Cachexia is a complex syndrome associated with certain underlying medical conditions such as HIV/AIDS, tuberculosis, chronic obstructive pulmonary disease, Crohn’s disease and cancer. Cachexia is characterized by abnormal loss of muscle mass, with or without fat loss. The loss of muscle mass is rapid in cancer cachexia patients,as compared to other disease states.
Cancer-related cachexia is led by loss of body mass including skeletal and cardiac muscles, inflammatory response, altered protein and energy balance, and changed body composition that leads to net weight loss. Cachexia is a common complication that occurs in the terminal stages of cancer, and is responsible for 22% of mortalities.
The role of increased systemic inflammation is mediated by pro-inflammatory cytokines leading to the pathogenesis of cancer. Some of the pro-inflammatory cytokines involved in the pathogenesis are TNF-α, IFN-gamma, IL-6 and PGE2. The latter directly acts in the higher centers and mediates appetite suppression. These molecular pathological events induce anorexia and muscle catabolism, resulting in the loss of lean muscle mass.
Some of the conventional treatments of cancer-associated cachexia are megestrol acetate and medroxyprogesterone, ghrelin, melanocortin antagonists, thalidomide and etanercept to improve weight mass and anabolism. Additionally, dietary supplements (including omega-3 fatty acids), corticosteroids, NSAIDs, beta-2 adrenergic agonists and physical therapy are also prescribed to treat cancer cachexia. However, the treatment outcomes are marginal, and the prognosis is usually poor.
Treating Cachexia in Cancer Patients with Cannabinoids
The central and psychoactive actions of Δ9-tetrahydrocannabinol (THC) are well known and are mediated by centrally-expressed CB1 receptors. These receptors are also present in the peripheral tissues and mediate various molecular signals. Similarly, CB2 receptors are also widely present all over the body, and are involved in the regulation of inflammatory processes.
The immunomodulatory role of CB2 receptors and its ligands is established. CB2 receptors act as pleiotropic modulator of TNF-alpha signal transduction, and regulate the circulatory levels of TNF-alpha in various inflammatory disease conditions. Activation of CB2 receptors has been shown to induce anti-inflammatory IL-10 release via activation of Erk1/2, thereby attenuating IL-6 and other pro-inflammatory interferons. These pro-inflammatory factors are reported to be involved in the pathogenesis of cachexia and inhibition of these cytokines by cannabinoids might have therapeutic benefits.
Conventionally, cachexia is being treated by intravenous feeding, hyper-caloric diet and appetizers including testosterone, growth hormones etc. The appetite-inducing effect of cannabis is well-known; the cannabinoids bind with its receptors responsible for food intake homeostasis and induce food intake. Among the naturally-occurring cannabinoids, THC acts centrally and modulates the neural networks associated with the food intake process and significantly induces appetite in cancer-related cachexia patients. The appetite inducing and body weight stabilizing effects of cannabinoids were also reported in AIDS-cachexia patients.
There is also evidence to suggest that cannabis can modestly improve the mood, physical activity levels and energy, by which lowers the risk of muscular atrophy, which may benefit cachexia patients.
Despite this molecular pharmacological evidence, the research community has not acknowledged/accepted the therapeutic benefits of cannabinoids for cancer-associated cachexia treatment. This may be due to the clinical trial results, that is equivocal, mixed and even conflicting.
In human clinical trials, the cannabis was reported to be well tolerated by cancer cachexia patients. The study found no benefits in terms of improved appetite or quality of life in various dosages tested. Similar results were observed in other studies. However, the study lacked a placebo comparator arm to ascertain the efficacy or inefficacy of THC and dronabinol. The observed increase in appetite (49% of patients) was unclear, whether if the effect was due to treatment or placebo effect. Additionally, no incidences of ‘feeling high’ or psychoactive effects were reported in the cannabinoid-treated patients, suggesting the employed dose might be ‘sub-optimal’ or lower than the normal dose for treatment of cachexia. Meaning, the reported ‘no effect’ in these clinical trials may be related to administration of inadequate dose and lack of drug exposure, but not due to absence of treatment effect.
Despite these limitations, the study concluded that megestrol acetate was found to be superior in treating cancer-related cachexia. Scientifically speaking, poorly-designed studies with evidential bias cannot draw any conclusions regarding the efficacy of cannabinoids for cachexia treatment. These types of ill-designed studies are intended to dampen the medical use of cannabis and/or their derivatives. Based on these ‘findings’ the regulatory authorities concluded that there were not enough convincing evidence to support the use of cannabinoids for the treatment of cancer-associated cachexia.
Another study that involved 469 cancer patients with anorexia and cachexia reported that megestrol was superior to cannabinoids in terms of improving body weight gain and stabilization, appetite and tolerability. Similar results were reported in another study; namely that megestrol treated anorexia – and improved cachexia symptoms – better than dronabinol alone. This study looked into the pharmacology of synthetic cannabinoids but not plant-derived cannabinoid.
Contrary to these findings, marijuana smoking dose-dependently increased daily caloric intake and weight gain in HIV-positive individuals, albeit with moderate adverse events. Low dose THC significantly improved sleep quality, and all these results were comparable to dronabinol.
Early stage clinical trials of THC as a treatment for cancer-related cachexia found potential therapeutic efficacy of THC with improved appetite and weight gain. Similar results have also been observed in the treatment of HIV-associated cachexia.
We may wonder why there are discrepancies in the study findings. The possible explanation is that these studies investigated the selected fixed-dose regimens for all the enrolled patients without considering inter-individual and intra-individual variations in dose response and treatment outcomes. It is unlikely to conduct a clinical trial study with individual dose-titration design, in which dose adjustments can be done based on a patient’s tolerance and treatment response. Age and other factors may also influence the pharmacokinetics and pharmacodynamics of cannabinoids; younger cancer-associated cachexia patients may have a different drug metabolic rate than the elderly. Taking these issues into consideration, dosing, efficacy and toxicity are unlikely to be the same or consistent for all the patient populations. Hence, the same dose cannot help all and this study design is flawed.
Analyzing the currently available research literature, the supporting evidence for the use of cannabinoids as a treatment for cancer-related cachexia remains equivocal. A well-informed patient population is demanding a large-scale clinical trials to demonstrate the safety and efficacy of cannabinoids as a treatment for cancer-related cachexia.
However, it is not possible with oral dosing, considering the inter-individual heterogeneity in pharmacokinetics of cannabinoids in patients with dysfunctional metabolism, and altered body composition. In these individuals, dose-effect relationship and concentration-effect relationship cannot be established – even in well designed clinical trials – as these effects are not universal across all patient populations. Possibly, the reported benefits, or lack of benefits, of cannabinoids in cancer-associated cachexia are likely to be an individual’s unique dose-concentration relationship.
Until this point, data of rigorous pharmacokinetics data in cancer cachexia patients are lacking. Before conducting efficacy clinical trials, it is critical to explore and understand the pharmacokinetics and pharmacodynamics of cannabinoids in the unique cachexic population. In this way, the rationale of employing cannabis for cancer-related cachexia treatment can be justified, and also the cause for variable treatment outcomes could be understood. Until that time, the efficacy should be considered as patient-dependent and variable.
As of now, nearly 23 states have approved medical cannabis as a treatment for cachexia. Additionally, other states – including Georgia, New York, Florida, Ohio, Massachusetts and Pennsylvania – allow the use of medical cannabis for cachexia-related medical conditions such as HIV/AIDS, cancer and Crohn’s disease.