• 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The cannabis trial never accruedand the funding was withdrawn.Both dronabinol and nabilone areFDA-approved for the treatment of nau-sea and vomiting associated with can-cer chemotherapy in patients who havefailed to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.
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
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.
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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
compared to normal human glial cells
After 20 hours of treatment,death of nearly all of the GBM cells is evidenced by cells shrinking to inanimate whitespheres
The normal cells exposed to the same concentration of delta-9-THC continue to migrate and divide (lower right). Photo by McAllister and Yount.