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

Cannabinoids and Cancer - Abrams and Guzman

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Page 1: Cannabinoids and Cancer - Abrams and Guzman

O’Shaughnessy’s • Summer 2009 —7—

Cannabinoids and CancerEvidence from cell culture systems and animal models indicates

that THC and other cannabinoids may inhibit the growth of some tumorsby the modulation of signaling pathways.

By Donald I. Abrams and Manuel Guzman

Donald I. Abrams, MD, is Chief of He-matology-Oncology at San Francisco GeneralHospital; Director of Clinical Programs at theOsher Center for Integrative Medicine; andProfessor of Clinical Medicine at the Univer-sity of California San Francisco.

Manuel Guzman, PhD, is Professor of Bio-chemistry and Molecular Biology at theSchool of Biology, Complutense University,Madrid, Spain. This article appears in “Inte-grative Oncology,” edited by Dr. Abrams andAndrew Weil, MD, and published by OxfordUniversity Press (2009). O’Shaughnessy’sthanks the authors and Oxford UniversityPress, Inc, for permission to publish it.

Although long-recognized for itsmedicinal values and widely used bymillions throughout the world, marijuanareceives little attention in the standardliterature because of its status as a con-trolled substance and classification in theUnited States as a Schedule I agent witha high potential for abuse and no knownmedical use. Data on the potential effec-tiveness of medicinal cannabis is diffi-cult to find due to the limited numbersof clinical trials that have been conductedto date.

As a botanical, cannabis shares thosedifficulties encountered in the study ofplants that are grown in many climatesand environments from diverse geneticstrains and harvested under variable con-ditions. However, the potential benefitsof medicinal cannabis have not been loston a large number of people living withcancer, some of whom have been quitevocal in attributing their ability to com-plete their prescribed course of chemo-therapy to the anti-emetic effects ofsmoked cannabis.

In the practice of integrative oncol-ogy, the provider is frequently faced withsituations where being able to recom-mend medicinal cannabis seems like theright thing to do. A growing body of pre-clinical evidence suggests that cannabismay not only be effective for symptommanagement, but may have a direct anti-tumor effect as well. This article willreview the role of cannabinoids in can-cer.

CANNABIS AS MEDICINE:A BRIEF HISTORY

Use of cannabis as medicine datesback at least 2000 years.1-4 Widely em-ployed on the Indian subcontinent, can-nabis was introduced into Western medi-cine in the 1840s by W.B. O’Shaugh-nessy, a surgeon who learned of its me-dicinal benefits first hand while work-ing in the British East Indies Company.Promoted for reported analgesic, seda-tive, anti-inflammatory, antispasmodicand anticonvulsant properties, cannabiswas said to be the treatment of choicefor Queen Victoria’s dysmen-norhea. Inthe early 1900s, medicines that were in-dicated for each of cannabis’ purportedactivities were introduced into the West-ern armamentarium, making its use lesswidespread.

Physicians in the United States werethe main opponents to the introductionof the Marihuana Tax Act by the Trea-sury Department in 1937. The legisla-tion was masterminded by HarryAnslinger, director of the Federal Bureauof Narcotics from its inception in 1931

until 1962, who testified in Congress that“Marijuana is the most violence-causingdrug in the history of mankind.” The Actimposed a levy of $1 an ounce for me-dicinal use and $100 an ounce for recre-ational use, which in 1937 dollars was aprohibitive cost.

By using the Mexican name for theplant and associating it with nefariousSouth-of the-Border activities, the pro-ponents fooled many physicians. The Actwas singly opposed by the AmericanMedical Association, who felt that ob-jective evidence that cannabis was harm-ful was lacking and that its passagewould impede further research into itsmedical utility. In 1942, cannabis wasremoved from the U.S. Pharmacopoeia.

Mayor Fiorello LaGuardia of NewYork commissioned an investigation intothe reality of the potential risks and ben-efits of cannabis that reported in 1944that the substance was not associatedwith any increased risk of criminal ac-tivity, addiction or insanity as had beenclaimed. The LaGuardia CommissionReport, as well as subsequent similarinvestigations that have been commis-sioned nearly every decade since, wentlargely ignored.

In 1970 with the initiation of the Con-trolled Substances Act, marijuana wasclassified as a Schedule I drug. Whereboth Schedule I and Schedule II sub-stances have a high potential for abuse,Schedule I drugs are distinguished byhaving no accepted medical use. OtherSchedule I substances include heroin,LSD, mescaline, methylqualone and,most recently, gammahydroxybutyrate(GHB).

In 1973, President Nixon’s investiga-tion into the risks and benefits of mari-juana, the Shafer Commission, con-

cluded that it was a safe substance withno addictive potential that had medici-nal benefits. Despite the fact that it wasdeemed to have no medical use, mari-juana was distributed to patients by theUnited States government on a case-by-case basis by way of a CompassionateUse Investigational New Drug (IND)program established in 1978.

In the late 1980s and early 1990s,many people living with human immu-nodeficiency virus-1 (HIV) developed awasting syndrome as a pre-terminalevent.5 The wasting syndrome, charac-terized by anorexia, weight loss ofgreater than 10 percent body weight, andfrequently, fever and diarrhea, createdhordes of cachectic individuals in searchof any potential therapeutic intervention.Many turned to smoking marijuana.6-8

Fearful that there might be a run onthe Compassionate Use program, the

Synthetic delta-9-THC in sesame oilwas first licensed and approved in 1986for the treatment of chemotherapy-asso-ciated nausea and vomiting. Clinical tri-als done at the time determined thatdronabinol was as effective, if not moreso, than the available antiemetic agents.9

The potent class of serotonin receptor an-tagonists which have subsequently revo-lutionized the ability to administeremetogenic chemotherapy had not yetcome to market.

Dronabinol was investigated for itsability to stimulate weight gain in pa-tients with the AIDS wasting syndromein the late 1980s. Results from a num-ber of trials suggested that although pa-tients reported an improvement in appe-tite, no statistically significant weightgain was appreciated.10-11 In one trialevaluating megestrol acetate anddronabinol alone and together, the can-nabinoid seemed to negate some of theweight increase seen in those only re-ceiving the hormone.12

CANNABINOID CHEMISTRYAND BIOLOGIC EFFECTS

Cannabinoids are a group of 21 car-bon terpenophenolic compounds pro-duced uniquely by Cannabis sativa andCannabis indica species.13-14 With thediscovery of endogenous cannabinoidsand to distinguish them from pharma-ceutical compounds, the plant com-pounds may also be referred to asphytocannabinoids.

Although delta-9-THC is the primaryactive ingredient in cannabis, there area number of non-THC cannabinoids andnon-cannabinoid compounds that alsohave biologic activity. Cannabinol, can-nabidiol, cannabichromene, cannabi-gerol, tetrahydrocannabivarin and delta-8-THC are just some of the additionalcannabinoids that have been identified.

It is postulated that the secondarycompounds may enhance the beneficialeffects of delta-9-THC, for example bymodulating the THC-induced anxiety,anticholinergic or immunosuppressiveeffects. In addition, cannabis-associatedterpenoids and flavonoids may increasecerebral blood flow, enhance corticalactivity, kill respiratory pathogens andprovide anti-inflammatory activity.

The neurobiology of the cannabinoids

Key Concepts• Cannabis has been used in medicine for thousands of years prior to

achieving its current status as an illicit substance.• Cannabinoids, the active components of Cannabis sativa, mimic the

effects of the endogenous cannabinoids (the so-called endocannabinoids),activating specific cannabinoid receptors, particularly CB1 found predomi-nantly in the central nervous system and CB2 found in cells involved withimmune function.

Delta-9-tetrahydrocannabinol, the main psychoactive cannabinoid in theplant, has been available as a prescription medication approved for chemo-therapy-induced nausea and vomiting and treatment of anorexia associatedwith the AIDS wasting syndrome.

• In addition to treatment of nausea and anorexia, cannabinoids may beof benefit in the treatment of cancer-related pain, possibly in a synergisticfashion with opioid analgesics.

• Cannabinoids have been shown to be of benefit in the treatment ofHIV-related peripheral neuropathy suggesting that they may be worthy ofstudy in patients with chemotherapy-related neuropathic symptoms.

• Cannabinoids have a favorable drug safety profile, medical use pre-dominantly limited by their psychoactive effects and their limitedbioavailability.

• There is no conclusive evidence that chronic cannabis use leads to thedevelopment of any malignancies; some preclinical studies actually sug-gest a protective effect.

• Cannabinoids inhibit tumor growth in laboratory animal models bymodulation of key cell-signaling pathways, inducing direct growth arrestand tumor cell death, as well as by inhibiting tumor angiogenesis and me-tastasis.

• Cannabinoids appear to be selective antitumor compounds as they killtumor cells without affecting their non-transformed counterparts.

• More basic and clinical research is needed to ascertain not only therole of cannabinoids in palliative cancer care, but to delineate their role aspotential anti-cancer agents with activity at a number of sites by way ofmultiple mechanisms of action.

CANNABINOIDS are a group of 21-carbon terpeno-phenolic compounds. Delta-9-tetrahydrocannabinol(THC) is the most potent of the phytocannabinoidsproduced by the Cannabis species. The cannabinoidscomplex with two receptors, CB1 and CB2, to producephysiologic effects.

Bush administration shutit down in 1992, the sameyear that dronabinol(delta-9-tetrahydrocan-nabinol, Marinol(r)) wasapproved for treatment ofanorexia associated withthe AIDS wasting syn-drome.

Delta-9-tetrahydro-cannabinol is one of theapproximately 70 cannab-inoids found in the can-nabis plant and is felt to bethe main psychoactivecomponent. Overall, theplant contains about 400compounds derived fromits secondary metabolism,many of which may con-tribute to its medicinal ef-fect.

continued on next page

Page 2: Cannabinoids and Cancer - Abrams and Guzman

—8— O’Shaughnessy’s • Summer 2009

has only been identified within the past20 years during which time an explosionof knowledge has occurred.15-18 In themid-1980’s, researchers developed apotent cannabinoid agonist to be used inresearch investigations.

In 1986 it was discovered that can-nabinoids inhibited the accumulation ofcyclic adenosine monophosphate(cAMP), suggesting the presence of areceptor-mediated mechanism. By at-taching a radiolabel to the synthetic can-nabinoid, the first cannabinoid receptor,CB1, was pharmacologically identifiedin the brain in 1988.

The CB1 receptor is coupled to Gi/oproteins. Its engagement inhibitsadenylyl cyclase and voltage-gated cal-cium channels, and stimulates rectifyingpotassium conductances and mitogen-activated protein kinase activity.

By 1990, investigators had cloned theCB1 receptor, identified its DNA se-quence and mapped its location in thebrain, with the largest concentration be-ing in the basal ganglia, cerebellum, hip-pocampus and cerebral cortex.

In 1993 a second cannab-inoid receptor, CB2, was iden-tified outside the brain.

In 1993 a second cannabinoid recep-tor, CB2, was identified outside thebrain. Originally detected in macroph-ages and the marginal zone of the spleen,the highest concentration of CB2 recep-tors is located on the B lymphocytes andnatural killer cells, suggesting a possiblerole in immunity.

The existence of cannabinoid recep-tors has subsequently been demonstratedin animal species all the way down toinvertebrates. Are these receptors presentin the body solely to complex with in-gested phytocannabinoids?

The answer came in 1992 with theidentification of a brain constituent thatbinds to the cannabinoid receptor.Named “anandamide” from the Sanskritword for bliss, the first endocannabinoidhad been discovered. Subsequently 2-arachidonoylglycerol (2-AG) has alsobeen confirmed as part of the body’s en-dogenous cannabinoid system.

These endocanabinoids function asneurotransmitters. As the ligands for the7-transmembrane domain cannabinoidreceptors, binding of the endocan-nabinoid leads to G-protein activationand the cascade of events transpires re-sulting in the opening of potassium chan-nels which decreases cell firing and theclosure of calcium channels which de-

creases neurotransmitter release.The function of the endogenous can-

nabinoid system in the body is becom-ing more appreciated through advancesin cannabinoid pharmacology. The iden-tification of the cannabinoid receptorshas led to a host of agonists and antago-nists being synthesized. Utilizing thesetools, investigators are discovering thatthe system is likely to be important inthe modulation of pain and appetite,suckling in the newborn and the com-plexities of memory. (Michael Pollan in“The Botany of Desire” gives a particu-larly entertaining description of the natu-ral function of endocannabinoids inmemory.19)

In addition to being utilized to learnmore about the natural function of theendocannabinoid system, a number ofthese cannabinoid receptor agonists andantagonists are being developed as po-tential pharmaceutical therapies. In themeantime, dronabinol, nabilone(Cesamet(r), a synthetic cannabinoid)and cannabis are the currently availablecannabinoid therapies in the UnitedStates. Levonantradol (Nantrodolum (r))is a synthetic cannabinoid administeredintramuscularly, not used as much clini-cally since the oral agents became avail-able.

A whole cannabis extract (Sativex(r))delivered as an oro-mucosal spray withvarying combinations of THC and can-nabidiol is available in Canada and un-dergoing late phase testing in the US andother countries.

Through the receptors describedabove, cannabis delivered by way of in-halation or orally can produce a host ofbiologic effects. The Institute of Medi-cine report makes the following generalconclusions about the biology of can-nabis and cannabinoids:2

• Cannabinoids likely have a naturalrole in pain modulation, control of move-ment, and memory.

• The natural role of cannabinoids inimmune systems is likely multifacetedand remains unclear.

• The brain develops tolerance to can-nabinoids.

• Animal research has demonstratedthe potential for dependence, but this po-tential is observed under a narrowerrange of conditions than with benzodi-azepines, opiates, cocaine, or nicotine.

• Withdrawal symptoms can be ob-served in aminals but appear mild com-pared with those of withdrawal fromopiates of benzodiazepines.

Pharmacology of CannabisWhen taken by mouth, there is a low

(6-20%) and variable oral bioavailabil- continued on next page

Cannabinoids and Cancer from previous page

SIGNALING PATHWAYS COUPLED TO THE CB1 CANNABINOID RECEPTORare outlined above. The CB1 cannabinoid receptor signals to a number of differentcellular pathways. These include (i) inhibition of the adenylyl cyclase (AC)-cyclic AMP-protein kinase A (PKA) pathway; (ii) modulation of ion conductances, by inhibition ofvoltage-sensitive Ca2+ channels (VSCC) and activation of G protein-coupled inwardly-rectifying K+ channels (GIRK); and (iii) activation of mitogen-activated protein kinase(MAPK) cascades. Other less established cannabinoid receptor effectors and the cross-talk among the different pathways have been omitted for simplification.

ity.13-20 Peak plasma concentrations oc-cur after 1-6 hours and remain elevatedwith a terminal half-life of 20-30 hours.When consumed orally, delta-9-THC isinitially metabolized in the liver to 11-OH-THC, also a potent psychoactivemetabolite.

On the other hand, when smoked, thecannabinoids are rapidly absorbed intothe bloodstream with a peak concentra-tion in 2-10 minutes which rapidly de-clines over the next 30 minutes. Smok-ing thus achieves a higher peak concen-tration with a shorter duration of effect.Less of the psychoactive 11-OH-THCmetabolite is formed.

Cannabinoids can interact with thehepatic cytochrome P450 enzyme sys-tem.21-22 Cannabidiol, for example, caninactivate CYP 3A4. After repeateddoses, some of the cannabinoids mayinduce P450 isoforms. The effects arepredominantly related to the CYP1A2,CYP2C and CYP3A isoforms. The po-tential for a cannabinoid interaction withcytochrome P450 and, hence, possiblymetabolism of chemotherapeutic agentshas lead to a small amount of data onthe possibility of botanical:drug interac-tions.

In one study, 24 cancer patients weretreated with intravenous irinotecan (600mg, n = 12) or docetaxel (180 mg, n =12), followed three weeks later by thesame drugs concomitant with medicinalcannabis taken as an herbal tea for 15consecutive days, starting 12 days be-fore the second treatment.23 The care-fully conducted pharmacokinetic analy-ses showed that cannabis administrationdid not significantly influence exposureto and clearance of irinotecan ordocetaxel.

SYMPTOM MANAGEMENT

Antiemetic effectThe nausea and vomiting related to

cancer chemotherapy continues to be asignificant clinical problem even in lightof the newer agents that have been addedto our armamentarium since the 1970sand 1980s when clinical trials of cannab-inoids were first conducted.24

In those days, phenothiazines andmetoclopropramide were the main anti-emetic agents used. Dronabinol (syn-thetic THC) and nabilone (a syntheticanalog of THC) were both tested as noveloral agents in a number of controlledclinical trials. Nabilone was approved in

Canada in 1982, but only recently be-came available in the US. Dronabinolwas approved as an antiemetic to be usedin cancer chemotherapy in the US in1986.

Numerous meta-analyses confirm theutility of these THC-related agents in thetreatment of chemotherapy-induced nau-sea and vomiting. Tramer et al. con-ducted a systematic review of 30 ran-domized comparisons of cannabis withplacebo or antiemetics from which di-chotomous data on efficacy and harmwere available.25 Oral nabilone, oraldronabinol, and intramuscular levonan-tradol were tested. No smoked cannabistrials were included. Thirteen hundredsixty-six patients were involved in thesystematic review. Cannabinoids werefound to be significantly more effectiveantiemetics than prochlorperazine,metoclopramide, chlorpromazine,thiethylperazine, haloperidol, domperi-done, or alizapride.

In this analysis, the number neededto treat (NNT) for complete control ofnausea was 6; the NNT for completecontrol of vomiting was 8. Cannabinoidswere not more effective in patients re-ceiving very low or very high emetogen-ic chemotherapy. In crossover trials, pa-tients preferred cannabinoids for futurechemotherapy cycles.

Tramer identified some “potentiallybeneficial side effects” that occurredmore often with cannabinoids, includ-ing the “high,” sedation or drowsiness,and euphoria. Less desirable side effectsthat occurred more frequently with can-nabinoids included dizziness, dysphoriaor depression, hallucinations, paranoiaand hypotension.

A later analysis by Ben Amar reportedthat 15 controlled studies comparednabilone to placebo or available anti-emetic drugs.26 In 600 patients with a va-riety of malignant diagnoses, nabilonewas found to be superior to prochlorpera-zine, domperidone and alizapride, withpatients clearly favoring the nabilone forcontinuous use.

Nabilone has also been shown to bemoderately effective in managing thenausea and vomiting associated with ra-diation therapy and anesthesia after ab-dominal surgery.25-28 In the same meta-analysis, Ben Amar reports that in 14studies of dronabinol involving 681 pa-tients, the cannabinoid antiemetic effectwas equivalent or significantly greater

ENDOGENOUS CANNABINOIDS, anandamide (AEA) and 2-arachidonoylglycerol(2-AG), function as neurotransmitters. Synthetic cannabinoids have also been producedas pharmaceutical agents. Cannabinoids exert their effects by binding to specific Gi/oprotein-coupled receptors.

Page 3: Cannabinoids and Cancer - Abrams and Guzman

O’Shaughnessy’s • Summer 2009 —9—

than chlorpromazine and equivalent tometochlopramide, thiethylperazine andhaloperidol.

It is noted that the efficacy of the can-nabinoids in these studies was some-times outweighed by the adverse reac-tions and that none of the comparatorantiemetics were of the serotonin recep-tor antagonist class that is the mainstayof treatment today.

There have been only three controlledtrials evaluating the efficacy of smokedmarijuana in chemotherapy-inducednausea and vomiting.26 In two of thestudies, the smoked cannabis was onlymade available after patients faileddronabinol.

The third trial was a randomized,double-blind, placebo-controlled, cross-over trial involving 20 adults where bothsmoked marijuana and oral THC wereevaluated. One-quarter of the patientsreported a positive antiemetic responseto the cannabinoid therapies. On directquestioning of the participants, 35% pre-ferred the oral dronabinol, 20% preferredthe smoked marijuana and 45% did notexpress a preference. Four participantsreceiving dronabinol alone experienceddistorted time perception or hallucina-tions which were also reported by twowith smoked marijuana and one withboth substances.

The University of California Centerfor Medicinal Cannabis Research alsoapproved and funded a double-dummydesign clinical trial to compare smokedcannabis, oral dronabinol or placebo inpatients with delayed nausea and vom-iting, a condition for which the seroto-nin receptor antagonists are ineffective.29

Unfortunately the trial was launchedconcurrently with the first release ofaprepitant (Emend (r)), the first commer-cially available drug from the new classof agents, the Substance P/neurokininNK-1 receptor antagonists, which are ap-proved for the treatment of delayed nau-sea.30 The cannabis trial never accruedand the funding was withdrawn.

Both dronabinol and nabilone areFDA-approved for the treatment of nau-sea and vomiting associated with can-cer chemotherapy in patients who havefailed to respond adequately to conven-tional antiemetic therapy. Nabilone’sextended duration of action allows fortwice-a-day dosing of one or two milli-grams commencing 1 to 3 hours prior toreceiving chemotherapy. A dose of 1 or2 milligrams the night before adminis-tration of chemotherapy might also beuseful.

It is recommended to commencedronabinol at an initial dose of 5 mg/m2,also 1 to 3 hours prior to the administra-tion of chemotherapy, then every 2 to 4hours after chemotherapy, for a total of4 to 6 doses/day. Should the 5 mg/m2dose prove to be ineffective, and in theabsence of significant side effects, thedose may be escalated by 2.5 mg/m2increments to a maximum of 15 mg/m2per dose.

Nabilone, with fewer metabolites anda lower dose range may be associatedwith fewer side effects. The need to doseone to three hours prior to chemotherapyis one factor that drives patients to pre-fer smoked cannabis where the deliveryand effect peak within minutes. Patientsalso prefer the ability to more tightly ti-trate the dose of cannabinoids they re-ceive when smoking compared to oralingestion.

Appetite stimulationAnorexia, early satiety, weight loss

and cachexia are some of the most daunt-ing symptom management challenges

faced by the practicing oncologist. Thereare very few tools in the tool-box foraddressing these concerns. Patients arenot only disturbed by the disfigurementassociated with wasting, but also by theirinability to engage in the social interac-tion associated with breaking bread andpartaking of a meal. For many the hor-monal manipulation with megestrol ac-etate (synthetically derived progester-one) may be contraindicated or the sideeffects undesirable. Two small controlledtrials demonstrated that oral THC stimu-lates appetite and may slow weight lossin patients with advanced malignan-cies.26

In a larger randomized, double-blind,parallel group study of 469 adults withadvanced cancer and weight loss, pa-tients received either 2.5 mg of oral THCtwice daily, 800 mg of oral megestroldaily or both. In the megestrol mono-therapy group, appetite increased in 75%and weight in 11% compared to 49% and3% respectively in the oral THC group.These differences were statistically sig-nificant. The combined therapy did notconfer additional benefits.

Similar studies in patients with HIV-associated wasting syndrome also foundthat cannabinoids were more effectivein improving appetite than in increasingweight. In our own study of the safetyof smoked and oral cannabinoids in pa-tients with HIV on protease inhibitorregimens, we did find an increase inweight in both cannabinoid groups com-pared to the placebo recipients; howeverthe study was not powered with weightgain as an endpoint.31-32

Many animal studies have previouslydemonstrated that THC and other can-nabinoids have a stimulatory effect onappetite and increase food intake. It isfelt that the endogenous cannabinoidsystem may serve as a regulator of feed-ing behavior. For example, anandamidein mice leads to a potent enhancementof appetite.33

It is felt that the CB1 receptors,present in the hypothalamus where foodintake is controlled and in themesolimbic reward system, may be in-volved in the motivational or reward as-pects of eating. This has led to the de-velopment of the pharmaceutical CB1antagonist rimonabant (Acomplia (r)),which was approved in Europe for thetreatment of obesity on the basis of PhaseIII clinical trials where it was shown toinduce a 4-5 kg mean weight loss withimproved glycemic and lipid profiles. 34

This first of a new class of agents has

not yet been approved in the US becauseit was found to induce anxiety and de-pressive disorders that were deemed highrisk.

Anecdotal as well as clinical trial evi-dence also supports the appetite-stimu-lating effect of smoking cannabis. Inclassic trials conducted in the 1970s inhealthy controls, it was found that, es-pecially when smoked in a social/com-munal setting, cannabis ingestion led toan increase in caloric intake, predomi-nantly in the form of between mealsnacks, mainly in the form of fatty andsweet foods.

In cancer patients with anorexia aswell as chemotherapy-induced nausea,it is worth noting that cannabis is the onlyantiemetic that also has orexigenic ac-tion. Although cannabis thus providestwo potential benefits to the patient withcancer, the appetite-stimulation does notalways reverse the cancer cachexiawhich is a function of energy wasting inaddition to decreased food intake.

AnalgesiaOur understanding of the possible

mechanisms of cannabinoid-inducedanalgesia has been greatly increasedthrough study of the cannabinoid recep-tors, endocannabinoids and syntheticagonists and antagonists. The CB1 re-ceptor is found in the central nervoussystem as well as in peripheral nerve ter-minals. Elevated levels of the CB1 re-ceptor –like opioid receptors– are foundin areas of the brain that modulate noci-ceptive processing.35

In contrast, CB2 receptors are locatedin peripheral tissue and are present atvery low expression levels in the CNS.Of the endogenous cannabinoids identi-fied, anandamide has high affinity forCB1 receptors, whereas 2-AG has affin-ity for both CB1 and CB2 receptors.

With the development of receptor-specific antagonists (SR141716 for CB1and SR144528 for CB2), additional in-formation has been obtained regardingthe roles of the receptors and endogenouscannabinoids in modulation of pain.36-37

Where the CB1 agonists exert anal-gesic activity in the CNS, both CB1 andCB2 agonists have peripheral analgesicactions.38-39

Cannabinoids may also contribute topain modulation through an anti-inflam-matory mechanism –a CB2 effect withcannabinoids acting on mast cell recep-tors to attenuate the release of inflam-matory agents such as histamine and se-rotonin and on keratinocytes to enhance

the release of analgesic opioids.40-42

Cannabinoids are effective in animalmodels of both acute and persistent pain.The central analgesic mechanism differsfrom the opioids in that it cannot beblocked by opioid antagonists. The po-tential for additive analgesic effects withopioids as well as the potential for can-nabinoids to reduce nausea and increaseappetite make a strong case for the evalu-ation of marijuana as adjunctive therapyfor patients on morphine.

Medical literature cites evidence ofcannabinoids’ ability to reduce naturallyoccurring pain, but few human studieshave been performed. Early studies ofcannabinoids on experimental pain inhuman volunteers produced inconsistentresults. In some cases, the administra-tion of cannabinoids failed to produceobservable analgesic effects; in others,cannabinoids resulted in an increase ofpain sensitivity (hyperalgesia). Uponreview, Institute of Medicine research-ers noted that these studies suffered frompoor design and methodological prob-lems and dubbed their findings incon-clusive.2

Cancer pain results from in-flammation, mechanical invasionof bone or other pain-sensitivestructure, or nerve injury. It issevere, persistent, and often re-sistant to treatment with opioids.

Encouraging clinical data on the ef-fects of cannabinoids on chronic paincome from three studies of cancer pain.Cancer pain results from inflammation,mechanical invasion of bone or otherpain-sensitive structure, or nerve injury.It is severe, persistent, and often resis-tant to treatment with opioids. Noyesand colleagues conducted two studies onthe effects of oral THC on cancer pain.Both studies used standard single-doseanalgesic study methodology and metthe criteria for well-controlled clinicaltrials of analgesic efficacy.

The first experiment measured bothpain intensity and pain relief in a double-blind, placebo controlled study of 10subjects.43 Observers compared the ef-fects of placebo and 5, 10, 15 and 20 mgdoses of delta-9-THC over a 6-hour pe-riod. Researchers reported that 15 and20 mg doses produced significant anal-gesia, as well as anti-emesis and appe-tite stimulation. Authors cautioned thatsome subjects reported unwanted sideeffects such as sedation and depersonal-ization at the 20 mg dose level.

In a follow up single-dose study of36 subjects, Noyes et al reported that10 mg of THC produced analgesic ef-fects over a seven-hour observation pe-riod comparable to 60 mg of codeine,and that 20 mg of THC induced effectsequivalent to 120 mg of codeine.44 Au-thors noted that respondents foundhigher doses of THC to be more seda-tive than codeine. However, in a sepa-rate publication, Noyes et al reported thatpatients administered THC had im-proved mood, sense of well-being, andless anxiety.45

A study by Staquet and colleagues onthe effects of a THC nitrogen analogueon cancer pain yielded similar results.46

Authors found the THC analogueequivalent to 50 mg of codeine and su-perior to both placebo and 50 mg of seco-barbital in subjects with mild, moderateand severe pain.

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DELTA-9-THC KILLS BRAIN TUMOR CELLS at a concentration that is nontoxic tonormal brain cells. Images obtained through a time-lapse microscope illustrate theselective induction of cell death in cultures of human Glioblastoma multiforme cells(upper left) compared to normal human glial cells (lower left). After 20 hours of treatment,death of nearly all of the GBM cells is evidenced by cells shrinking to inanimate whitespheres (upper right). The normal cells exposed to the same concentration of delta-9-THC continue to migrate and divide (lower right). Photo by McAllister and Yount.

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Neuropathic pain is a trou-bling symptom in cancer pa-tients, especially those treatedwith platinum-based chemo-therapy or taxanes.

Cannabinoids have also been shownto be of potential benefit in an animalmodel of neuropathic pain.47 Neuropathicpain is a troubling symptom in cancerpatients, especially those treated withplatinum-based chemotherapy ortaxanes. A painful sensory peripheralneuropathy is also commonly encoun-tered in patients with HIV infection ei-ther as a consequence of HIV itself orantiretroviral drugs used in treatment ofthe infection.

We completed a randomized, con-trolled trial of smoked cannabis com-pared to placebo in 50 subjects with HIV-related peripheral neuropathy.48 Smokedcannabis reduced daily pain by 34%compared to 17% with placebo (p=0.03).Greater than 30% reduction in pain wasreported by 52% in the cannabis groupand by 24% in the placebo group(p=0.04). The first cannabis cigarette re-duced chronic pain by a median of 72%compared to 15% with placebo(p<0.001). Cannabis also reduced experi-mentally-induced hyperalgesia to bothbrush and von Frey hair stimuli (p≤0.05)in a heat-capsaicin experimental painmodel used to anchor the more subjec-tive response of the chronic neuropathicpain. No serious adverse events werereported.

Two recent placebo-controlled stud-ies of cannabinioids for central neuro-pathic pain associated with multiple scle-rosis produced results similar to thepresent study. In a crossover trial of syn-thetic delta-9-THC up to 10 mg/day, anNNT of 3.5 was reported.49

A trial of a sublingual spray contain-ing delta-9-THC alone or combined withcannabidiol showed a 41% pain reduc-tion with active drug compared to a 22%reduction with placebo.50 In this study,the cannabidiol alone preparation was in-effective in pain relief. Improvement insleep quality was also reported with thesublingual spray. To date, no clinical tri-als have examined the effectiveness ofcannabinoid preparations in chemo-therapy-induced neuropathic pain.

If cannabinoids and opioidsare synergistic, it is possiblethat lower doses of opioids maybe effective for longer periodsof time with fewer side effects

Synergism between opioids and can-nabinoids has been postulated and sub-sequently demonstrated in a number ofanimal models.51-55 The antinociceptiveeffects of morphine are predominantlymediated by mu receptors but may beenhanced by delta-9-THC activation ofkappa and delta opioid receptors.55

It has been further postulated that thecannabinoid:opioid interaction may oc-cur at the level of their signal transduc-tion mechanisms.56-57 Receptors for bothclasses of drugs are coupled to similarintracellular signaling mechanisms thatlead to a decrease in cAMP productionby way of Gi protein activation.58-60

There has also been some evidencethat cannabinoids might increase the syn-thesis or release of endogenous opioids,or both. With this background, we areconducting a pharmacokinetic interactionstudy to investigate the effect of con-

comitant cannabis on disposition kinet-ics of opioid analgesics. If cannabinoidsand opioids are synergistic, it is possiblethat lower doses of opioids may be ef-fective for longer periods of time withfewer side effects, clearly a benefit tothe cancer patient with pain.

Anxiety, Depression and SleepIn clinical trials of cannabis, eupho-

ria is often scored as an adverse effect.Although not all patients experiencemood elevation after exposure to can-nabis, it is a frequent outcome. Muchdepends on the “set and setting” and theindividual’s prior experience with can-nabis.

Some people develop dysphoria withor without paranoia upon exposure tocannabis; for them cannabis or its con-stituents may not be clinically useful.

Sleepiness is another common sideeffect which can easily be recast as im-proved sleep quality as has been re-ported in trials of the sublingual spraycannabis-based medicine.61 For the can-cer patient suffering from anorexia, nau-sea, pain, depression, anxiety and in-somnia, a single agent that can addressall of these symptoms would be a valu-able addition to the armamentarium.

SAFETY AND SIDE EFFECTS

Cannabinoids have an extremely fa-vorable drug safety profile.13, 14, 24, 62Un-like opioid receptors, cannabinoid recep-tors are not located in brainstem areascontrolling respiration, so lethal over-doses due to respiratory suppression donot occur. The LD50 has been estimatedto be 1500 pounds smoked in 15 min-utes as extrapolated from animal stud-ies where the median lethal dose was es-timated to be several grams per kilogramof body weight.63

As cannabinoid receptors are not justlocated in the central nervous system butare present in tissues throughout thebody, additional side effects of note in-clude tachycardia and hypotension, con-junctival injection, bronchodilation,muscle relaxation and decreased gas-trointestinal motility.

Tolerance to the unwanted side ef-fects of cannabis appears to develop rap-idly in laboratory animals and humans.This is felt to occur due to a decrease inthe number of total and functionallycoupled cannabinoid receptors on thecell surface with a possible minor con-tribution from increased cannabinoidbiotransformation and excretion with re-peated exposure.

Although cannabinoids areconsidered by some to be ad-dictive drugs, their addictivepotential is considerably lowerthan other prescribed agents orsubstances of abuse.

Although cannabinoids are consid-ered by some to be addictive drugs, theiraddictive potential is considerably lowerthan other prescribed agents or sub-stances of abuse. The brain develops tol-erance to cannabinoids. Animal researchdemonstrates a potential for depen-dence, but this potential is observed un-der a narrower range of conditions thanwith benzodiazepines, opiates, cocaineor nicotine.

Withdrawal symptoms –irritability,insomnia with sleep EEG disturbance,restlessness, hot flashes and rarely nau-sea and cramping– have been observed,but appear mild compared with the with-

drawal from opiates or benzodiazepinesand usually dissipate after a few days.Unlike other commonly used drugs, can-nabinoids are stored in adipose tissue andexcreted at a low rate (half-life 1-3 days),so even abrupt cessation of THC intakeis not associated with rapid declines inplasma concentration that would precipi-tate withdrawal symptoms or drug crav-ing.

Most drug users begin withalcohol and nicotine beforemarijuana.

The 1999 Institute of Medicine reportaddressed the frequent concern thatmarijuana is a “gateway drug” leadingto use of other subsequent more potentand addictive substances of abuse.2 Thereport recounts that marijuana is the mostwidely used illicit drug and, predictably,the first most people encounter. Not sur-prisingly, most users of other illicit drugshave used marijuana first. However,most drug users begin with alcohol andnicotine before marijuana; hence mari-juana is not the most common and israrely the first “gateway” drug.

The report concludes that there is noconclusive evidence that the drug effectsof marijuana are causally linked to thesubsequent abuse of other illicit drugsand cautions that data on drug use pro-gression cannot be assumed to apply tothe use of drugs for medical purposes,which is certainly pertinent to the dis-cussion of cannabis in cancer patients.

CANNABIS AND CANCER RISK

A study conducted by the NationalToxicology Program of the US Depart-ment of Health and Human Services onmice and rats suggested that cannab-inoids may have a protective effectagainst tumor development.64 In this two-year evaluation, rats and mice were givenincreasing doses of THC by gavage. Adose-related decrease in the incidence ofboth benign and malignant tumors wasobserved. Animals receiving THC dos-ing also survived longer than those re-ceiving vehicle alone.

Mice and rats are not people and gav-age is not equivalent to smoking a com-busted botanical product. Many wouldfind the combustion and inhalation of atherapeutic agent to be an undesirableand perhaps counter-intuitive way todeliver a drug. Most of the evidenceavailable on the risk of cancer from mari-juana smoking comes from epidemio-logic studies, naturally, as prospective,randomized control trials are not pos-sible. Over the years, reports of increasedrisks of lung cancer, oropharyngeal can-cers and prostate and cervical cancerhave been most consistently reported.For each trial suggesting a possible in-crease in cancer incidence in chronicmarijuana users, others have been pub-lished that appear to refute the associa-tion.

A retrospective cohort study of 64,855Kaiser Permanente health care membersseen between 1979-1985 and followedthrough 1993 yielded an interesting find-ing.65 Men aged 15-49 were divided intofour cohorts based on their use of to-bacco and marijuana: never smoked ei-ther, smoked only cannabis, smoked onlytobacco, smoked tobacco and cannabis.There were 5600-8200 men in each cellfollowed for an average of nearly nineyears.

In the men who never smoked, therewere two cases of lung cancer diagnosed

over the follow-up period. In the menwho smoked tobacco, either alone or inaddition to marijuana, the risk of lungcancer was increased 10-fold. In the over50,000 person-years of follow-up of menwho only smoked marijuana, there wereno documented cases of lung cancer; lessthan in the never smokers!

A systematic review evaluating 19studies that involved persons 18 yearsor older who smoked marijuana and ex-amined premalignant or cancerous lunglesions concluded that observationalstudies failed to demonstrate significantassociations between marijuana smok-ing and lung cancer after adjusting fortobacco use.66

The authors cite the selection bias,small sample size, limited generalizabil-ity and overall young participant in stat-ing that because of the biological plau-sibility of an association of marijuanasmoking and lung cancer, physiciansshould still caution patients regardingpotential risks until further rigorous stud-ies permit definitive conclusions.

A population-based case-controlstudy of the association between mari-juana use and the risk of lung and upperaerodigestive tract cancers was per-formed in Los Angeles.67 One thousandone hundred twelve incident cancercases (611 lung, 303 oral, 108 esopha-gus, 100 pharynx, 90 larynx) werematched to 1040 cancer-free controls onage, gender and neighborhood.

A standardized questionnaire usedduring face-to-face interview collectedinformation on marijuana use expressedin joint-years, where 1 joint-year is theequivalent of smoking one marijuanacigarette per day for one year. The inter-views also requested information on theuse of other drugs including hashish, to-bacco (all forms) and alcohol,sociodemographic factors, diet, occupa-tional history, environmental factors in-cluding exposure to smoke, medical his-tory and family history of cancer.

Data were presented as crude oddsratios and adjusted odds ratios usingthree models of covariate adjustment(with only Model 3 including tobaccouse and pack/years). The results showedthat although using marijuana for > 30joint-years was positively associated inthe crude analysis with each cancer ex-cept pharyngeal, no positive associationswere found when adjusting for severalconfounders including cigarette smok-ing. In fact, in the Model 3 analysis forlung cancer, the cohort who reported >0 to < 1 joint-years of marijuana use hada 37% reduction in the risk of develop-ing lung cancer compared to those whonever smoked marijuana.

Although this was the only cohortwhere the reduction in lung cancer riskreached statistical significance, in themodel, all levels of marijuana use (in-cluding > 60 joint-years) had adjustedodds ratios less than 1.0. The authorsreport adjusted ORs <1 for all cancersexcept oral cancer and found no consis-tent association of marijuana use withany malignant outcome. In what appearsto be an overly aggressive attempt todelineate the possible limitations of theirwork which could have led to such aconsistent yet startling result, the authorsmention that “it is possible that mari-juana use does not increase cancer risk...Although the adjusted ORs < 1 may bechance findings, they were observed forall non-reference exposure categorieswith all outcomes except oral cancer.Although purely speculative, it is pos-sible that such inverse associations may

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reflect a protective effect of marijuana.”

CANNABINOIDSAS ANTICANCER AGENTS

There has been an increasing body ofevidence over the past decade that can-nabinoids may have a role in cancertherapy.62 Evidence from cell culturesystems as well as animal models havesuggested that THC and other cannab-inoids may inhibit the growth of sometumors by the modulation of signalingpathways that lead to growth arrest andcell death as well as by inhibition of an-giogenesis and metastasis.

The antiproliferative effects wereoriginally reported in 1975 by Munsonand colleagues, who demonstrated thatdelta-9-THC, delta-8-THC and cannab-inol inhibited Lewis lung adenocarci-noma cell growth in vitro as well as inmice. Curiously, there was no real fol-low-up of these findings for twenty yearswhen the line of investigation was pickedup by scientists in Spain and Italy whohave remained at the forefront of thisemerging field.62. 68. 69

Since the late 1990s, several plant de-rived (THC and cannabidiol), synthetic(WIN-55,212-2 and HU-210) and en-dogenous cannabinoids (anandamideand 2-arachidonoylglycerol) have beenshown to exert antiproliferative effectsof a wide variety of tumor cells in cul-ture systems. In addition to the originallung adenocarcinoma study, other tumorcells that have been shown to be sensi-tive to cannabinoid-induced growth in-hibition include glioma, thyroid epithe-lioma, leukemia/lymphoma, neuroblas-toma and skin, uterus, breast, gastric,colorectal, pancreatic and prostate car-cinomas.70-81

Perhaps even more compelling, can-nabinoid administration to nude miceslows the growth of various tumor xe-nografts including lung and skin carci-nomas, thyroid epitheliomas, melano-mas, pancreatic carcinomas, lymphomasand gliomas. The requirement of CB1and/or CB2 receptors for the antitumoreffect has been shown by various bio-chemical and pharmacological ap-proaches already mentioned and the cu-mulative effects of CB signaling in thecontrol of cell fate are expected to haveimportant implications in the potentialof cannabinoids for regulating tumor cellgrowth.

Cannabinoids may exert their antitu-mor effects by a number of differentmechanisms including direct inductionof transformed cell death, direct inhibi-tion of transformed-cell growth and in-hibition of tumor angiogenesis and me-tastasis.82-83 A desirable property of anti-tumor compounds is their preferentialtargeting of malignant cells. Cannab-inoids appear to kill tumor cells but donot affect their non-transformed coun-terparts and may even protect them fromcell death. This is best exemplified byglial cells.

Cannabinoids have been shown toinduce apoptosis of glioma cells in cul-ture and induce regression of gliomacells in mice and rats. In contrast, can-nabinoids protect normal glial cells ofastroglial and oligodendroglial lineagesfrom apoptosis mediated by the CB1 re-ceptor.

Immunohistochemical and functionalanalyses in mouse models of gliomas andskin carcinomas have demonstrated thatcannabinoid administration alters thevascular hyperplasia characteristic ofactively growing tumors into a patterncharacterized by small, differentiated,

impermeable capillaries, thus thwartingangiogenesis. This is accompanied by areduced expression of vascular endothe-lial growth factor (VEGF) and other pro-angiogenic cytokines, as well as ofVEGF receptors.

Activation of cannabinoid receptorsin vascular endothelial cells inhibits cellmigration and survival, also contribut-ing to impaired tumor vascularization.Cannabinoid administration to tumor-bearing mice decreases the activity andexpression of matrix metalloproteinase2, a proteolyic enzyme that allows tis-sue breakdown and remodeling duringangiogenesis and metastasis. This sup-ports the inhibitory effect of cannab-inoids in inhibiting tumor invasion inanimal models.

Further support comes from studiesin human non-small cell lung cancer celllines that overexpress epidermal growthfactor receptor, in which THC inhibitsepidermal growth factor-inducedgrowth, chemotaxis and chemo-inva-sion.84

In an in vivo model using severe com-bined immunodeficient mice, subcuta-neous tumors were generated by inocu-lating the animals with the same celllines. Tumor growth in THC-treated ani-mals was inhibited by 60% comparedwith vehicle-treated controls. The inhi-bition was significant both regarding thesubcutaneous xenograft as well as thenumber and weight of lung metastases.Tumor specimens revealed antipro-liferative and antiangiogenic effects ofTHC.

Most recently, another potential anti-cancer and particularly anti-metastasismechanism for cannabinoids has beenidentified. Id helix-loop-helix proteinscontrol processes related to tumor pro-gression85 Reducing Id-1 using antisensetechnology led to significant reductionsin breast cancer cell proliferation andinvasiveness in in vitro models and me-tastases in mice. Reducing Id-1 expres-sion with antisense technology is not apossible intervention in humans withbreast cancer at this time, however. Can-nabidiol has been demonstrated to down-regulate Id-1 expression in aggressivehuman breast cancer cells. The investi-gators suggest that cannabidiol repre-sents the first nontoxic exogenous agentthat can significantly decrease Id-1 ex-pression in metastatic breast cancer cellsleading to the down-regulation of tumoraggressiveness.

\Two additional potential mechanismsof anticancer activity warrant brief men-tion. Cannabinoids, both plant-derivedand endogenous, are believed to haveanti-inflammatory effects. Inflammationis being increasingly linked to the de-velopment of various malignancies. Per-haps one of the most obvious associa-tions is the development of colorectalcarcinoma in patients with inflammatorybowel disease.

A mouse study has demonstrated thatsignaling of the endogenous cannabinoidsystem is likely to provide intrinsic pro-tection against colonic inflammation.86

This has led to the development of ahypothesis that phytocannabinoids andendocannabinoids may be useful in theprevention and treatment of colorectalcancer.87

Kaposi’s sarcoma-associated herpes-virus/Human herpesvirus-8 (KSHV/HHV-8) and Epstein-Barr virus (EBV)are related and implicated in the causeof a number of malignant diseases in-cluding Kaposi’s sarcoma and primaryeffusion lymphoma (KSHV) andBurkitt’s lymphoma, primary central

nervous system lymphoma, Hodgkin’sdisease and nasopharyngeal carcinoma(EBV).

A group of investigators has demon-strated that THC is a potent and selec-tive antiviral agent against KSHV.88 It isfelt that THC may inhibit KSHV repli-cation through the activation of cannab-inoid receptors. The authors concludethat further studies on cannabinoids andherpesviruses are important as they maylead to development of drugs that inhibitreactivation of these oncogenic viruses.

Counter to these findings, however,is the recent suggestion that delta-9-THCmay actually enhance KSHV infectionand replication and foster KSHV-medi-ated endothelial transformation.88

These investigators caution that useof cannabinoids may thus place individu-als at greater risk for the developmentand progression of Kaposi’s sarcoma,although epidemiologic data have notsupported these in vitro findings.

So with the body of evidence increas-ing, where are the clinical trials in hu-mans with malignant disease? True, can-nabinoids have psychoactive side effects,but these could be considered to bewithin the boundaries of tolerance for thetoxicity profiles of cytotoxic chemo-therapeutic and targeted small moleculetherapies widely used in oncology.

The Spanish Ministry of Health ap-proved a pilot clinical trial carried out incollaboration between the Tenerife Uni-versity Hospital and the Guzman labo-ratory in Madrid to investigate the ef-fect of local administration of THC in-tracranially through an infusion catheteron the growth of recurrent glioblastomamultiforme.90

In this ground-breaking pilot study,THC administration was shown to besafe and associated with decreased tu-mor cell proliferation in at least two ofnine patients studied. Hopefully this pi-lot trial may open the door to furtherclinical investigations aimed at assess-ing the antitumor activity of cannabinoidtherapies.

ALTERNATIVEDELIVERY SYSTEMS

And what if clinical trials were todemonstrate that smoked marijuana maybe of benefit to patients with a condi-

tion like, for example, recurrentglioblastma multiforme?

It is not likely that even a meta-analy-sis of a number of similar studies in anycondition would convince the necessaryregulatory bodies that cannabis shouldbe re-instated to the U.S. Pharmacoepiaand made widely available to patientswho may benefit from its use. The Insti-tute of Medicine Report in 1999 clearlystated that the accumulated data indicatea potential therapeutic value for cannab-inoid drugs, particularly in the areas ofpain relief, control of nausea and vomit-ing and appetite stimulation. The authorswent on to suggest that the “goal of clini-cal trials of smoked marijuana would notbe to develop it as a licensed drug, butas a first step towards the developmentof non-smoked, rapid-onset cannabinoiddelivery systems.” 2

To this end, we conducted a trial inhealthy marijuana-smoker volunteerscomparing the blood levels of cannab-inoids achieved upon inhaling marijuanathat has been vaporized in a device thatheated the plant product to below thetemperature of combustion and collectedthe volatilized gases with those obtainedupon smoking a comparable dosed ciga-rette.91

Eighteen healthy subjects were evalu-ated. One dose (1.7, 3.4 or 6.8% tetrahy-drocannabinol) and delivery system(smoked cannabis cigarette or vaporiza-tion system) was randomly assigned foreach of the six inpatient study days. Thepeak plasma concentrations and six-hourarea under the plasma concentration-time curve of THC after inhalation ofvaporized cannabis were similar to thoseof smoked cannabis.

Carbon monoxide levels were sub-stantially reduced with vaporization sug-gesting less exposure to noxious sub-stances. Neuropsychologic effects wereequivalent and participants expressed aclear preference for vaporization as adelivery method.

No adverse events were observed.Vaporization of cannabis is a safe andeffective mode of delivery of THC. Con-sequently, our ongoing evaluation ofopioid:cannabinoid interactions is usingthe vaporizer as a smokeless deliverysystem.

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OTHER ANTI-TUMOR EFFECTS OF CANNABINOIDS:Besides inducing apoptosis of tumor cells, cannabinoid administration can decreasethe growth of gliomas by other mechanisms, including at least: (i) reduction of tumorangiogenesis, by inhibition of the vascular endothelial growth factor (VEGF) pathway;(ii) inhibition of tumor cell invasion, by down-regulation of matrix metalloproteinase-2 (MMP-2) expression; (iii) induction of tumor cell differentiation, by down-regulationof epidermal growth factor (EGF) receptor expression; and perhaps (iv) arrest of thecell cycle, by down-regulation of cyclin-dependent kinase-1 (CDK1) expression. Therelative contribution of these processes to the inhibition of tumor growth depends onvarious factors such as the type of tumor under study, the experimental model usedand the intensity of cannabinoid signaling.

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smoked or inhaled cannabis is the sub-lingual preparation of whole plant ex-tract.50, 61, 92 Sativex(r) was first approvedas a prescription medication in Canadain 2005 for symptomatic relief of neu-ropathic pain in multiple sclerosis andsubsequently as adjunctive therapy forpatients with cancer pain on other anal-gesic medications. The cannabis-basedmedication is available in Spain, under-going regulatory review by the EuropeanUnion and is being evaluated in a PhaseII/III clinical trial in patients with can-cer-related pain in the U.S..

GUIDELINES FOR PROVIDERS

The Institute of Medicine is awarethat the development and acceptance ofsmokeless marijuana delivery systems“may take years; in the meantime thereare patients with debilitating symptomsfor whom smoked marijuana may pro-vide relief.” So what is a provider to do?

Patients with cancer have a numberof symptoms that may be responsive tocannabinoid therapies. As enumerated,these include nausea, vomiting, anor-exia, pain, insomnia, anxiety and depres-

sion. Many providers would frown uponthe use of a relatively benign smokedpsychotropic agent while freely writingprescriptions for pharmaceutical agentswith significantly greater cost, potentialfor addiction or abuse, and more nega-tive societal impact overall.

The Medical Board of California intheir July 2004 Action Report providesa model for how states with medicalmarijuana legislation should advise phy-sicians.93

“The intent of the board at this timeis to reassure physicians that if they usethe same proper care in recommendingmedical marijuana to their patients asthey would any other medication or treat-ment, their activity will be viewed by theMedical Board just as any other appro-priate medical intervention.... If physi-cians use the same care in recommend-ing medical marijuana to patients as theywould recommending or approving anyother medication or prescription drugtreatment, they have nothing to fear fromthe Medical Board.”

The Board recommends following theaccepted standards that would be usedin recommending any medication. A his-

tory and physical examination should bedocumented. The provider should ascer-tain that medical marijuana use is notmasking an acute or treatable progres-sive condition. A treatment plan shouldbe formulated. A patient need not havefailed all standard interventions beforemarijuana can be recommended. Thephysician may have little guidelines inactually recommending a concrete dosefor the patient to use.94

As there are so many variables asso-ciated with effect, the physician and pa-tient should develop an individual self-titration dosing paradigm that allows thepatient to achieve the maximum benefitwith tolerable side effects. Discussion ofpotential side effects and obtaining ver-bal informed consent are desirable. Pe-riodic review of the treatment efficacyshould be documented. Consultationshould be obtained when necessary.Proper record keeping that supports thedecision to recommend the use of medi-cal marijuana is advised.

Despite all these guidelines, the Medi-cal Board of California still reminds phy-sicians that making a written recommen-dation “could trigger a federal action.”

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Thousand Years. New York: Plenum Press;1980.

2. Joy JE, Watson SJ and Benson JA, eds.Marijuana and Medicine: Assessing theScience Base. Washington, DC; NationalAcademy Press, 1999.

3. Mack A, Joy JE. Marijuana as medi-cine? –The science beyond the controversy.Washington, D.C; National Academy Press,2001.

4. Booth M. Cannabis: A History. St.Martin’s Press, New York, 2003.

5. Chan ISF, Naton JD, Saravolatz LD,Crane LR, Osterberger J. Frequencies of op-portunistic diseases prior to death amongHIV-infected persons. AIDS 1995: 9: 1145-1151.

6. Abrams DI, Child CC, Mitchell T. Mari-juana, the AIDS wasting syndrome and theUS government. N Engl J Med. 1995;333:670-671.

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8. Werner CA. Medical marijuana and theAIDS crisis. Journal of Cannabis Therapeu-tics, 2001;1:17-33.

9. Sallen SE, Zinberg NE, Frei E. Anti-emetic effect of delta-9-THC in patients re-ceiving cancer chemotherapy. New Engl JMed. 1975; 293:795-797.

10. Gorter R, Seefried M and VolberdingP. Dronabinol effects on weight in patientswith HIV infection. AIDS. 1992; 6: 127.

11. Beal JE, Olson RLL, Morales JO, etal. Dronabinol as a treatment for anorexiaassociated with weight loss in patients withAIDS. J Pain and Symptom Manag. 1995;10:89-97.

12. Timpone JG, Wright DJ, Li N, EgorinMJ, Enama ME, Mayers J, Galleto G. Thesafety and pharmacokinetics of single-agentand combination therapy with megestrol ac-etate and dronabinol for the treatment of theHIV wasting syndrome. The DATRI 004Study Group. AIDS Res Hum Retroviruses1997;13:305-315.

13. Adams IB and Martin BR. Cannabis:pharmacology and toxicology in animals andhumans. Addiction 1996; 91:1585-1614

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22. Watanabe K, Matsunaga T, YamamotoI, Funae Y, Yoshimura H. Involvement ofCYP2C in the metabolism of cannabinoidsby human hepatic microsomes from an oldwoman. Biol Pharm Bull. 1995; 18: 1138-1141.

23. Engels FK, de Jong FA, SparreboomA, Mathot RA, Loos WJ, Kitzen JJ, de BruijnP, Verweij J, Mathijssen RH. Medicinal can-nabis does not influence the clinical pharma-cokinetics of irinotecan and docetaxel. On-cologist. 2007 Mar;12(3):291-300.

24. Sutton IR, Daeninck P. Cannabinoidsin the management of intractable chemo-therapy-induced nausea and vomiting andcancer-related pain. J Support Oncol 2006;4:531-535.

25. Tramer MR et al. Cannabinoids forcontrol of chemotherapy-induced nausea andvomiting: quantitative systematic review.BMJ 2001; 323: 16-21.

26. Cannabinoids in medicine: a reviewof their therapeutic potential. Ben Amar M.Journal of Ethnopharmacology 2006; 105:1-25.

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28. Walsh D, Nelson KA, Mahmoud FA.Established and potential therapeutic appli-cations of cannabinoids in oncology. SupportCare Cancer. 2003; 11:137-143.

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30. Poli-Bigelli S, Rodrigues-Pereira J,Carides AD, Julie Ma G, Eldridge K et al.Addition of the neurokinin-1 receptor antago-nist aprepitant to standard antiemetic therapyimproves control of chemotherapy-inducednausea and vomiting. Results from a random-ized, double-blind, placebo-controlled trial

in Latin America. Cancer. 2003; 97: 3090-3098.

31: Abrams DI, Hilton JF, Leiser RJ,Shade SB, Elbeik TA, Aweeka FT, BenowitzNL, Bredt BM, Kosel B, Aberg JA, DeeksSG, Mitchell TF, Mulligan K, McCune JM,Schambelan M. Short-term safety of cannab-inoids in HIV infection: Results of a random-ized, controlled clinical trial. Annals InternMed, 139:258-266, 2003.

32. Mulligan K, Abrams DI, Leiser RJ,Schambelan M. Body composition changesin HIV-infected men consuming self-selecteddiets during a placebo-controlled inpatientstudy of cannabinoids. Proceedings 8th Con-ference on Retroviruses and Opportunistic In-fections, Chicago. 2001; Abstract 647, p 238.

33. Mechoulam R, Berry EM, AvrahamY, DiMarzo V, Fride E. Endocannabinoids,feeding and suckling - from our perspective.Int J Obes (Lond). 2006; Suppl 1:S24-S28.

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35. Walker JM, Hohmann AG, Martin WJ,Strangman NM, Huang SM, Tsou K. Theneurobiology of cannabinoid analgesia. LifeSci. 1999; 65:665-673.

36. Meng ID, Manning BH, Martin WJ,Fields HJ. An analgesic circuit activated bycannabinoids. Nature. 1998; 395: 381-383.

37. Walker JM, Huang SM, StrangmanNM, Tsou K and Sanudo-Pena MC. Painmodulation by release of the endogenouscannabinoid anandamide. Proc Natl Acad SciUSA 96:pp, 1999.

38.Calignano A, LaRana G, Giuffrida Aand Piomelli D. Control of pain initiation byendogenous cannabinoids. Nature 394:277-281, 1998.

39. Fields HL and Meng ID. Watching thepot boil. Nature Medicine 4:1008-9, 1998.

40. Facci L, Dal Toso R, Romanello S etal. Mast cells express a peripheral cannab-inoid receptor with differential sensitivity toanandamide and palmitoylethanolamide.Proc Natl Acad Sci USA 92:3376-3380,1995.

41. Ibrahim MM, Porreca F, Lai J,Albrecht PJ, Rice FL, Khodorova A et al.CB2 cannabinoid receptor activation pro-duces antinociception by stimulating periph-eral release of endogenous opioids. Proc NatlAcad Sci .2005; 102:3093-3098.

42. Richardson J, Kilo S, Hargreaves K.Cannabinoids reduce hyperalgesia and in-flammation via interaction with peripheralCB1 receptors. Pain. 1998; 75:111-119.

43. Noyes R, Brunk S, Baram D, CanterA. Analgesic Effect of delta-9-tetrahydrocan-nabinol. Journal of Clinical Pharmacology

1975;15: 139-143.44. Noyes R, Brunk S, Avery D, Canter

A. The analgesic properties of delta-9-tertrahydrocannabinol and codeine. ClinicalPharmacology and Therapeutics 1975;18: 84-89.

45. Noyes R, Baram D. 1974. Cannabisanalgesia. Compr. Psychiatry. 15: 531.

46. Staquet M, Gantt C, Machin D. 1978.Effect of a nitrogen analog of tetrahydrocan-nabinol on cancer pain. Clinical Pharmacol-ogy and Therapeutics 23: 397-401.

47. Herzberg U, Eliav E, Bennett GJ,Kopin IJ. The analgesic effect of R(+)-WIN55,212-2 mesylate, a high affinity cannab-inoid agonist, in a rat model of neuropathicpain. Neuroscience Letters. 1997; 221: 157-160.

48. Abrams DI, Jay C, Shade S, VizosoH, Reda H, Press S, Kelly ME, RowbothamM, Petersen K. Cannabis in painful HIV-as-sociated sensory neuropathy: a randomized,placebo-controlled trial. Neurology 68:515-521, 2007.

49. Svendsen KB, Jensen TS, Back FW.Does the cannabinoid dronabinol reduce cen-tral pain in multiple sclerosis? Randomiseddouble blind placebo controlled crossovertrial. BMJ. 2004;329:253-260.

50. Rog DJ, Nurmikko TJ, Fride T, YoungCA. Randomized, controlled trial of can-nabis-based medicine in central pain in mul-tiple sclerosis. Neurology. 2005;65:812-819.

51. Cichewicz DL. Synergistic interac-tions between cannabinoid and opioid anal-gesics. Life Sci. 2004;74(11):1317-24.

52. Smith FL, Cichewicz D, Martin ZL,Welch SP. The enhancement of morphineantinociception in mice by delta9-tetrahydro-cannabinol. Pharmacol Biochem Behav.1998;60(2):559-66.

53. Cichewicz DL, Martin ZL, Smith FL,Welch SP. Enhancement mu opioidantinociception by oral delta9-tetrahydrocan-nabinol: dose-response analysis and recep-tor identification. J Pharmacol Exp Ther.1999;289(2):859-67.

54. Cichewicz DL, McCarthy EA.Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oraladministration. J Pharmacol Exp Ther.2003;304(3):1010-5.

55. Manzanares J, Corchero J, Romero J,Fernandez-Ruiz JJ, Ramos JA, Fuentes JA.Pharmacological and biochemical interac-tions between opioids and cannabinoids.Trends Pharmacol Sci. 1999;20(7):287-94.

56. Pugh G, Jr., Smith PB, DombrowskiDS, Welch SP. The role of endogenous opio-ids in enhancing the antinociception pro-duced by the combination of delta 9-tetrahy-drocannabinol and morphine in the spinal

On a more positive note, in a unani-mous vote, the Assembly of the Ameri-can Psychiatric Association recently ap-proved a strongly worded statement sup-porting legal protection for patients us-ing medical marijuana with their doctor’srecommendation.95 The APA action pa-per reiterates that “the threat of arrest byfederal agents, however, still exists. Se-riously ill patients living in these stateswith medical marijuana recommenda-tions from their doctors should not besubjected to the threat of punitive fed-eral prosecution for merely attemptingto alleviate the chronic pain, side effects,or symptoms associated with their con-ditions or resulting from their overalltreatment regimens. ... [We] support pro-tection for patients and physicians par-ticipating in state-approved medicalmarijuana programs.”

It behooves the integrative oncologistto follow closely future studies of can-nabinoids and cancer. It is likely thatthese agents will not only prove to beuseful in symptom management and pal-liative care, but as anti-tumor agents aswell.

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58. Welch SP, Eads M. Synergistic inter-actions of endogenous opioids and cannab-inoid systems. Brain Res. 1999;848(1-2):183-90.

59. Pugh G, Welch SP, Bass PP. Modula-tion of free intracellular calcium and cAMPby morphine and cannabinoids, alone and incombination in mouse brain and spinal cordsynaptpsomes. Pharmacol Biochem Behav.1994; 49:1093-1100.

60. Welch SP, Thomas C, Patrick GS.Modulation of cannabinoid-inducedantinociception after intracerebroventricularversus intrathecal administration to mice:possible mechanisms for interaction withmorphine. J Pharmacol Exp Ther. 1995;272:310-321.

61. Russo EB, Guy GW, Robson PJ. Can-nabis, pain, and sleep: lessons from thera-peutic clinical trials of Sativex(r), a cannabis-based medicine. Chemistry & Biodiversity2007; 4:1729-1743.

62. Guzman M. Cannabinoids: potentialanticancer agents. Nature Reviews/Cancer2003; 3:745-755.

63. Young FL. In the matter of marijuanamedical rescheduling petition. Excerpt fromUS Federal Court Decision, 1988. http://www.fcda.org/pdf/young88.fcda.pdf

64. U.S. Department of Health and Hu-man Services NTP Technical Report on theToxicology and Carcinogenesis Studies of 1-Trans-Delta9-Tetrahydrocannabinol in F344/N Rats and B6C3F1 Mice (Gavage Studies).TR-446, November 1996. http://ntp.niehs.nih.gov/ntp/htdocs/LT_rpts/tr446.pdf

65. Sidney S, Quesenberry CP, FriedmanGD, Tekewa IS. Marijuana use and cancerincidence (California, USA). Cancer Causesand Control. 1997; 8:722-728.

66. Mehra R, Moore BA, Crothers K,

Tetrault J, Fiellin DA. The association be-tween marijuana smoking and lung cancer:a systematic review. Arch Intern Med 2006;166:1359-1367.

67. Hashibe M, Morgenstern H, Cui Y,Tashkin DP, Zhang Z-F, Cozen W et al. Mari-juana use and the risk of lung and upperaerodigestive tract cancers: results of a popu-lation-based case-control study. EpidemiolBiomarkers Prev 2006; 15:1829-1834.

68. Bifulco M, DiMarzo V. Targeting theendocannabinoid system in cancer therapy:a call for further research. Nature Medicine2002; 8:547-550.

69. Bifulco M, Laezza C, Pisanti S,Gazzerro P. Cannabinoids and cancer: prosand cons of an antitumour strategy. BritishJournal of Pharmacology 2006; 148:123-135.

70. De Petrocellis L, Melck D, PalmisanoA, Bisogno T, Laezza C, Bifulco M, DiMarzo V. The endogenous cannabinoidanandamide inhibits human breast cancer cellproliferation. Proc Natl Acad Sci 1998;95:8375-8380.

71. Sanchez C, de Ceballos ML, Gomezdel Pulgar T, Rueda D, Corbacho C, VelascoG et al. Inhibition of glioma growth in vivoby selective activation of the CB2 cannab-inoid receptor. Cancer Research 2001;61:5784-5789.

72. McKallip RJ, Lombard C, Fisher M,Martin BR, Ryu Seongho, Grant S et al. Tar-geting CB2 cannabinoid receptors as a noveltherapy to treat malignant lymphoblastic dis-ease. Blood 2002; 100:627-634.

73. Llanos Casanova M, Blazquez C,Martinez-Palacio J, Villanueva C, Fernandez-Acenero MJ, Huffman JW et al. Inhibitionof skin tumor growth and angiogenesis invivo by activation of cannabinoid recptors. JClin Invest 2003; 111:43-50.

74. Velasco G, Galve-Roperh I, SanchezC, Blazquez C, Guzman M. Hypothesis: can-nabinoid therapy for the treatment of glio-mas? Neuropharmacology 2004; 47:315-323.

75. Blazquez C, Gonzalez-Feria L,Alvarez L, Haro A, Llanos Casanova M,Guzman M. Cannabinoids inhibit the vascu-lar endothelial growth factor pathway in glio-

mas. Cancer Research 2004; 64:5617-5623.76. Patsos HA, Hicks DJ, Greenhough A,

Williams AC, Paraskeva C. Cannabinoidsand cancer: potential for colorectal cancertherapy. Biochemical Society Transactions2005; 33:712-714.

77. Vaccani A, Massi P, Colombo A,Rubino T, Parolaro D. Cannabidiol inhibitshuman glioma cell migration through a can-nabinoid receptor-independent mechanism.British Journal of Pharmacology 2005;144:1032-1036.

78. Sarfaraz S, Afaq F, Adhami VM,Mukhtar H. Cannabinoid receptor as a noveltarget for the treatment of prostate cancer.Cancer Res 2005; 65:1635-1641.

79. McAllister SD, Chan C, Taft RJ, LuuT, Abood ME, Moore DH. Cannabinoids se-lectively inhibit proliferation and inducedeath of cultured glioblastoma multiformecells. Journal of Neuro-Oncology 2005;74:31-40.

80. Sarfaraz S, Afaq F, Adhami VM,Mukhtar H. Cannabinoid receptor as a noveltarget for the treatment of prostate cancer.Cancer Res 2005; 65:1635-1641.

81. Ligresti A, Moriello AS, Starowicz K,Matias I, Pisanti S, De Petrocellis L et al.Anti-tumor activity of plant cannabinoidswith emphasis on the effect of cannabidiolon human breast carcinoma. J Pharmacol ExpTher 2006; 318:1375-1387.

82. Blazquez C, Llanos Casanova M,Planas A, Gomez del Pulgar T, VillanuevaC, Fernandez-Acenero MJ, Aragones J,Huffman JW, Jorcano JL, Guzman M. Inhi-bition of tumor angiogenesis by cannab-inoids. FASEB J. 2003; 17:529-531.

83. Vaccani A, Massi P, Colombo A,Rubino T, Parolaro D. Cannabidiol inhibitshuman glioma cell migration through a can-nabinoid receptor-independent mechanism.British Journal of Pharmacology 2005;144:1032-1036.

84. Preet A, Ganju RK, Groopman JE.Delta-9-tetrahydrocannabinol inhibits epithe-lial growth-factor-induced lung cancer cellmigration in vitro as well as its growth andmetastasis in vivo. Oncogene 2007; 1-8.

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continued on next page

By Fred GardnerOne in three Americans will be af-

flicted with cancer, we are told by thegovernment (as if it’s our immutable fateand somehow acceptable). Cancer is thesecond-leading cause of death in the U.S.and lung cancer the leading killer amongcancers.

You’d think it would have been verybig news in June 2005 when UCLAmedical school professor DonaldTashkin reported that components ofmarijuana smoke –although they dam-age cells in respiratory tissue– somehowprevent them from becoming malignant.In other words, something in marijuanaexerts an anti-cancer effect!

Tashkin has special credibility. Hewas the lead investigator on studies dat-ing back to the 1970s that identified thecomponents in marijuana smoke that aretoxic. It was Tashkin et al who publishedphotomicrographs showing that mari-juana smoke damages cells lining theupper airways. It was the Tashkin lab’sfinding that benzpyrene – a componentof tobacco smoke that plays a role inmost lung cancers– is especially preva-lent in marijuana smoke. It was Tashkin’sdata showing that marijuana smokers aremore likely than non-smokers to cough,wheeze, and produce sputum.

Tashkin reviewed his findings in April2008, at a conference organized by “Pa-tients Out of Time,” a reform group de-voted to educating doctors and the pub-lic (as opposed to lobbying politicians).Some 30 MDs and nurses got continu-ing medical education credits for attend-

Tashkin Reiterates to Patients Out of Time:

Smoking Cannabis Does Not Cause Lung Cancering the event, which was held atAsilomar, on the Monterey Peninsula.

The National Institute on Drug Abuse,which supported Tashkin’s marijuana-re-lated research over the decades, readilygave him a grant in 2002 to conduct alarge, population-based, case-controlledstudy that would prove definitively thatheavy, long-term marijuana use in-creases the risk of lung and upper-air-ways cancers.

What Tashkin and his colleaguesfound, however, disproved their hypoth-esis. (Tashkin is to marijuana as a causeof lung cancer what Hans Blix was toIraq’s weapons of mass destruction –anhonest investigator who set out to findsomething, concluded that it wasn’tthere, and reported his results.)

Tashkin’s team interviewed 1,212cancer patients from the Los AngelesCounty Cancer Surveillance program,matched for age, gender, and neighbor-hood with 1,040 cancer-free controls.Marijuana use was measured in “jointyears” (number of years smoked timesnumber of joints per day).

It turned out that increased marijuanause did not result in higher rates of lungand pharyngeal cancer, whereas tobaccosmokers were at greater risk the morethey smoked. Tobacco smokers who alsosmoked marijuana were at slightly lowerrisk of getting lung cancer than tobacco-only smokers.

These findings were not deemed wor-thy of publication in “NIDA Notes.”Tashkin reported them at the 2005 meet-ing of the International Cannabinoid

Research Society. They were publishedin the October 2006 issue of “CancerEpidemiology Biomarkers & Preven-tion.”

Without a press release from NIDAcalling attention to its significance, theassignment editors of America had noidea that “Marijuana Use and the Riskof Lung and Upper Aerodigestive TractCancers: Results of a Population-BasedCase-Control Study” by Mia Hashibe1,Hal Morgenstern, Yan Cui, Donald P.Tashkin, Zuo-Feng Zhang, Wendy

Cozen, Thomas M. Mack and SanderGreenland was a blockbuster story.

I suggested to Eric Bailey of the L.A.Times that he write up Tashkin’s find-ings –UCLA provided the local angle ifthe anti-cancer effect wasn’t enough.Bailey said his editors wouldn’t be in-terested for some time because he hadjust filed a marijuana-related piece. TheTashkin scoop is still there for the tak-ing!

Tashkin Defends His FindingsInvestigators from New Zealand re-

cently got widespread media attentionfor a study contradicting Tashkin’s re-sults. “Heavy cannabis users may be atgreater risk of chronic lung disease –in-cluding cancer– compared to tobaccosmokers,” is how BBC News summedup the New Zealanders’ findings.

The very small size of the study –79smokers took part, 21 of whom smokedcannabis only– was not held against theauthors. In fact, the small New Zealandstudy was given much more coverage bythe corporate press than the large UCLAstudy that preceded it.

The New Zealand study was por-trayed as the latest word on this impor-tant subject. As if scientific inquiry weresome kind of tennis match and the truthjust gets truthier with every volley.

Tashkin criticized the NewZealanders’ methodology in his talk atAsilomar: “There’s some cognitive dis-sonance associated with the interpreta-tion of their findings. I think this has todo with the belief model among the in-vestigators and –I wish they were here

TASHKIN AT ASILOMAR showedphotomicrographs of cells damaged bycannabis smoke. Having identified knowncarcinogens in the smoke, he was surprisedwhen study results showed that cannabissmoking doesn’t lead to lung cancer.

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to defend themselves– the integrity ofthe investigators... They actually pub-lished another paper in which they mim-icked the design that we used for look-ing at lung function.”

Tashkin spoke from the stage of anairy redwood chapel designed by JuliaMorgan. He is pink-cheeked, 70ish,wears wire-rimmed spectacles. “For to-bacco they found what you’d expect: ahigher risk for lung cancer and a cleardose-response relationship. A 24-foldincrease in the people who smoked themost... What about marijuana? If theysmoked a small or moderate amountthere was no increased risk, in factslightly less than one. But if they werein the upper third of the group, then theirrisk was six-fold... A rather surprisingfinding, and one has to be cautious aboutinterpreting the results because of thevery small number of cases —fourteen—and controls —four.”

Tashkin said the New Zealandersemployed “statistical sleight of hand.”

He deemed it “completely implausiblethat smokers of only 365 joints of mari-juana have a risk for developing lungcancer similar to that of smokers of 7,000tobacco cigarettes... Their small samplesize led to vastly inflated estimates...They had said ‘it’s ideal to do the studyin New Zealand because we have a muchhigher prevalence of marijuana smok-ing.’ But 88 percent of their controls hadnever smoked marijuana, whereas 36%of our controls (in Los Angeles) hadnever smoked marijuana. Why did sofew of the controls smoke marijuana?Something fishy about that!”

Strong words for a UCLA School ofMedicine professor!

As to the highly promising implica-tion of his own study –that something inmarijuana stops damaged cells from be-coming malignant— Tashkin noted thatan anti-proliferative effect of THC hasbeen observed in cell-culture systemsand animal models of brain, breast, pros-tate, and lung cancer. THC has been

shown to promote apoptosis (damagedcells die instead of reproducing) and tocounter angiogenesis (the process bywhich blood vessels are formed —a re-quirement of tumor growth). Other anti-oxidants in cannabis may also be in-volved in countering malignancy, saidTashkin.

COPDMuch of Tashkin’s talk was devoted

to Chronic Obstructive Pulmonary Dis-ease, another condition prevalent amongtobacco smokers. Chronic bronchitis andemphysema are two forms of COPD,which is the fourth-leading cause ofdeath in the United States. Air pollutionand tobacco smoke are known culprits.Inhaled pathogens cause an inflamma-tory response, resulting in diminishedlung function. COPD patients have in-creasing difficulty clearing the airwaysas they get older.

Tashkin and colleagues at UCLA con-ducted a major study in which they mea-

from previous pageTashkin

sured lung function of various cohortsover eight years and found that tobacco-only smokers had an accelerated rate ofdecline, but marijuana smokers –even ifthey smoked tobacco as well– experi-enced the same rate of decline as non-smokers.

“The more tobacco smoked, thegreater the rate of decline,” said Tashkin.“In contrast, no matter how much mari-juana was smoked, the rate of declinewas similar to normal.”

Tashkin concluded that his and otherstudies “do not support the concept thatregular smoking of marijuana leads toCOPD.”

Breathe easier, everybody.

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.

A Sociologist Walks Into a Cannabis Club...At the 2008 Patients Out of Time Con-

ference sociologist Amanda Reiman de-scribed a forthcoming study of the Ber-keley Patients Group. The BPG, foundedin 1999, is one of the few dispensariesthat allow medicating on-site —an ap-proach Reiman calls “the social model.”Reiman gave a written survey to 350 pa-tients as they arrived at BPG, interviewedfive members who received hospice de-livery services, and conducted a focusgroup with six participants. Excerpts ofthe study follow.

Every patient surveyed agreed thatthere are benefits from BPG services be-yond the medication. All patients men-tioned the social support that they gotfrom visiting with other patients and re-ceiving visitors through the hospice pro-gram. Patients also mentioned the ben-efits of having a community room wherethey could relax and medicate in a safeenvironment and speak with other pa-tients.

Most patients stressed theimportance of regular socialcontact as being extremely ben-eficial to their health.

Also mentioned were BPG programssuch as acupressure and the differentclasses and speakers available to patients.Most patients stressed the importance ofregular social contact as being extremelybeneficial to their health.

One patient described the benefits of

having consistency in a life that was oth-erwise unpredictable; knowing that a visi-tor would come every Wednesday pro-vided this patient with comfort.

One patient mentioned that in additionto medical help gained from the cannabis,the weekly hospice visits served as peercounseling and allowed her time to ventabout her illness and the stresses of be-ing ill.

Patients who are also part of the low-income “Helping Hands” program men-tioned the huge financial burden that hasbeen lifted for them by having access tohigh-grade medicine.

Other patients mentioned the help thatthey got from medical cannabis to dealwith pain, eating and sleep issues.

One patient mentioned that, due toperiods of wasting, they would not behere if it were not for their medicine andBPG.

All patients mentioned the social sup-port that they get from other patients andthe staff at the dispensary. One patientspoke about how services help her man-age the stress of the struggle to stayhealthy. She talked about the safe spacecreated at BPG where patients can openup and be vulnerable, which might behard for some who must maintain a toughexterior to get through their day. She alsomentioned that coming to BPG helps getpatients out of the house and helps tocounteract the isolation that can comealong with experiencing a chronic or ter-minal illness.

Another patient mentioned that hear-ing about other patients’ problems helpshim feel like he is not alone and that oth-ers are going through the same thing,which can be of great comfort.

One patient mentioned that BPG usedto have a daily organic fruit and vegetabledelivery service that had to cease opera-tions due to financial reasons. Other pa-tients mentioned that BPG has helped

them pay utility bills, and two patientswere extremely excited to relate their sto-ries of how BPG gave them Christmastrees when they could not afford them andhow much that gesture meant to them.

Patients speak about the staff at BPGas if they are family and express suchgratitude for the personal interest that thestaff has taken in them, adding to theirfeelings of importance and self-worth.

Participants reported that they do notpurchase cannabis every time they visitBPG and stated that there are many timesthey visit just to receive services or so-cialize with other patients.

Participants reported using a range ofservices at BPG including acupuncture,massage, renter’s assistance classes, andrecreation activities such as open mic.

Access to free services allows patientsto try out an alternative therapy to see ifthey get relief from it before seeking itout as part of their permanent health careregime. Many participants stated that theservices at BPG act as a bridge betweenthe times that they can receive health ser-vices elsewhere, either due to the cost ofthe service or the cost of transportation.

Patients report that losing BPG ser-vices would disrupt their entire healthcare treatment plan. For example, onepatient receives acupuncture both at BPGand at a clinic where she receives a moreintensive and longer treatment. She re-ported that she cannot afford these inten-sive treatments regularly, so she uses theBPG treatments to supplement the morecostly ones, as to not interrupt her treat-ment schedule.

Another participant reported that shelives near BPG and cannot afford thetransportation to get to her more inten-sive treatments on a regular basis, soagain, BPG is used to supplement thesetreatments.

Participants also reported getting peersupport from other patients at BPG and

forming relationships with other patientsfor friendship and support. Participantsmentioned that exposure to other patientswith a range of ailments and circum-stances are therapeutic.

Participants who received medicinethrough Helping Hands reported that theylearned of the program through word ofmouth and they felt that the criteria shouldbe clearer. Participants reported that mostof their other medicines were coveredthrough Medi-Cal or Medicaid.

SuggestionsParticipants had several suggestions

for how BPG could be more service-ori-ented and patient-focused:

1. There should be a designated pa-tient liaison that patients know they cango to with complaints, questions, sugges-tions. Participants felt that they did notknow who to approach about problemsor suggestions. Perhaps a board could beformed of staff and patients to discussactivities, services and issues related toBPG operations.

2. More arts and crafts.3. Post the calendar where people can

see it while they wait in line.4. A way to inform folks when time is

almost up. Participants felt that some-times they were rushed out and that some-times a patient’s appearance affected howthey were treated when their time was up.

5. Not enough chairs in the commu-nity room.

6. There should be a designatedcounter person for those with lots of ques-tions to speed up the line for those whoalready know what they want.

Amanda Reiman, MSW PhD, is anacademic coordinator/lecturer at the UCBerkeley School of Social Welfare.

“no matter how much mari-juana was smoked, the rate ofdecline was similar to nor-mal.” —Tashkin re COPD


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