Accumulating evidence from single studies and meta-analyses of multiple studies indicates that smoked marijuana is associated with, or a causative agent in specific cancers. Yet, a growing body of evidence, in very early stages, has introduced a potential role for cannabinoids (not smoked marijuana) in the treatment of various cancers. Can these two seemingly contradictory data sets be reconciled? Foremost, it is necessary to exclude marijuana, as there is no credible evidence that smoked marijuana is an anti-tumor agent – in fact data show the opposite.

Secondly, the promise of cannabinoids as anti-tumor agents are derived principally from preclinical research, using either cultured cells (cells growing in a petri dish) derived from human or rodent tumors or mouse tumor models. Both are insufficient to satisfy stringent criteria to approve use of cannabinoids in humans. Third, there are contradictory studies from cell cultures, showing that THC potentiates or inhibits tumor proliferation, as a function of tumor type and its pathology.

Finally, after all the prolific preclinical research, there is but one small Phase I trial of nine patients with brain cancer, treated with direct infusions of THC (2006). No follow-up, no replications. Surprisingly, this study was a highlight of a glowing report of cannabinoids as anti-tumor agents by Martin E. Lee of the Daily Beast (Sept 6, 2012).

I begin with the Guzman study (2006) and contrast it with the report from the Daily Beast. In viewing the association of smoked marijuana and cancer risk, it should be pointed out, that this is not the only or most important risk of marijuana to health and well-being.

Guzmán M, Duarte MJ, Blázquez C, Ravina J, Rosa MC, Galve-Roperh I, Sánchez C,Velasco G, González-Feria L. A pilot clinical study of Delta9-tetrahydrocannabinol in patients with recurrent glioblastoma multiforme. Br J Cancer. 2006 Jul 17;95(2):197-203.

Guzman study In this pilot Phase I safety study, nine male and female patients with aggressive glioblastomas has two surgeries and then were treated with 1 or more infusions into the tumor site with Delta(9)-Tetrahydrocannabinol (THC). The mean life span of the patients was 24 weeks after initiation of the THC, with the shortest life span 9 weeks and the longest 53 weeks. Apparently THC did not extend the life span of these patients, although a placebo control group was not used for comparison. In only 2 patients, THC decreased tumour-cell staining. The authors conclude that THC “is not the most appropriate cannabinoid agonist for future antitumoral strategies owing to its high hydrophobicity, relatively weak agonistic potency and ability to elicit CB1-mediated psychoactivity”. “Owing to the characteristics of this study the effect of THC on patient survival was unclear, and an evaluation of survival would require a larger trial with a different design”. “a few studies have shown that THC may induce proliferation of tumour cells in vitro and in vivo”. The most parsimonious conclusion of the study was that THC did not facilitate tumor growth (but there was no comparative group to confirm this assertion) and that THC did not decrease patient survival, at least in the cohort of brain tumor patients expressing cannabinoid receptors.

Daily Beast (Sept 6, 2012), Martin E. Lee: “A team of Spanish scientists led by Manuel Guzman conducted the first clinical trial assessing the antitumoral action of THC on human beings. Guzman administered pure THC via a catheter into the tumors of nine hospitalized patients with glioblastoma, who had failed to respond to standard brain-cancer therapies. The results were published in 2006 in the British Journal of Pharmacology: (Actually, British Journal of Cancer). THC treatment was associated with significantly reduced tumor cell proliferation in every test subject.” (Actually, all patients died, average duration 24 weeks, and only two showed any signs of improvement – 1 with one episode of the treatment, the other with six episodes of treatment).

Conclusions

Intervention with THC in 9 patients harboring this aggressive brain tumor was a failure.

The Daily Beast misrepresented the findings of the study.

Guzman et al, stated they would follow up with “our next goal is to evaluate the efficacy of THC in patients with newly diagnosed gliobastoma multiforme”, but 6 years later there is no follow up.

No other investigator has rushed in to confirm, to extend the number of patients, to convert this trial in a placebo-controlled trial.

Is smoked marijuana associated with increased risk of cancer?

1. Lacson JC, Carroll JD, Tuazon E, Castelao EJ, Bernstein L, Cortessis VK Population-based case-control study of recreational drug use and testis cancer risk confirms an association between marijuana use and nonseminoma risk. Cancer. 2012 Sep 10. doi: 10.1002/cncr.27554. [Epub ahead of print] Testicular germ cell tumor (TGCT) incidence increased steadily in recent decades, but causes remain elusive. Germ cell function may be influenced by cannabinoids, and 2 prior epidemiologic studies reported that the use of marijuana may be associated with nonseminomatous TGCT.

Methods: 163 patients who were diagnosed with TGCT in Los Angeles County from December 1986 to April 1991 were enrolled, and 292 controls were matched on age, race/ethnicity, and neighborhood.

Results: Compared with never use, ever use of marijuana had a 2-fold increased risk, whereas ever use of cocaine had a negative association with TGCT. A specific association of marijuana use with nonseminoma and mixed histology tumors increased risk 2.42 fold or 240%).

Conclusions: The current results warrant mechanistic studies of marijuana’s effect on the endocannabinoid system and TGCT risk and caution that recreational and therapeutic use of cannabinoids by young men may confer malignant potential to testicular germ cells. Cancer 2012. © 2012 American Cancer Society.

2. Daniel W. Bowles, Cindy L. O’Bryant, D. Ross Camidge, Antonio Jimeno. The intersection between cannabis and cancer in the United States. Critical Reviews in Oncology/Hematology, Vol 83, Issue 1, July 2012, Pages 1–10

One of the principle concerns of the use of cannabinoids, particularly inhaled marijuana, is carcinogenic potential. Cannabis smoke is carcinogenic in rodents and mutagenic in the Ames test (a cancer test routinely performed for candidate medications in rodents, before drug testing in humans). Cannabis smoke contains several of the same carcinogens as tobacco smoke, at up to 50% higher concentrations and with three times the tar per cigarette. Respiratory mucosa exposed to chronic cannabis smoke shows pre-neoplastic histological and molecular changes. Despite this in vitro and in vivo evidence, however, it has been difficult to strongly correlate cannabis use and the development of human cancers.

Head and neck squamous cell carcinoma (HNSCC) risk and cannabis are inconsistent. Three studies have found a statistically significant increased risk of HNSCC in cannabis users – 2.6-fold increased risk of HNSCC compared with blood-bank controls when adjusted for cannabis dose, duration of use, and confounding variables such as alcohol or tobacco use. Similarly, heavy cannabis smokers in Northern Africa had a 2.62 increased risk for nasopharyngeal carcinomas. A recent study found that human papilloma virus HNSCC was associated with increased cannabis smoking intensity, and cumulative joint-years, due to cannabis-induced immune suppression through CB2? Seven studies, 4 small, others larger found no association. At this point the majority of studies do not support the hypothesis that smoked cannabis is strongly associated with an increased risk of HNSCC, once tobacco and alcohol intake are controlled, though smoked cannabis may raise the risk of HPV-16-associated HNSCC.

Lung cancer A systematic review evaluating 19 studies from 1966 to 2006 found no significant tobacco-adjusted association between cannabis smoking and lung cancer development despite evidence of precancerous histopathologic changes of the respiratory mucosa. However, a pooled analysis of three studies of male cannabis smokers in North Africa found that the risk for developing lung cancer was increased 2.4 times, for ever cannabis smokers. A case control study of patients with lung cancer under 55 years of age in New Zealand found an 8% increased risk for each joint-year (one joint/day/year) of cannabis use. This effect persisted only in the highest tertile of cannabis use (>10.5 joint-years of exposure) when adjusted for tobacco use (risk 5.7 fold).

A study of 65,855 members of a U.S. health management organization (HMO) that classified member as experimenters (six or fewer lifetime usages), former users, or current users found no increased risk of HNSCC, lung, colorectal, melanoma, or breast cancers in current or former cannabis smokers versus never smokers or experimenters when controlled for tobacco use, alcohol intake, and socioeconomic status.

Prostate and cervical cancer There was a trend towards increased prostate cancer (3-fold risk), and cervical cancer (1.4 fold risk).

Glioma A U.S. study of 105,005 HMO members found an increased risk of malignant primary gliomas (2.8 fold or 280% increased risk), in people who smoked cannabis once per month or more.

Bladder cancer and testicular germ cell cancer Smaller studies have implicated cannabis use in the development of bladder cancer and testicular germ cell tumors. The reasons for the great heterogeneity in epidemiologic studies correlating cannabis use and cancer may be related to difficulties in quantifying cannabis use, unmeasured confounders in the cases or controls, and variable expression of cannabinoid receptors in target tissues.

Conclusions

Smoked marijuana is associated with an elevated risk for certain cancers.

There is no future in smoked marijuana as an anti-tumor therapy.

How do cannabinoids act biologically, and can these mechanisms portend safe and effective anti-tumor agents?

Some background tips on understanding why CB1 and CB2 are so important

The brain and body have a cannabinoid signaling system. What does this mean? Cells communicate with each other by releasing chemical messages, with the brain the master communication system. Each signal has three main components: a chemical message, an interpreter (receptor) that receives the message and interprets it, and a transport system that “deletes” the message once sent and processed. The brain and body produce their own chemical messages (such as dopamine or serotonin). Drugs (such as THC or LSD or amphetamine or morphine) resemble these messages (imposters) and can bind to the receptor. When a message binds to the receptor, it undergoes a change in shape and triggers a cascade of changes in cells in the brain activity, or immune system, or blood vessels and other tissues. Incidentally, the signaling process involves more than a hundred other components that orchestrate this exquisite process.

The CB2 receptor, which does not produce psychoactive effects, is the critical mediator of anti-tumor activity. The body produces two types of cannabinoid targets or receptors, the CB1 and CB2 receptors (and quite a few others) that become active in the presence of cannabinoids (THC, cannabidiol, 2-AG, anandamide, etc). Whether the cannabinoids arise from the body itself (endocannabinoids), are made by plants (phyto-cannabinoids from marijuana) or made in a medicinal chemistry laboratory (synthetic cannabinoids), cannabinoids have different effects at these receptors. THC binds equally well to CB1 and CB2, while others do not. Interestingly, the majority of cannabinoids that display anti-tumor activity in cell culture act through the CB2 receptor. This is a critical discovery, because the CB2 receptor does not trigger psychoactive effects, memory cognitive, impairment, etc.

Some tips on assessing the research studies: There is some evidence from in cell culture (cells growing on a petri dish) and from whole body experiments, that cannabinoids promote cancer and evidence that they protect cells from cancer. A few critical questions should be asked when evaluating the validity of these reports:

Is the anti-tumor effect seen only if cells are exposed to concentrations of THC or other cannabinoids that that are unrealistically high compared to levels reached with ingested or inhaled marijuana? Why is thisa problem? In certain experiments in this field, the concentrations of THC or other cannabinoids are much higher than levels found in blood after smoking marijuana or cannabinoids. For example, a 6.8% THC marijuana cigarette generates a plasma blood level of 0.24 uM in humans (MW of THC is 314.45). Yet some researchers strongly advocating for the anti-tumor effect of THC used THC at 5 uM concentration in cell cultures to detect an anti-tumor effect. This concentration is 20 times higher than the tumor would be exposed to in a living human who smoked a high dose (6.8%) marijuana cigarette.

Is the anti-tumor effect observed in whole animals – not only in cultured cells? Many factors, including metabolism are among the “absent elephants” in petri dishes. The body can convert THC and the other 60+ cannabinoids in marijuana smoke to a myriad of metabolites which may work in the opposite direction of THC or other cannabinoids. You would not be able to observe this in cell culture.

Is the effect observed with a single cannabinoid, or with smoked marijuana that has more than 60 cannabinoids? No biomedical scientist would attempt to promote a treatment for cancer that contains >400 compounds, 60 of which are cannabinoids.

Is a selective CB2 cannabinoid as effective or exclusively effective compared with a CB1 cannabinoid? This is important because some evidence suggests the anti-tumor effects are mediated largely by the CB2 receptor – THE ONE THAT PRODUCES NO PSYCHOACTIVE EFFECTS. So theoretically, it is possible to design a CB2 agent without the psychoactive properties of THC.

The key question: Has the effect been observed only in mice, or also in men? Unless effectiveness is shown in Phase I, II, III randomized controlled multi-center clinical trials (in patients without a history of marijuana use) and approved by FDA, there is no meaningful evidence to support patient use of cannabinoids for this purpose.

Conclusions

It is critical to view the details of manuscripts that purport anti-tumor activity: cells, mice, or men? Appropriate concentrations, controls, outcomes?

It is necessary to exercise caution in promoting anti-cancer drugs, for they can influence patient choices.

Do cannabinoids, not smoked marijuana, have potential for treating cancer?

Daniel J. Hermanson & Lawrence J. Marnett. Cannabinoids, endocannabinoids and cancer Published online: Cancer Metastasis Rev (2011) 30:599–612. Velasco G, Sánchez C, Guzmán M. Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer. 2012 May 4;12(6):436-44.

Paraphrased below from manuscripts cited above

Breast cancer cells, expressing low levels of cannabinoid receptors, showed growth enhancement when exposed to cannabinoids, possibly due to altered immune response. Some studies suggest that abnormal regulation of the endocannabinoid system may promote cancer by fostering conditions that allow cancer cells to divide and migrate to other locations. For this reason, the endocannabinoid is a new target for pharmacological intervention in the treatment of cancer.

Cannabinoids and the endocannabinoid system are implicated in inhibiting cancer cell proliferation and angiogenesis (growth of blood supply for the cancer), reducing tumor growth and metastases, and inducing apoptosis (programmed cell death) in these cells. Laboratories have observed that cannabinoids and endocannabinoids inhibit growth of several types of cancers in test tubes and in animal tumor models (glioma, glioblastoma, breast cancer, prostate cancer, thyroid cancer, colon carcinoma, leukemia, and lymphoid tumors). These have been inhibited by natural (plant derived) or synthetic cannabinoids or endocannabinoids (made by the body), or cannabinoids that block natural processing of endocannabinoids.

Non-psychoactive cannabinoids – not smoked marijuana – that target the CB2 receptor have potential as anti-tumor agents. The CB2 receptor is non-psychoactive.

Modulation of the endocannabinoid system to treat cancer. Modulation of the body’s own cannabinoids has been shown in some studies to affect tumor cells while not affecting normal cells (many anti-cancer agents have more robust effects on tumor cells).

CB2 may be more important than CB1 in mediating cannabinoids’ anti-cancer activity. Recall that the CB2 has no psychoactive effects. High concentrations of anandamide or methanadamide, made by the body, killed prostate cancer cells, but tumor growth was inhibited exclusively through CB2.

CB2 may be more important than CB1 in mediating cannabinoids’ anti-cancer activity. JWH-133, by selective activity at CB2, produced programmed cell death in a brain tumor model (glioblastoma).

CB2 may be more important than CB1 in mediating cannabinoids’ anti-cancer activity. In a mouse model of human positive breast cancer, THC and JHW-133 decreased tumor size and lung metastasis via CB2.

The anti-cancer effects of cannabidiol may occur completely independently of cannabinoid receptor activation. Cannabidiol (non psychoactive) is effective in tumor models.

Cannabidiol together with temozolomide produces a striking reduction in the growth of glioma even when low doses of THC are used.

Cannabidiol has also been shown to alleviate some of the undesired effects of THC administration, such as convulsions, discoordination and psychotic events, and, therefore, improves the tolerability of cannabis-based medicines.

Some other cannabinoids in marijuana might attenuate the psychoactive side effects of THC or might even produce other therapeutic benefits.

Although there is accumulating data from test tube studies (cell culture), and some in living mice, there is scant, insufficient, inadequate clinical data on cannabinoid effects on cancer treatment in living humans. This is puzzling, as many cannabinoids have been tested in non-human model systems. In one clinical phase I study, the safety and efficacy of THC in patients with refractory glioblastoma was assessed. A total of nine patients underwent tumor surgery to remove the bulk tumor, then had a catheter perfuse THC into the cavity daily for 10–64 days for total doses ranging from 0.80 to 3.29 mg. One patient had mild psychotropic effects but it was otherwise well-tolerated. No significant conclusions can be extracted from nine patients, but some patients responded, at least partially, to THC treatment in terms of decreased tumor growth rate.

Further preclinical and clinical studies are required to fully define cannabinoids’ potential as anti-cancer agents.

Conclusions

Smoked marijuana is associated with increased risk for cancer, and not with potential as an anti-tumor agent.

Preclinical research demonstrates that some cannabinoids have anti-tumor activity.

The activity is mainly at the CB2 receptor, which has no psychoactive effects. Drugs selective for this receptor (and for other non- CB targets) may have a therapeutic role in tumor regression.

More preclinical research is needed, to define with precision, which class of cannabinoids will function and how genotypes may affect therapeutic benefit.

It is premature to surmise that cannabinoids will succeed as anti-tumor agents, until rigorous Phase III clinical trials in human subjects display therapeutic potential.

Does Marijuana have any role in cancer treatment?

Todaro B. Cannabinoids in the treatment of chemotherapy-induced nausea and vomiting. J Natl Compr Canc Netw. 2012 Apr;10(4):487-92.

Chemotherapy-induced nausea Before the introduction of the serotonin receptor antagonists (5-HT3 receptor antagonists) in the early 1990s, limited effective options were available to prevent and treat chemotherapy-induced nausea and vomiting (CINV). In 1985, the FDA approved 2 cannabinoid derivatives, dronabinol and nabilone, for the treatment of CINV not effectively treated by other agents. Today, the standard of care for prevention of CINV for highly and moderately emetogenic chemotherapy is a 5-HT3 receptor antagonist, dexamethasone, with or without aprepitant or fosaprepitant. With the approval of safer and more effective agents, cannabinoids are not recommended as first-line treatment for the prevention of CINV and are reserved for patients with breakthrough nausea and vomiting. Because of medical and legal concerns, the use of marijuana is not recommended for management of CINV and is not part of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Antiemesis. Although patients may like to pursue this treatment option in states that have approved the use of marijuana for medical purposes, its use remains legally and therapeutically controversial.

Pain suppression There are little data regarding inhaled cannabis or cannabis extract in comparison to conventional pain medications for cancer related or chronic non-neuropathic pain. A systematic review of single dose studies of dronabinol, nabilone, and levonandradol found them to be as effective as 50–120 mg of oral codeine. One study found nabilone to be less effective than modest doses of dihydrocodeine in patients with neuropathic pain and has less desirable side effects.No studies comparing inhaled or ingested cannabis to conventional analgesics could be identified. Therefore, it appears that inhaled cannabis and pharmaceutical cannabinoids are more effective than placebo in treating neuropathic pain, but their effectiveness compared to conventional pain medications is uncertain.

Appetite enhancement A recent double-blinded, randomized, 46 patient study suggested that cancer patients with altered chemosensory had increased pre-meal appetite and improved taste when given dronabinol (THC) compared to placebo. However, large randomized studies have been discouraging. In a randomized trial of patients with cancer-associated anorexia, low dose dronabinol as a single agent or in combination with high dose megestrol, a synthetic progestin, was less effective at generating weight gain and improving quality of life than megestrol alone. A subsequent randomized, double blinded trial from Europe for patients with cancer-associated anorexia found no difference in weight gain or quality of life at 6 weeks for patients treated with cannabis extract or THC compared to patients given placebo. Patients given cannabinoids had increased side effects. The data for cannabinoids in cancer-associated anorexia based on these three randomized studies are weak and the data for inhaled cannabis for cancer-associated cachexia are lacking.

Nausea and vomiting Since the CINV systematic review the use of 5-hydroxytryptamine 3 receptor and protachykinin antagonists have been major advances in the treatment of acute and chronic CINV. The current American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) guidelines do not recommend cannabinoids as first-line therapies.