters. Synthetic cannabinoids have also been produced are outlined above. The CB1 cannabinoid receptor signals to a number of different
as pharmaceutical agents. Cannabinoids exert their effects by binding to specific Gi/o cellular pathways. These include (i) inhibition of the adenylyl cyclase (AC)-cyclic AMP-
protein-coupled receptors. protein kinase A (PKA) pathway; (ii) modulation of ion conductances, by inhibition of
has only been identified within the past creases neurotransmitter release. voltage-sensitive Ca2+ channels (VSCC) and activation of G protein-coupled inwardly-
rectifying K+ channels (GIRK); and (iii) activation of mitogen-activated protein kinase
20 years during which time an explosion The function of the endogenous can-
(MAPK) cascades. Other less established cannabinoid receptor effectors and the cross-
of knowledge has occurred.15-18 In the nabinoid system in the body is becom-
talk among the different pathways have been omitted for simplification.
mid-1980’s, researchers developed a ing more appreciated through advances
potent cannabinoid agonist to be used in in cannabinoid pharmacology. The iden- ity.13-20 Peak plasma concentrations oc- Canada in 1982, but only recently be-
research investigations. tification of the cannabinoid receptors cur after 1-6 hours and remain elevated came available in the US. Dronabinol
In 1986 it was discovered that can- has led to a host of agonists and antago- with a terminal half-life of 20-30 hours. was approved as an antiemetic to be used
nabinoids inhibited the accumulation of nists being synthesized. Utilizing these When consumed orally, delta-9-THC is in cancer chemotherapy in the US in
cyclic adenosine monophosphate tools, investigators are discovering that initially metabolized in the liver to 11- 1986.
(cAMP), suggesting the presence of a the system is likely to be important in OH-THC, also a potent psychoactive Numerous meta-analyses confirm the
receptor-mediated mechanism. By at- the modulation of pain and appetite, metabolite. utility of these THC-related agents in the
taching a radiolabel to the synthetic can- suckling in the newborn and the com- On the other hand, when smoked, the treatment of chemotherapy-induced nau-
nabinoid, the first cannabinoid receptor, plexities of memory. (Michael Pollan in cannabinoids are rapidly absorbed into sea and vomiting. Tramer et al. con-
CB1, was pharmacologically identified “The Botany of Desire” gives a particu- the bloodstream with a peak concentra- ducted a systematic review of 30 ran-
in the brain in 1988. larly entertaining description of the natu- tion in 2-10 minutes which rapidly de- domized comparisons of cannabis with
The CB1 receptor is coupled to Gi/o ral function of endocannabinoids in clines over the next 30 minutes. Smok- placebo or antiemetics from which di-
proteins. Its engagement inhibits memory.19) ing thus achieves a higher peak concen- chotomous data on efficacy and harm
adenylyl cyclase and voltage-gated cal- In addition to being utilized to learn tration with a shorter duration of effect. were available. 25 Oral nabilone, oral
cium channels, and stimulates rectifying more about the natural function of the Less of the psychoactive 11-OH-THC dronabinol, and intramuscular levonan-
potassium conductances and mitogen- endocannabinoid system, a number of metabolite is formed. tradol were tested. No smoked cannabis
activated protein kinase activity. these cannabinoid receptor agonists and Cannabinoids can interact with the trials were included. Thirteen hundred
By 1990, investigators had cloned the antagonists are being developed as po- hepatic cytochrome P450 enzyme sys- sixty-six patients were involved in the
CB1 receptor, identified its DNA se- tential pharmaceutical therapies. In the tem.21-22 Cannabidiol, for example, can systematic review. Cannabinoids were
quence and mapped its location in the meantime, dronabinol, nabilone inactivate CYP 3A4. After repeated found to be significantly more effective
brain, with the largest concentration be- (Cesamet(r), a synthetic cannabinoid) doses, some of the cannabinoids may antiemetics than prochlorperazine,
ing in the basal ganglia, cerebellum, hip- and cannabis are the currently available induce P450 isoforms. The effects are metoclopramide, chlorpromazine,
pocampus and cerebral cortex. cannabinoid therapies in the United predominantly related to the CYP1A2, thiethylperazine, haloperidol, domperi-
States. Levonantradol (Nantrodolum (r)) CYP2C and CYP3A isoforms. The po- done, or alizapride.
In 1993 a second cannab- is a synthetic cannabinoid administered tential for a cannabinoid interaction with In this analysis, the number needed
intramuscularly, not used as much clini- cytochrome P450 and, hence, possibly to treat (NNT) for complete control of
inoid receptor, CB2, was iden- cally since the oral agents became avail- metabolism of chemotherapeutic agents nausea was 6; the NNT for complete
tified outside the brain. able. has lead to a small amount of data on control of vomiting was 8. Cannabinoids
A whole cannabis extract (Sativex(r)) the possibility of botanical:drug interac- were not more effective in patients re-
In 1993 a second cannabinoid recep- delivered as an oro-mucosal spray with tions. ceiving very low or very high emetogen-
tor, CB2, was identified outside the varying combinations of THC and can- In one study, 24 cancer patients were ic chemotherapy. In crossover trials, pa-
brain. Originally detected in macroph- nabidiol is available in Canada and un- treated with intravenous irinotecan (600 tients preferred cannabinoids for future
ages and the marginal zone of the spleen, dergoing late phase testing in the US and mg, n = 12) or docetaxel (180 mg, n = chemotherapy cycles.
the highest concentration of CB2 recep- other countries. 12), followed three weeks later by the Tramer identified some “potentially
tors is located on the B lymphocytes and Through the receptors described same drugs concomitant with medicinal beneficial side effects” that occurred
natural killer cells, suggesting a possible above, cannabis delivered by way of in- cannabis taken as an herbal tea for 15 more often with cannabinoids, includ-
role in immunity. halation or orally can produce a host of consecutive days, starting 12 days be- ing the “high,” sedation or drowsiness,
The existence of cannabinoid recep- biologic effects. The Institute of Medi- fore the second treatment.23 The care- and euphoria. Less desirable side effects
tors has subsequently been demonstrated cine report makes the following general fully conducted pharmacokinetic analy- that occurred more frequently with can-
in animal species all the way down to conclusions about the biology of can- ses showed that cannabis administration nabinoids included dizziness, dysphoria
invertebrates. Are these receptors present nabis and cannabinoids:2 did not significantly influence exposure or depression, hallucinations, paranoia
in the body solely to complex with in- • Cannabinoids likely have a natural to and clearance of irinotecan or and hypotension.
gested phytocannabinoids? role in pain modulation, control of move- docetaxel. A later analysis by Ben Amar reported
The answer came in 1992 with the ment, and memory. that 15 controlled studies compared
identification of a brain constituent that • The natural role of cannabinoids in SYMPTOM MANAGEMENT nabilone to placebo or available anti-
binds to the cannabinoid receptor. immune systems is likely multifaceted emetic drugs.26 In 600 patients with a va-
Named “anandamide” from the Sanskrit and remains unclear. Antiemetic effect riety of malignant diagnoses, nabilone
word for bliss, the first endocannabinoid • The brain develops tolerance to can- The nausea and vomiting related to was found to be superior to prochlorpera-
had been discovered. Subsequently 2- nabinoids. cancer chemotherapy continues to be a zine, domperidone and alizapride, with
arachidonoylglycerol (2-AG) has also • Animal research has demonstrated significant clinical problem even in light patients clearly favoring the nabilone for
been confirmed as part of the body’s en- the potential for dependence, but this po- of the newer agents that have been added continuous use.
dogenous cannabinoid system. tential is observed under a narrower to our armamentarium since the 1970s Nabilone has also been shown to be
These endocanabinoids function as range of conditions than with benzodi- and 1980s when clinical trials of cannab- moderately effective in managing the
neurotransmitters. As the ligands for the azepines, opiates, cocaine, or nicotine. inoids were first conducted.24 nausea and vomiting associated with ra-
7-transmembrane domain cannabinoid • Withdrawal symptoms can be ob- In those days, phenothiazines and diation therapy and anesthesia after ab-
receptors, binding of the endocan- served in aminals but appear mild com- metoclopropramide were the main anti- dominal surgery.25-28 In the same meta-
nabinoid leads to G-protein activation pared with those of withdrawal from emetic agents used. Dronabinol (syn- analysis, Ben Amar reports that in 14
and the cascade of events transpires re- opiates of benzodiazepines. thetic THC) and nabilone (a synthetic studies of dronabinol involving 681 pa-
sulting in the opening of potassium chan- Pharmacology of Cannabis analog of THC) were both tested as novel tients, the cannabinoid antiemetic effect
nels which decreases cell firing and the When taken by mouth, there is a low oral agents in a number of controlled was equivalent or significantly greater
closure of calcium channels which de- (6-20%) and variable oral bioavailabil- clinical trials. Nabilone was approved in continued on next page
O’Shaughnessy’s • Summer 2009 —9—

Cannabinoids and Cancer from previous page


than chlorpromazine and equivalent to the release of analgesic opioids.40-42
metochlopramide, thiethylperazine and Cannabinoids are effective in animal
haloperidol. models of both acute and persistent pain.
It is noted that the efficacy of the can- The central analgesic mechanism differs
nabinoids in these studies was some- from the opioids in that it cannot be
times outweighed by the adverse reac- blocked by opioid antagonists. The po-
tions and that none of the comparator tential for additive analgesic effects with
antiemetics were of the serotonin recep- opioids as well as the potential for can-
tor antagonist class that is the mainstay nabinoids to reduce nausea and increase
of treatment today. appetite make a strong case for the evalu-
There have been only three controlled ation of marijuana as adjunctive therapy
trials evaluating the efficacy of smoked for patients on morphine.
marijuana in chemotherapy-induced Medical literature cites evidence of
nausea and vomiting.26 In two of the cannabinoids’ ability to reduce naturally
studies, the smoked cannabis was only occurring pain, but few human studies
made available after patients failed have been performed. Early studies of
dronabinol. cannabinoids on experimental pain in
The third trial was a randomized, human volunteers produced inconsistent
double-blind, placebo-controlled, cross- results. In some cases, the administra-
over trial involving 20 adults where both tion of cannabinoids failed to produce
DELTA-9-THC KILLS BRAIN TUMOR CELLS at a concentration that is nontoxic to
smoked marijuana and oral THC were normal brain cells. Images obtained through a time-lapse microscope illustrate the observable analgesic effects; in others,
evaluated. One-quarter of the patients selective induction of cell death in cultures of human Glioblastoma multiforme cells cannabinoids resulted in an increase of
reported a positive antiemetic response (upper left) compared to normal human glial cells (lower left). After 20 hours of treatment, pain sensitivity (hyperalgesia). Upon
to the cannabinoid therapies. On direct death of nearly all of the GBM cells is evidenced by cells shrinking to inanimate white review, Institute of Medicine research-
questioning of the participants, 35% pre- spheres (upper right). The normal cells exposed to the same concentration of delta-9- ers noted that these studies suffered from
ferred the oral dronabinol, 20% preferred THC continue to migrate and divide (lower right). Photo by McAllister and Yount. poor design and methodological prob-
the smoked marijuana and 45% did not faced by the practicing oncologist. There not yet been approved in the US because lems and dubbed their findings incon-
express a preference. Four participants are very few tools in the tool-box for it was found to induce anxiety and de- clusive.2
receiving dronabinol alone experienced addressing these concerns. Patients are pressive disorders that were deemed high
distorted time perception or hallucina- not only disturbed by the disfigurement risk. Cancer pain results from in-
tions which were also reported by two associated with wasting, but also by their Anecdotal as well as clinical trial evi- flammation, mechanical invasion
with smoked marijuana and one with inability to engage in the social interac- dence also supports the appetite-stimu- of bone or other pain-sensitive
both substances. tion associated with breaking bread and lating effect of smoking cannabis. In
The University of California Center classic trials conducted in the 1970s in
structure, or nerve injury. It is
partaking of a meal. For many the hor-
for Medicinal Cannabis Research also monal manipulation with megestrol ac- healthy controls, it was found that, es- severe, persistent, and often re-
approved and funded a double-dummy etate (synthetically derived progester- pecially when smoked in a social/com- sistant to treatment with opioids.
design clinical trial to compare smoked one) may be contraindicated or the side munal setting, cannabis ingestion led to
cannabis, oral dronabinol or placebo in effects undesirable. Two small controlled an increase in caloric intake, predomi- Encouraging clinical data on the ef-
patients with delayed nausea and vom- trials demonstrated that oral THC stimu- nantly in the form of between meal fects of cannabinoids on chronic pain
iting, a condition for which the seroto- lates appetite and may slow weight loss snacks, mainly in the form of fatty and come from three studies of cancer pain.
nin receptor antagonists are ineffective.29 in patients with advanced malignan- sweet foods. Cancer pain results from inflammation,
Unfortunately the trial was launched cies.26 In cancer patients with anorexia as mechanical invasion of bone or other
concurrently with the first release of In a larger randomized, double-blind, well as chemotherapy-induced nausea, pain-sensitive structure, or nerve injury.
aprepitant (Emend (r)), the first commer- parallel group study of 469 adults with it is worth noting that cannabis is the only It is severe, persistent, and often resis-
cially available drug from the new class advanced cancer and weight loss, pa- antiemetic that also has orexigenic ac- tant to treatment with opioids. Noyes
of agents, the Substance P/neurokinin tients received either 2.5 mg of oral THC tion. Although cannabis thus provides and colleagues conducted two studies on
NK-1 receptor antagonists, which are ap- twice daily, 800 mg of oral megestrol two potential benefits to the patient with the effects of oral THC on cancer pain.
proved for the treatment of delayed nau- daily or both. In the megestrol mono- cancer, the appetite-stimulation does not Both studies used standard single-dose
sea.30 The cannabis trial never accrued therapy group, appetite increased in 75% always reverse the cancer cachexia analgesic study methodology and met
and the funding was withdrawn. and weight in 11% compared to 49% and which is a function of energy wasting in the criteria for well-controlled clinical
Both dronabinol and nabilone are 3% respectively in the oral THC group. addition to decreased food intake. trials of analgesic efficacy.
FDA-approved for the treatment of nau- These differences were statistically sig- The first experiment measured both
sea and vomiting associated with can- nificant. The combined therapy did not Analgesia pain intensity and pain relief in a double-
cer chemotherapy in patients who have confer additional benefits. Our understanding of the possible blind, placebo controlled study of 10
failed to respond adequately to conven- Similar studies in patients with HIV- mechanisms of cannabinoid-induced subjects.43 Observers compared the ef-
tional antiemetic therapy. Nabilone’s associated wasting syndrome also found analgesia has been greatly increased fects of placebo and 5, 10, 15 and 20 mg
extended duration of action allows for that cannabinoids were more effective through study of the cannabinoid recep- doses of delta-9-THC over a 6-hour pe-
twice-a-day dosing of one or two milli- in improving appetite than in increasing tors, endocannabinoids and synthetic riod. Researchers reported that 15 and
grams commencing 1 to 3 hours prior to weight. In our own study of the safety agonists and antagonists. The CB1 re- 20 mg doses produced significant anal-
receiving chemotherapy. A dose of 1 or of smoked and oral cannabinoids in pa- ceptor is found in the central nervous gesia, as well as anti-emesis and appe-
2 milligrams the night before adminis- tients with HIV on protease inhibitor system as well as in peripheral nerve ter- tite stimulation. Authors cautioned that
tration of chemotherapy might also be regimens, we did find an increase in minals. Elevated levels of the CB1 re- some subjects reported unwanted side
useful. weight in both cannabinoid groups com- ceptor –like opioid receptors– are found effects such as sedation and depersonal-
It is recommended to commence pared to the placebo recipients; however in areas of the brain that modulate noci- ization at the 20 mg dose level.
dronabinol at an initial dose of 5 mg/m2, the study was not powered with weight ceptive processing.35 In a follow up single-dose study of
also 1 to 3 hours prior to the administra- gain as an endpoint.31-32 In contrast, CB2 receptors are located 36 subjects, Noyes et al reported that
tion of chemotherapy, then every 2 to 4 Many animal studies have previously in peripheral tissue and are present at 10 mg of THC produced analgesic ef-
hours after chemotherapy, for a total of demonstrated that THC and other can- very low expression levels in the CNS. fects over a seven-hour observation pe-
4 to 6 doses/day. Should the 5 mg/m2 nabinoids have a stimulatory effect on Of the endogenous cannabinoids identi- riod comparable to 60 mg of codeine,
dose prove to be ineffective, and in the appetite and increase food intake. It is fied, anandamide has high affinity for and that 20 mg of THC induced effects
absence of significant side effects, the felt that the endogenous cannabinoid CB1 receptors, whereas 2-AG has affin- equivalent to 120 mg of codeine.44 Au-
dose may be escalated by 2.5 mg/m2 system may serve as a regulator of feed- ity for both CB1 and CB2 receptors. thors noted that respondents found
increments to a maximum of 15 mg/m2 ing behavior. For example, anandamide With the development of receptor- higher doses of THC to be more seda-
per dose. in mice leads to a potent enhancement specific antagonists (SR141716 for CB1 tive than codeine. However, in a sepa-
Nabilone, with fewer metabolites and of appetite.33 and SR144528 for CB2), additional in- rate publication, Noyes et al reported that
a lower dose range may be associated It is felt that the CB1 receptors, formation has been obtained regarding patients administered THC had im-
with fewer side effects. The need to dose present in the hypothalamus where food the roles of the receptors and endogenous proved mood, sense of well-being, and
one to three hours prior to chemotherapy intake is controlled and in the cannabinoids in modulation of pain.36-37 less anxiety.45
is one factor that drives patients to pre- mesolimbic reward system, may be in- Where the CB1 agonists exert anal- A study by Staquet and colleagues on
fer smoked cannabis where the delivery volved in the motivational or reward as- gesic activity in the CNS, both CB1 and the effects of a THC nitrogen analogue
and effect peak within minutes. Patients pects of eating. This has led to the de- CB2 agonists have peripheral analgesic on cancer pain yielded similar results.46
also prefer the ability to more tightly ti- velopment of the pharmaceutical CB1 actions.38-39 Authors found the THC analogue
trate the dose of cannabinoids they re- antagonist rimonabant (Acomplia (r)), Cannabinoids may also contribute to equivalent to 50 mg of codeine and su-
ceive when smoking compared to oral which was approved in Europe for the pain modulation through an anti-inflam- perior to both placebo and 50 mg of seco-
ingestion. treatment of obesity on the basis of Phase matory mechanism –a CB2 effect with barbital in subjects with mild, moderate
Appetite stimulation III clinical trials where it was shown to cannabinoids acting on mast cell recep- and severe pain.
Anorexia, early satiety, weight loss induce a 4-5 kg mean weight loss with tors to attenuate the release of inflam-
and cachexia are some of the most daunt- improved glycemic and lipid profiles. 34 matory agents such as histamine and se-
ing symptom management challenges This first of a new class of agents has rotonin and on keratinocytes to enhance continued on next page
—10— O’Shaughnessy’s • Summer 2009
Cannabinoids and Cancer from previous page
Neuropathic pain is a trou- comitant cannabis on disposition kinet- drawal from opiates or benzodiazepines over the follow-up period. In the men
ics of opioid analgesics. If cannabinoids and usually dissipate after a few days. who smoked tobacco, either alone or in
bling symptom in cancer pa- and opioids are synergistic, it is possible Unlike other commonly used drugs, can- addition to marijuana, the risk of lung
tients, especially those treated that lower doses of opioids may be ef- nabinoids are stored in adipose tissue and cancer was increased 10-fold. In the over
with platinum-based chemo- fective for longer periods of time with excreted at a low rate (half-life 1-3 days), 50,000 person-years of follow-up of men
fewer side effects, clearly a benefit to so even abrupt cessation of THC intake who only smoked marijuana, there were
therapy or taxanes. the cancer patient with pain. is not associated with rapid declines in no documented cases of lung cancer; less
plasma concentration that would precipi- than in the never smokers!
Cannabinoids have also been shown Anxiety, Depression and Sleep tate withdrawal symptoms or drug crav- A systematic review evaluating 19
to be of potential benefit in an animal In clinical trials of cannabis, eupho- ing. studies that involved persons 18 years
model of neuropathic pain.47 Neuropathic ria is often scored as an adverse effect. or older who smoked marijuana and ex-
pain is a troubling symptom in cancer Although not all patients experience amined premalignant or cancerous lung
patients, especially those treated with
Most drug users begin with
mood elevation after exposure to can- lesions concluded that observational
platinum-based chemotherapy or nabis, it is a frequent outcome. Much
alcohol and nicotine before studies failed to demonstrate significant
taxanes. A painful sensory peripheral depends on the “set and setting” and the marijuana. associations between marijuana smok-
neuropathy is also commonly encoun- individual’s prior experience with can- ing and lung cancer after adjusting for
tered in patients with HIV infection ei- nabis. The 1999 Institute of Medicine report tobacco use.66
ther as a consequence of HIV itself or Some people develop dysphoria with addressed the frequent concern that The authors cite the selection bias,
antiretroviral drugs used in treatment of or without paranoia upon exposure to marijuana is a “gateway drug” leading small sample size, limited generalizabil-
the infection. cannabis; for them cannabis or its con- to use of other subsequent more potent ity and overall young participant in stat-
We completed a randomized, con- stituents may not be clinically useful. and addictive substances of abuse.2 The ing that because of the biological plau-
trolled trial of smoked cannabis com- Sleepiness is another common side report recounts that marijuana is the most sibility of an association of marijuana
pared to placebo in 50 subjects with HIV- effect which can easily be recast as im- widely used illicit drug and, predictably, smoking and lung cancer, physicians
related peripheral neuropathy.48 Smoked proved sleep quality as has been re- the first most people encounter. Not sur- should still caution patients regarding
cannabis reduced daily pain by 34% ported in trials of the sublingual spray prisingly, most users of other illicit drugs potential risks until further rigorous stud-
compared to 17% with placebo (p=0.03). cannabis-based medicine.61 For the can- have used marijuana first. However, ies permit definitive conclusions.
Greater than 30% reduction in pain was cer patient suffering from anorexia, nau- most drug users begin with alcohol and A population-based case-control
reported by 52% in the cannabis group sea, pain, depression, anxiety and in- nicotine before marijuana; hence mari- study of the association between mari-
and by 24% in the placebo group somnia, a single agent that can address juana is not the most common and is juana use and the risk of lung and upper
(p=0.04). The first cannabis cigarette re- all of these symptoms would be a valu- rarely the first “gateway” drug. aerodigestive tract cancers was per-
duced chronic pain by a median of 72% able addition to the armamentarium. The report concludes that there is no formed in Los Angeles.67 One thousand
compared to 15% with placebo conclusive evidence that the drug effects one hundred twelve incident cancer
(p<0.001). Cannabis also reduced experi- SAFETY AND SIDE EFFECTS of marijuana are causally linked to the cases (611 lung, 303 oral, 108 esopha-
mentally-induced hyperalgesia to both subsequent abuse of other illicit drugs gus, 100 pharynx, 90 larynx) were
brush and von Frey hair stimuli (p≤0.05) Cannabinoids have an extremely fa- and cautions that data on drug use pro- matched to 1040 cancer-free controls on
in a heat-capsaicin experimental pain vorable drug safety profile.13, 14, 24, 62Un- gression cannot be assumed to apply to age, gender and neighborhood.
model used to anchor the more subjec- like opioid receptors, cannabinoid recep- the use of drugs for medical purposes, A standardized questionnaire used
tive response of the chronic neuropathic tors are not located in brainstem areas which is certainly pertinent to the dis- during face-to-face interview collected
pain. No serious adverse events were controlling respiration, so lethal over- cussion of cannabis in cancer patients. information on marijuana use expressed
reported. doses due to respiratory suppression do in joint-years, where 1 joint-year is the
Two recent placebo-controlled stud- not occur. The LD50 has been estimated CANNABIS AND CANCER RISK equivalent of smoking one marijuana
ies of cannabinioids for central neuro- to be 1500 pounds smoked in 15 min- cigarette per day for one year. The inter-
pathic pain associated with multiple scle- utes as extrapolated from animal stud- A study conducted by the National views also requested information on the
rosis produced results similar to the ies where the median lethal dose was es- Toxicology Program of the US Depart- use of other drugs including hashish, to-
present study. In a crossover trial of syn- timated to be several grams per kilogram ment of Health and Human Services on bacco (all forms) and alcohol,
thetic delta-9-THC up to 10 mg/day, an of body weight.63 mice and rats suggested that cannab- sociodemographic factors, diet, occupa-
NNT of 3.5 was reported.49 As cannabinoid receptors are not just inoids may have a protective effect tional history, environmental factors in-
A trial of a sublingual spray contain- located in the central nervous system but against tumor development.64 In this two- cluding exposure to smoke, medical his-
ing delta-9-THC alone or combined with are present in tissues throughout the year evaluation, rats and mice were given tory and family history of cancer.
cannabidiol showed a 41% pain reduc- body, additional side effects of note in- increasing doses of THC by gavage. A Data were presented as crude odds
tion with active drug compared to a 22% clude tachycardia and hypotension, con- dose-related decrease in the incidence of ratios and adjusted odds ratios using
reduction with placebo.50 In this study, junctival injection, bronchodilation, both benign and malignant tumors was three models of covariate adjustment
the cannabidiol alone preparation was in- muscle relaxation and decreased gas- observed. Animals receiving THC dos- (with only Model 3 including tobacco
effective in pain relief. Improvement in trointestinal motility. ing also survived longer than those re- use and pack/years). The results showed
sleep quality was also reported with the Tolerance to the unwanted side ef- ceiving vehicle alone. that although using marijuana for > 30
sublingual spray. To date, no clinical tri- fects of cannabis appears to develop rap- Mice and rats are not people and gav- joint-years was positively associated in
als have examined the effectiveness of idly in laboratory animals and humans. age is not equivalent to smoking a com- the crude analysis with each cancer ex-
cannabinoid preparations in chemo- This is felt to occur due to a decrease in busted botanical product. Many would cept pharyngeal, no positive associations
therapy-induced neuropathic pain. the number of total and functionally find the combustion and inhalation of a were found when adjusting for several
coupled cannabinoid receptors on the therapeutic agent to be an undesirable confounders including cigarette smok-
If cannabinoids and opioids cell surface with a possible minor con- and perhaps counter-intuitive way to ing. In fact, in the Model 3 analysis for
tribution from increased cannabinoid deliver a drug. Most of the evidence lung cancer, the cohort who reported >
are synergistic, it is possible available on the risk of cancer from mari-
biotransformation and excretion with re- 0 to < 1 joint-years of marijuana use had
that lower doses of opioids may peated exposure. juana smoking comes from epidemio- a 37% reduction in the risk of develop-
be effective for longer periods logic studies, naturally, as prospective, ing lung cancer compared to those who
Although cannabinoids are randomized control trials are not pos- never smoked marijuana.
of time with fewer side effects sible. Over the years, reports of increased Although this was the only cohort
considered by some to be ad- risks of lung cancer, oropharyngeal can- where the reduction in lung cancer risk
Synergism between opioids and can- dictive drugs, their addictive cers and prostate and cervical cancer reached statistical significance, in the
nabinoids has been postulated and sub-
potential is considerably lower have been most consistently reported. model, all levels of marijuana use (in-
sequently demonstrated in a number of
For each trial suggesting a possible in- cluding > 60 joint-years) had adjusted
animal models.51-55 The antinociceptive than other prescribed agents or crease in cancer incidence in chronic odds ratios less than 1.0. The authors
effects of morphine are predominantly substances of abuse. marijuana users, others have been pub- report adjusted ORs <1 for all cancers
mediated by mu receptors but may be
lished that appear to refute the associa- except oral cancer and found no consis-
enhanced by delta-9-THC activation of Although cannabinoids are consid- tion. tent association of marijuana use with
kappa and delta opioid receptors.55 ered by some to be addictive drugs, their A retrospective cohort study of 64,855 any malignant outcome. In what appears
It has been further postulated that the addictive potential is considerably lower Kaiser Permanente health care members to be an overly aggressive attempt to
cannabinoid:opioid interaction may oc- than other prescribed agents or sub- seen between 1979-1985 and followed delineate the possible limitations of their
cur at the level of their signal transduc- stances of abuse. The brain develops tol- through 1993 yielded an interesting find- work which could have led to such a
tion mechanisms.56-57 Receptors for both erance to cannabinoids. Animal research ing.65 Men aged 15-49 were divided into consistent yet startling result, the authors
classes of drugs are coupled to similar demonstrates a potential for depen- four cohorts based on their use of to- mention that “it is possible that mari-
intracellular signaling mechanisms that dence, but this potential is observed un- bacco and marijuana: never smoked ei- juana use does not increase cancer risk...
lead to a decrease in cAMP production der a narrower range of conditions than ther, smoked only cannabis, smoked only Although the adjusted ORs < 1 may be
by way of Gi protein activation.58-60 with benzodiazepines, opiates, cocaine tobacco, smoked tobacco and cannabis. chance findings, they were observed for
There has also been some evidence or nicotine. There were 5600-8200 men in each cell all non-reference exposure categories
that cannabinoids might increase the syn- Withdrawal symptoms –irritability, followed for an average of nearly nine with all outcomes except oral cancer.
thesis or release of endogenous opioids, insomnia with sleep EEG disturbance, years. Although purely speculative, it is pos-
or both. With this background, we are restlessness, hot flashes and rarely nau- In the men who never smoked, there sible that such inverse associations may
conducting a pharmacokinetic interaction sea and cramping– have been observed, were two cases of lung cancer diagnosed
study to investigate the effect of con- but appear mild compared with the with- continued on next page
O’Shaughnessy’s • Summer 2009 —11—

Cannabinoids and Cancer from previous page


reflect a protective effect of marijuana.” impermeable capillaries, thus thwarting
angiogenesis. This is accompanied by a
CANNABINOIDS reduced expression of vascular endothe-
AS ANTICANCER AGENTS lial growth factor (VEGF) and other pro-
angiogenic cytokines, as well as of
There has been an increasing body of VEGF receptors.
evidence over the past decade that can- Activation of cannabinoid receptors
nabinoids may have a role in cancer in vascular endothelial cells inhibits cell
therapy.62 Evidence from cell culture migration and survival, also contribut-
systems as well as animal models have ing to impaired tumor vascularization.
suggested that THC and other cannab- Cannabinoid administration to tumor-
inoids may inhibit the growth of some bearing mice decreases the activity and
tumors by the modulation of signaling expression of matrix metalloproteinase
pathways that lead to growth arrest and 2, a proteolyic enzyme that allows tis-
cell death as well as by inhibition of an- sue breakdown and remodeling during
giogenesis and metastasis. angiogenesis and metastasis. This sup-
The antiproliferative effects were ports the inhibitory effect of cannab-
originally reported in 1975 by Munson inoids in inhibiting tumor invasion in
and colleagues, who demonstrated that animal models.
delta-9-THC, delta-8-THC and cannab- Further support comes from studies
inol inhibited Lewis lung adenocarci- in human non-small cell lung cancer cell OTHER ANTI-TUMOR EFFECTS OF CANNABINOIDS:
noma cell growth in vitro as well as in lines that overexpress epidermal growth Besides inducing apoptosis of tumor cells, cannabinoid administration can decrease
mice. Curiously, there was no real fol- factor receptor, in which THC inhibits the growth of gliomas by other mechanisms, including at least: (i) reduction of tumor
low-up of these findings for twenty years epidermal growth factor-induced angiogenesis, by inhibition of the vascular endothelial growth factor (VEGF) pathway;
when the line of investigation was picked growth, chemotaxis and chemo-inva- (ii) inhibition of tumor cell invasion, by down-regulation of matrix metalloproteinase-
up by scientists in Spain and Italy who sion.84 2 (MMP-2) expression; (iii) induction of tumor cell differentiation, by down-regulation
have remained at the forefront of this In an in vivo model using severe com- of epidermal growth factor (EGF) receptor expression; and perhaps (iv) arrest of the
emerging field.62. 68. 69 bined immunodeficient mice, subcuta- cell cycle, by down-regulation of cyclin-dependent kinase-1 (CDK1) expression. The
relative contribution of these processes to the inhibition of tumor growth depends on
Since the late 1990s, several plant de- neous tumors were generated by inocu-
various factors such as the type of tumor under study, the experimental model used
rived (THC and cannabidiol), synthetic lating the animals with the same cell and the intensity of cannabinoid signaling.
(WIN-55,212-2 and HU-210) and en- lines. Tumor growth in THC-treated ani-
dogenous cannabinoids (anandamide mals was inhibited by 60% compared nervous system lymphoma, Hodgkin’s tion like, for example, recurrent
and 2-arachidonoylglycerol) have been with vehicle-treated controls. The inhi- disease and nasopharyngeal carcinoma glioblastma multiforme?
shown to exert antiproliferative effects bition was significant both regarding the (EBV). It is not likely that even a meta-analy-
of a wide variety of tumor cells in cul- subcutaneous xenograft as well as the A group of investigators has demon- sis of a number of similar studies in any
ture systems. In addition to the original number and weight of lung metastases. strated that THC is a potent and selec- condition would convince the necessary
lung adenocarcinoma study, other tumor Tumor specimens revealed antipro- tive antiviral agent against KSHV.88 It is regulatory bodies that cannabis should
cells that have been shown to be sensi- liferative and antiangiogenic effects of felt that THC may inhibit KSHV repli- be re-instated to the U.S. Pharmacoepia
tive to cannabinoid-induced growth in- THC. cation through the activation of cannab- and made widely available to patients
hibition include glioma, thyroid epithe- Most recently, another potential anti- inoid receptors. The authors conclude who may benefit from its use. The Insti-
lioma, leukemia/lymphoma, neuroblas- cancer and particularly anti-metastasis that further studies on cannabinoids and tute of Medicine Report in 1999 clearly
toma and skin, uterus, breast, gastric, mechanism for cannabinoids has been herpesviruses are important as they may stated that the accumulated data indicate
colorectal, pancreatic and prostate car- identified. Id helix-loop-helix proteins lead to development of drugs that inhibit a potential therapeutic value for cannab-
cinomas.70-81 control processes related to tumor pro- reactivation of these oncogenic viruses. inoid drugs, particularly in the areas of
Perhaps even more compelling, can- gression85 Reducing Id-1 using antisense Counter to these findings, however, pain relief, control of nausea and vomit-
nabinoid administration to nude mice technology led to significant reductions is the recent suggestion that delta-9-THC ing and appetite stimulation. The authors
slows the growth of various tumor xe- in breast cancer cell proliferation and may actually enhance KSHV infection went on to suggest that the “goal of clini-
nografts including lung and skin carci- invasiveness in in vitro models and me- and replication and foster KSHV-medi- cal trials of smoked marijuana would not
nomas, thyroid epitheliomas, melano- tastases in mice. Reducing Id-1 expres- ated endothelial transformation.88 be to develop it as a licensed drug, but
mas, pancreatic carcinomas, lymphomas sion with antisense technology is not a These investigators caution that use as a first step towards the development
and gliomas. The requirement of CB1 possible intervention in humans with of cannabinoids may thus place individu- of non-smoked, rapid-onset cannabinoid
and/or CB2 receptors for the antitumor breast cancer at this time, however. Can- als at greater risk for the development delivery systems.” 2
effect has been shown by various bio- nabidiol has been demonstrated to down- and progression of Kaposi’s sarcoma, To this end, we conducted a trial in
chemical and pharmacological ap- regulate Id-1 expression in aggressive although epidemiologic data have not healthy marijuana-smoker volunteers
proaches already mentioned and the cu- human breast cancer cells. The investi- supported these in vitro findings. comparing the blood levels of cannab-
mulative effects of CB signaling in the gators suggest that cannabidiol repre- So with the body of evidence increas- inoids achieved upon inhaling marijuana
control of cell fate are expected to have sents the first nontoxic exogenous agent ing, where are the clinical trials in hu- that has been vaporized in a device that
important implications in the potential that can significantly decrease Id-1 ex- mans with malignant disease? True, can- heated the plant product to below the
of cannabinoids for regulating tumor cell pression in metastatic breast cancer cells nabinoids have psychoactive side effects, temperature of combustion and collected
growth. leading to the down-regulation of tumor but these could be considered to be the volatilized gases with those obtained
Cannabinoids may exert their antitu- aggressiveness. within the boundaries of tolerance for the upon smoking a comparable dosed ciga-
mor effects by a number of different \Two additional potential mechanisms toxicity profiles of cytotoxic chemo- rette.91
mechanisms including direct induction of anticancer activity warrant brief men- therapeutic and targeted small molecule Eighteen healthy subjects were evalu-
of transformed cell death, direct inhibi- tion. Cannabinoids, both plant-derived therapies widely used in oncology. ated. One dose (1.7, 3.4 or 6.8% tetrahy-
tion of transformed-cell growth and in- and endogenous, are believed to have The Spanish Ministry of Health ap- drocannabinol) and delivery system
hibition of tumor angiogenesis and me- anti-inflammatory effects. Inflammation proved a pilot clinical trial carried out in (smoked cannabis cigarette or vaporiza-
tastasis.82-83 A desirable property of anti- is being increasingly linked to the de- collaboration between the Tenerife Uni- tion system) was randomly assigned for
tumor compounds is their preferential velopment of various malignancies. Per- versity Hospital and the Guzman labo- each of the six inpatient study days. The
targeting of malignant cells. Cannab- haps one of the most obvious associa- ratory in Madrid to investigate the ef- peak plasma concentrations and six-hour
inoids appear to kill tumor cells but do tions is the development of colorectal fect of local administration of THC in- area under the plasma concentration-
not affect their non-transformed coun- carcinoma in patients with inflammatory tracranially through an infusion catheter time curve of THC after inhalation of
terparts and may even protect them from bowel disease. on the growth of recurrent glioblastoma vaporized cannabis were similar to those
cell death. This is best exemplified by A mouse study has demonstrated that multiforme.90 of smoked cannabis.
glial cells. signaling of the endogenous cannabinoid In this ground-breaking pilot study, Carbon monoxide levels were sub-
Cannabinoids have been shown to system is likely to provide intrinsic pro- THC administration was shown to be stantially reduced with vaporization sug-
induce apoptosis of glioma cells in cul- tection against colonic inflammation.86 safe and associated with decreased tu- gesting less exposure to noxious sub-
ture and induce regression of glioma This has led to the development of a mor cell proliferation in at least two of stances. Neuropsychologic effects were
cells in mice and rats. In contrast, can- hypothesis that phytocannabinoids and nine patients studied. Hopefully this pi- equivalent and participants expressed a
nabinoids protect normal glial cells of endocannabinoids may be useful in the lot trial may open the door to further clear preference for vaporization as a
astroglial and oligodendroglial lineages prevention and treatment of colorectal clinical investigations aimed at assess- delivery method.
from apoptosis mediated by the CB1 re- cancer.87 ing the antitumor activity of cannabinoid No adverse events were observed.
ceptor. Kaposi’s sarcoma-associated herpes- therapies. Vaporization of cannabis is a safe and
Immunohistochemical and functional virus/Human herpesvirus-8 (KSHV/ effective mode of delivery of THC. Con-
analyses in mouse models of gliomas and HHV-8) and Epstein-Barr virus (EBV) ALTERNATIVE sequently, our ongoing evaluation of
skin carcinomas have demonstrated that are related and implicated in the cause DELIVERY SYSTEMS opioid:cannabinoid interactions is using
cannabinoid administration alters the of a number of malignant diseases in- the vaporizer as a smokeless delivery
vascular hyperplasia characteristic of cluding Kaposi’s sarcoma and primary And what if clinical trials were to system.
actively growing tumors into a pattern effusion lymphoma (KSHV) and demonstrate that smoked marijuana may Another non-synthetic alternative to
characterized by small, differentiated, Burkitt’s lymphoma, primary central be of benefit to patients with a condi- continued on next page
—12— O’Shaughnessy’s • Summer 2009

Cannabinoids and Cancer from previous page

smoked or inhaled cannabis is the sub- sion. Many providers would frown upon tory and physical examination should be On a more positive note, in a unani-
lingual preparation of whole plant ex- the use of a relatively benign smoked documented. The provider should ascer- mous vote, the Assembly of the Ameri-
tract.50, 61, 92 Sativex(r) was first approved psychotropic agent while freely writing tain that medical marijuana use is not can Psychiatric Association recently ap-
as a prescription medication in Canada prescriptions for pharmaceutical agents masking an acute or treatable progres- proved a strongly worded statement sup-
in 2005 for symptomatic relief of neu- with significantly greater cost, potential sive condition. A treatment plan should porting legal protection for patients us-
ropathic pain in multiple sclerosis and for addiction or abuse, and more nega- be formulated. A patient need not have ing medical marijuana with their doctor’s
subsequently as adjunctive therapy for tive societal impact overall. failed all standard interventions before recommendation.95 The APA action pa-
patients with cancer pain on other anal- The Medical Board of California in marijuana can be recommended. The per reiterates that “the threat of arrest by
gesic medications. The cannabis-based their July 2004 Action Report provides physician may have little guidelines in federal agents, however, still exists. Se-
medication is available in Spain, under- a model for how states with medical actually recommending a concrete dose riously ill patients living in these states
going regulatory review by the European marijuana legislation should advise phy- for the patient to use.94 with medical marijuana recommenda-
Union and is being evaluated in a Phase sicians.93 As there are so many variables asso- tions from their doctors should not be
II/III clinical trial in patients with can- “The intent of the board at this time ciated with effect, the physician and pa- subjected to the threat of punitive fed-
cer-related pain in the U.S.. is to reassure physicians that if they use tient should develop an individual self- eral prosecution for merely attempting
the same proper care in recommending titration dosing paradigm that allows the to alleviate the chronic pain, side effects,
GUIDELINES FOR PROVIDERS medical marijuana to their patients as patient to achieve the maximum benefit or symptoms associated with their con-
they would any other medication or treat- with tolerable side effects. Discussion of ditions or resulting from their overall
The Institute of Medicine is aware ment, their activity will be viewed by the potential side effects and obtaining ver- treatment regimens. ... [We] support pro-
that the development and acceptance of Medical Board just as any other appro- bal informed consent are desirable. Pe- tection for patients and physicians par-
smokeless marijuana delivery systems priate medical intervention.... If physi- riodic review of the treatment efficacy ticipating in state-approved medical
“may take years; in the meantime there cians use the same care in recommend- should be documented. Consultation marijuana programs.”
are patients with debilitating symptoms ing medical marijuana to patients as they should be obtained when necessary. It behooves the integrative oncologist
for whom smoked marijuana may pro- would recommending or approving any Proper record keeping that supports the to follow closely future studies of can-
vide relief.” So what is a provider to do? other medication or prescription drug decision to recommend the use of medi- nabinoids and cancer. It is likely that
Patients with cancer have a number treatment, they have nothing to fear from cal marijuana is advised. these agents will not only prove to be
of symptoms that may be responsive to the Medical Board.” Despite all these guidelines, the Medi- useful in symptom management and pal-
cannabinoid therapies. As enumerated, The Board recommends following the cal Board of California still reminds phy- liative care, but as anti-tumor agents as
these include nausea, vomiting, anor- accepted standards that would be used sicians that making a written recommen- well.
exia, pain, insomnia, anxiety and depres- in recommending any medication. A his- dation “could trigger a federal action.”

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and combination therapy with megestrol ac- of their therapeutic potential. Ben Amar M. pot boil. Nature Medicine 4:1008-9, 1998. antinociception by oral delta9-tetrahydrocan-
etate and dronabinol for the treatment of the Journal of Ethnopharmacology 2006; 105:1- 40. Facci L, Dal Toso R, Romanello S et nabinol: dose-response analysis and recep-
HIV wasting syndrome. The DATRI 004 25. al. Mast cells express a peripheral cannab- tor identification. J Pharmacol Exp Ther.
Study Group. AIDS Res Hum Retroviruses 27. Robson P. Therapeutic effects of can- inoid receptor with differential sensitivity to 1999;289(2):859-67.
1997;13:305-315. nabis and cannabinoids. Br J Psychiatry anandamide and palmitoylethanolamide. 54. Cichewicz DL, McCarthy EA.
13. Adams IB and Martin BR. Cannabis: 2001; 178:107-115. Proc Natl Acad Sci USA 92:3376-3380, Antinociceptive synergy between delta(9)-
pharmacology and toxicology in animals and 28. Walsh D, Nelson KA, Mahmoud FA. 1995. tetrahydrocannabinol and opioids after oral
humans. Addiction 1996; 91:1585-1614 Established and potential therapeutic appli- 41. Ibrahim MM, Porreca F, Lai J, administration. J Pharmacol Exp Ther.
14. Cannabis and Cannabinoids: Pharma- cations of cannabinoids in oncology. Support Albrecht PJ, Rice FL, Khodorova A et al. 2003;304(3):1010-5.
cology, Toxicology, and Therapeutic Poten- Care Cancer. 2003; 11:137-143. CB2 cannabinoid receptor activation pro- 55. Manzanares J, Corchero J, Romero J,
tial, eds. Grothenhermen F and Russo E. The 29. University of California Center for duces antinociception by stimulating periph- Fernandez-Ruiz JJ, Ramos JA, Fuentes JA.
Haworth Press., Binghamton, NY, 2002. . Medicinal Cannabis Research. Available at: eral release of endogenous opioids. Proc Natl Pharmacological and biochemical interac-
15. Devane WA, Dysarc FA, Johnson MR, http://www.cmcr.ucsd.edu. Acad Sci .2005; 102:3093-3098. tions between opioids and cannabinoids.
Melvin LS, Howlett AC. Determination and 30. Poli-Bigelli S, Rodrigues-Pereira J, 42. Richardson J, Kilo S, Hargreaves K. Trends Pharmacol Sci. 1999;20(7):287-94.
characterization of a cannabinoid receptor in Carides AD, Julie Ma G, Eldridge K et al. Cannabinoids reduce hyperalgesia and in- 56. Pugh G, Jr., Smith PB, Dombrowski
rat brain. .Molecular Pharmacology 1988; Addition of the neurokinin-1 receptor antago- flammation via interaction with peripheral DS, Welch SP. The role of endogenous opio-
34:605-613. nist aprepitant to standard antiemetic therapy CB1 receptors. Pain. 1998; 75:111-119. ids in enhancing the antinociception pro-
16. Devane WA, Hanus L, Breuer A, improves control of chemotherapy-induced 43. Noyes R, Brunk S, Baram D, Canter duced by the combination of delta 9-tetrahy-
Pertwee RG, Stevenson LA, Griffing F et al. nausea and vomiting. Results from a random- A. Analgesic Effect of delta-9-tetrahydrocan- drocannabinol and morphine in the spinal
Isolation and structure of a brain constituent ized, double-blind, placebo-controlled trial nabinol. Journal of Clinical Pharmacology continued at right, bottom
O’Shaughnessy’s • Summer 2009 —13—

Tashkin Reiterates to Patients Out of Time:


Smoking Cannabis Does Not Cause Lung Cancer
By Fred Gardner ing the event, which was held at Cozen, Thomas M. Mack and Sander
One in three Americans will be af- Asilomar, on the Monterey Peninsula. Greenland was a blockbuster story.
flicted with cancer, we are told by the The National Institute on Drug Abuse, I suggested to Eric Bailey of the L.A.
government (as if it’s our immutable fate which supported Tashkin’s marijuana-re- Times that he write up Tashkin’s find-
and somehow acceptable). Cancer is the lated research over the decades, readily ings –UCLA provided the local angle if
second-leading cause of death in the U.S. gave him a grant in 2002 to conduct a the anti-cancer effect wasn’t enough.
and lung cancer the leading killer among large, population-based, case-controlled Bailey said his editors wouldn’t be in-
cancers. study that would prove definitively that terested for some time because he had
You’d think it would have been very heavy, long-term marijuana use in- just filed a marijuana-related piece. The
big news in June 2005 when UCLA creases the risk of lung and upper-air- Tashkin scoop is still there for the tak-
medical school professor Donald ways cancers. ing!
Tashkin reported that components of What Tashkin and his colleagues Tashkin Defends His Findings
marijuana smoke –although they dam- found, however, disproved their hypoth- Investigators from New Zealand re-
age cells in respiratory tissue– somehow esis. (Tashkin is to marijuana as a cause cently got widespread media attention
prevent them from becoming malignant. of lung cancer what Hans Blix was to for a study contradicting Tashkin’s re-
In other words, something in marijuana Iraq’s weapons of mass destruction –an sults. “Heavy cannabis users may be at
exerts an anti-cancer effect! honest investigator who set out to find greater risk of chronic lung disease –in-
Tashkin has special credibility. He something, concluded that it wasn’t cluding cancer– compared to tobacco
was the lead investigator on studies dat- there, and reported his results.) smokers,” is how BBC News summed
ing back to the 1970s that identified the Tashkin’s team interviewed 1,212 up the New Zealanders’ findings.
TASHKIN AT ASILOMAR showed The very small size of the study –79
components in marijuana smoke that are cancer patients from the Los Angeles
photomicrographs of cells damaged by smokers took part, 21 of whom smoked
toxic. It was Tashkin et al who published County Cancer Surveillance program, cannabis smoke. Having identified known
photomicrographs showing that mari- matched for age, gender, and neighbor- cannabis only– was not held against the
carcinogens in the smoke, he was surprised
juana smoke damages cells lining the hood with 1,040 cancer-free controls. when study results showed that cannabis authors. In fact, the small New Zealand
upper airways. It was the Tashkin lab’s Marijuana use was measured in “joint smoking doesn’t lead to lung cancer. study was given much more coverage by
finding that benzpyrene – a component years” (number of years smoked times the corporate press than the large UCLA
of tobacco smoke that plays a role in number of joints per day). Research Society. They were published study that preceded it.
most lung cancers– is especially preva- It turned out that increased marijuana in the October 2006 issue of “Cancer The New Zealand study was por-
lent in marijuana smoke. It was Tashkin’s use did not result in higher rates of lung Epidemiology Biomarkers & Preven- trayed as the latest word on this impor-
data showing that marijuana smokers are and pharyngeal cancer, whereas tobacco tion.” tant subject. As if scientific inquiry were
more likely than non-smokers to cough, smokers were at greater risk the more Without a press release from NIDA some kind of tennis match and the truth
wheeze, and produce sputum. they smoked. Tobacco smokers who also calling attention to its significance, the just gets truthier with every volley.
Tashkin reviewed his findings in April smoked marijuana were at slightly lower assignment editors of America had no Tashkin criticized the New
2008, at a conference organized by “Pa- risk of getting lung cancer than tobacco- idea that “Marijuana Use and the Risk Zealanders’ methodology in his talk at
tients Out of Time,” a reform group de- only smokers. of Lung and Upper Aerodigestive Tract Asilomar: “There’s some cognitive dis-
voted to educating doctors and the pub- These findings were not deemed wor- Cancers: Results of a Population-Based sonance associated with the interpreta-
lic (as opposed to lobbying politicians). thy of publication in “NIDA Notes.” Case-Control Study” by Mia Hashibe1, tion of their findings. I think this has to
Some 30 MDs and nurses got continu- Tashkin reported them at the 2005 meet- Hal Morgenstern, Yan Cui, Donald P. do with the belief model among the in-
ing medical education credits for attend- ing of the International Cannabinoid Tashkin, Zuo-Feng Zhang, Wendy vestigators and –I wish they were here
continued on next page

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—14— O’Shaughnessy’s • Summer 2009

Tashkin from previous page

to defend themselves– the integrity of He deemed it “completely implausible shown to promote apoptosis (damaged
the investigators... They actually pub- that smokers of only 365 joints of mari- cells die instead of reproducing) and to “no matter how much mari-
lished another paper in which they mim- juana have a risk for developing lung counter angiogenesis (the process by juana was smoked, the rate of
icked the design that we used for look- cancer similar to that of smokers of 7,000 which blood vessels are formed —a re-
ing at lung function.” tobacco cigarettes... Their small sample quirement of tumor growth). Other anti- decline was similar to nor-
Tashkin spoke from the stage of an size led to vastly inflated estimates... oxidants in cannabis may also be in- mal.” —Tashkin re COPD
airy redwood chapel designed by Julia They had said ‘it’s ideal to do the study volved in countering malignancy, said
Morgan. He is pink-cheeked, 70ish, in New Zealand because we have a much Tashkin. sured lung function of various cohorts
wears wire-rimmed spectacles. “For to- higher prevalence of marijuana smok- over eight years and found that tobacco-
bacco they found what you’d expect: a ing.’ But 88 percent of their controls had COPD only smokers had an accelerated rate of
higher risk for lung cancer and a clear never smoked marijuana, whereas 36% Much of Tashkin’s talk was devoted decline, but marijuana smokers –even if
dose-response relationship. A 24-fold of our controls (in Los Angeles) had to Chronic Obstructive Pulmonary Dis- they smoked tobacco as well– experi-
increase in the people who smoked the never smoked marijuana. Why did so ease, another condition prevalent among enced the same rate of decline as non-
most... What about marijuana? If they few of the controls smoke marijuana? tobacco smokers. Chronic bronchitis and smokers.
smoked a small or moderate amount Something fishy about that!” emphysema are two forms of COPD, “The more tobacco smoked, the
there was no increased risk, in fact Strong words for a UCLA School of which is the fourth-leading cause of greater the rate of decline,” said Tashkin.
slightly less than one. But if they were Medicine professor! death in the United States. Air pollution “In contrast, no matter how much mari-
in the upper third of the group, then their As to the highly promising implica- and tobacco smoke are known culprits. juana was smoked, the rate of decline
risk was six-fold... A rather surprising tion of his own study –that something in Inhaled pathogens cause an inflamma- was similar to normal.”
finding, and one has to be cautious about marijuana stops damaged cells from be- tory response, resulting in diminished Tashkin concluded that his and other
interpreting the results because of the coming malignant— Tashkin noted that lung function. COPD patients have in- studies “do not support the concept that
very small number of cases —fourteen— an anti-proliferative effect of THC has creasing difficulty clearing the airways regular smoking of marijuana leads to
and controls —four.” been observed in cell-culture systems as they get older. COPD.”
Tashkin said the New Zealanders and animal models of brain, breast, pros- Tashkin and colleagues at UCLA con- Breathe easier, everybody.
employed “statistical sleight of hand.” tate, and lung cancer. THC has been ducted a major study in which they mea-

A Sociologist Walks Into a Cannabis Club... having consistency in a life that was oth- them pay utility bills, and two patients forming relationships with other patients
At the 2008 Patients Out of Time Con-
ference sociologist Amanda Reiman de- erwise unpredictable; knowing that a visi- were extremely excited to relate their sto- for friendship and support. Participants
scribed a forthcoming study of the Ber- tor would come every Wednesday pro- ries of how BPG gave them Christmas mentioned that exposure to other patients
keley Patients Group. The BPG, founded vided this patient with comfort. trees when they could not afford them and with a range of ailments and circum-
in 1999, is one of the few dispensaries One patient mentioned that in addition how much that gesture meant to them. stances are therapeutic.
that allow medicating on-site —an ap- to medical help gained from the cannabis, Patients speak about the staff at BPG Participants who received medicine
proach Reiman calls “the social model.” the weekly hospice visits served as peer as if they are family and express such through Helping Hands reported that they
Reiman gave a written survey to 350 pa- counseling and allowed her time to vent gratitude for the personal interest that the learned of the program through word of
tients as they arrived at BPG, interviewed about her illness and the stresses of be- staff has taken in them, adding to their mouth and they felt that the criteria should
five members who received hospice de- ing ill. feelings of importance and self-worth. be clearer. Participants reported that most
livery services, and conducted a focus Patients who are also part of the low- Participants reported that they do not of their other medicines were covered
group with six participants. Excerpts of income “Helping Hands” program men- purchase cannabis every time they visit through Medi-Cal or Medicaid.
the study follow. tioned the huge financial burden that has BPG and stated that there are many times Suggestions
Every patient surveyed agreed that been lifted for them by having access to they visit just to receive services or so- Participants had several suggestions
there are benefits from BPG services be- high-grade medicine. cialize with other patients. for how BPG could be more service-ori-
yond the medication. All patients men- Other patients mentioned the help that Participants reported using a range of ented and patient-focused:
tioned the social support that they got they got from medical cannabis to deal services at BPG including acupuncture, 1. There should be a designated pa-
from visiting with other patients and re- with pain, eating and sleep issues. massage, renter’s assistance classes, and tient liaison that patients know they can
ceiving visitors through the hospice pro- One patient mentioned that, due to recreation activities such as open mic. go to with complaints, questions, sugges-
gram. Patients also mentioned the ben- periods of wasting, they would not be Access to free services allows patients tions. Participants felt that they did not
efits of having a community room where here if it were not for their medicine and to try out an alternative therapy to see if know who to approach about problems
they could relax and medicate in a safe BPG. they get relief from it before seeking it or suggestions. Perhaps a board could be
environment and speak with other pa- All patients mentioned the social sup- out as part of their permanent health care formed of staff and patients to discuss
tients. port that they get from other patients and regime. Many participants stated that the activities, services and issues related to
the staff at the dispensary. One patient services at BPG act as a bridge between BPG operations.
Most patients stressed the spoke about how services help her man- the times that they can receive health ser- 2. More arts and crafts.
age the stress of the struggle to stay vices elsewhere, either due to the cost of 3. Post the calendar where people can
importance of regular social healthy. She talked about the safe space the service or the cost of transportation. see it while they wait in line.
contact as being extremely ben- created at BPG where patients can open Patients report that losing BPG ser- 4. A way to inform folks when time is
eficial to their health. up and be vulnerable, which might be vices would disrupt their entire health almost up. Participants felt that some-
hard for some who must maintain a tough care treatment plan. For example, one times they were rushed out and that some-
exterior to get through their day. She also patient receives acupuncture both at BPG times a patient’s appearance affected how
Also mentioned were BPG programs
mentioned that coming to BPG helps get and at a clinic where she receives a more they were treated when their time was up.
such as acupressure and the different
patients out of the house and helps to intensive and longer treatment. She re- 5. Not enough chairs in the commu-
classes and speakers available to patients.
counteract the isolation that can come ported that she cannot afford these inten- nity room.
Most patients stressed the importance of
along with experiencing a chronic or ter- sive treatments regularly, so she uses the 6. There should be a designated
regular social contact as being extremely
minal illness. BPG treatments to supplement the more counter person for those with lots of ques-
beneficial to their health.
Another patient mentioned that hear- costly ones, as to not interrupt her treat- tions to speed up the line for those who
One patient described the benefits of
ing about other patients’ problems helps ment schedule. already know what they want.
him feel like he is not alone and that oth- Another participant reported that she
Amanda Reiman, MSW PhD, is an
ers are going through the same thing, lives near BPG and cannot afford the
academic coordinator/lecturer at the UC
which can be of great comfort. transportation to get to her more inten-
Berkeley School of Social Welfare.
One patient mentioned that BPG used sive treatments on a regular basis, so
to have a daily organic fruit and vegetable again, BPG is used to supplement these
delivery service that had to cease opera- treatments.
tions due to financial reasons. Other pa- Participants also reported getting peer
tients mentioned that BPG has helped support from other patients at BPG and

PATIENTS OUT OF TIME, ASILOMAR 2008: Al Byrne (who runs a tight meeting), Melanie Dreher, Laura Galli , Juan Sanchez-Ramos, Bill Britt, and MaryLynn Mathre.

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