Cachexia is a complex metabolic syndrome that is associated with underlying illness and “characterised by loss of muscle with or without loss of fat mass” that affects an estimated 9 million patients globally – the incidence of which is believed to be rising in line with increasing multimorbidity of chronic disease. The condition is particularly common among cancer and AIDS patients, affecting 30% and 35% of patients, respectively.
There are currently no standardised guidelines for the management of cachexia, with no agreed gold-standard pharmacological options for the treatment of the condition. Cachexia is believed to advance through a series of biological pathways, including by an upregulation of pathways that break down muscle and fat and a downregulation of pathways that stimulate muscle growth leading to an overall condition manifesting in weight loss, reduced strength, and wasting.
The cannabinoid receptor type 1 (CB1) is thought to play a significant role in modulating appetite and satiety through activity at both orexigenic and anorexigenic neurons. Medical cannabis is therefore increasingly being considered as a potential treatment option for cachexia. Furthermore, there is already evidence to suggest that cannabis medicines can be useful to prevent wasting associated with chemotherapy and AIDS.
Tetrahydrocannabinol (THC) has been shown to stimulate appetite, prevent feelings of nausea, and to improve functional status in cachexia patients. A recent systematic review and meta-analysis aimed to compare the effects of cannabis-based medicines against both placebo and active treatments in anorexia–cachexia syndrome for appetite stimulation, change in body mass, and quality of life (QoL).
Design and methods of the review
Researchers used the PICOS (patient, intervention, control, outcome, study type) acronym to define the research question by specific criteria. Relevant literature databases were used to find eligible studies for inclusion in the review and meta-analysis.
Included studies were randomised controlled trials (RCTs) which assessed patients with cachexia, from any underlying condition, having had a sustained weight loss >5% (or body mass index < 20 kg/m2) in less than 12 months with three of the five of the following characteristics: decreased muscle strength, fatigue, anorexia, low fat-free mass index, and abnormal biochemistry. They must also have assessed cannabis-based medicines or their synthetic analogues and compared them with either placebo or active treatments.
The chosen outcomes were objective measurements, such as weight gain and additionally subjective measures such as patient-reported QoL and change in appetite. All included studies mandated no previous cannabis use or a greater-than-1-month washout period of any appetite stimulants, including corticosteroids and cannabis products for at least the past month.
Results of the Study
Following database and hand-searches, and exclusion processes, 20 full-text articles were assessed for eligibility and five articles were included for review, including a total of 934 adult patients. Two of the studies focused on HIV-positive wasting syndrome with a clinical diagnosis of cachexia through a > 10% or > 2.3 kg of weight loss in the preceding 2 months. The other three studies included patients diagnosed with advanced cancer with an estimated life expectancy of at least 3 months and self-reported weight loss of > 5% or > 2.3 kg in the preceding months, not explained by other diseases or recent surgery.
Following meta-analysis, two of the studies found an overall trend that appetite scores had improved with cannabis-based medicine use; however, no statistically significant change in appetite was observed across all five studies.
The data for QoL outcomes were pooled for three studies but no statistically significant change was observed. In addition, all five studies suffered from some missing outcome data due to loss to follow-up – only one study explicitly explained how it handled missing outcome data through the nearest neighbour approach.
Overall, the findings in this review are in line with a previous systematic review on cannabinoid use in palliative medicine that observed no significant effect of cannabinoids on appetite or weight change. Furthermore, studies that were included in this review and others are considered to have a relatively high risk of bias and low-quality evidence.
Nonetheless, cannabinoids possess sufficient pharmacological potential for use in cachexia. CB1R agonists increase appetite in orexigenic and anorexigenic neurones. Moreover, THC and in particular CBD have demonstrated immunoregulatory function, particularly through modulating tumour necrosis factor-a and interleukin-6, suggesting a mechanism through which to treat cachexia.
Conclusions
The authors of this review concluded that the included studies yielded no high-quality evidence to recommend the use of cannabis-based medicines in the treatment of cachexia. The findings support previous findings that there is no high-quality evidence to support the use of any pharmacological agents in isolation for this condition.
Therefore, the researchers recommend that “based on the pharmacological potential of cannabinoids for increasing appetite and modulating immune function combined with the unmet need to develop an effective treatment option for cachectic patients, further trials be conducted.” In particular, it is concluded, THC/(cannabidiol)CBD combination regimens mat warrant specific further evaluation, as THC has been found to stimulate appetite, while CBD is immunomodulatory.
Finally, it is recommended that further studies be carried out to assess the potential of whole-plant cannabis extracts and determine how an entourage effect of cannabis compounds may be beneficial for the treatment of cachexia.
