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Cannabinoids and Cancer - Abrams and Guzman

Cannabinoids and Cancer - Abrams and Guzman

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Summer 2009 —7—
Cannabinoids and Cancer
Evidence from cell culture systems and animal models indicatesthat 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).
thanks the authors
d 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 of plants 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 of smoked 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.
Use of cannabis as medicine datesback at least 2000 years.
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 1931until 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.
The wasting syndrome, charac-terized by anorexia, weight loss of greater than 10 percent body weight, andfrequently, fever and diarrhea, createdhordes of cachectic individuals in searchof any potential therapeutic intervention.Many turned to smoking marijuana.
Fearful that there might be a run onthe Compassionate Use program, theSynthetic 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.
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.
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.
Cannabinoids are a group of 21 car-bon terpenophenolic compounds pro-duced uniquely by Cannabis sativa andCannabis indica species.
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 toachieving its current status as an illicit substance.• Cannabinoids, the active components of Cannabis sativa, mimic theeffects 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 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 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 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 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 of anorexia 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
Summer 2009
has only been identified within the past20 years during which time an explosionof knowledge has occurred.
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 of cyclic 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.
)In addition to being utilized to learnmore about the natural function of theendocannabinoid system, a number of these 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 of biologic effects. The Institute of Medi-cine report makes the following generalconclusions about the biology of can-nabis and cannabinoids:
• 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 Cannabis
When taken by mouth, there is a low(6-20%) and variable oral bioavailabil-
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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 of voltage-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.
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.
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.
The care-fully conducted pharmacokinetic analy-ses showed that cannabis administrationdid not significantly influence exposureto and clearance of irinotecan ordocetaxel.
The nausea and vomiting related tocancer 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.
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 inCanada 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.
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 of nausea 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.
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.
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.
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.
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.
Unfortunately the trial was launchedconcurrently with the first release of aprepitant (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.
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 of 4 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 stimulation
Anorexia, early satiety, weight lossand cachexia are some of the most daunt-ing symptom management challengesfaced 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.
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.
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.
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.
This first of a new class of agents hasnot 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.
Our understanding of the possiblemechanisms 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.
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.
Where the CB1 agonists exert anal-gesic activity in the CNS, both CB1 andCB2 agonists have peripheral analgesicactions.
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 enhancethe release of analgesic opioids.
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 of cannabinoids’ ability to reduce naturallyoccurring pain, but few human studieshave been performed. Early studies of cannabinoids 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 of pain 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.
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.
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 of 36 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.
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.
A study by Staquet and colleagues onthe effects of a THC nitrogen analogueon cancer pain yielded similar results.
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.
continued on next page from previous page
Cannabinoids and Cancer
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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