Anorexia/Cachexia

In a questionnaire based study completed by 523 HIV patients, a lack of appetite was reported as the most frequently experienced symptom (111 out of 523) and 97% experienced improvement with cannabis use (n = 79 reporting “much better”, while n = 18 reported a “little better”) (Woolridge et al, 2005). In a placebo controlled within-subject study, smoked cannabis, oral dronabinol (synthetic THC) and placebo were assessed across a range of behaviours including, appetite, mood and sleep. Smoked cannabis and dronabinol were found to be well tolerated and efficacious as both treatments were seen to increase daily calorie intake and weight in a dose dependent manner (Haney et al, 2007).

Furthermore, dronabinol, a synthetic version of THC, has been FDA approved in the US for the treatment of nausea and appetite loss associated with HIV and cancer.

Of note, a recent survey performed in Canada on 271 patients registered to purchase cannabis from Tilray, perceived cannabis to be an effective treatment for appetite loss (n = 79) and nausea (n = 79) (Lucas et al, 2017).

The following studies demonstrate safety and efficacy of cannabinoids in appetite and weight loss:

Dronabinol as a Treatment for Anorexia Associated with Weight Loss in Patients with AIDS (Beal et al 1995).

Objective:           A multicenter, double-blind, placebo-controlled, parallel-group trial to study the effects of dronabinol (synthetic THC), on appetite and weight in AIDS-related anorexia.

Cohort:                 Total n = 139

Dronabinol (2.5 mg bd.) n = 72

Placebo n = 67

Results:                Dronabinol was associated with a statistical significant improvement in appetite, nausea and mood: increased appetite above baseline (38 % vs 8 % for placebo, P =0.015), decreased nausea (20% vs 7%; P = 0.05) and improvement in mood (10% vs-2%, P =0.06).

Dronabinol treatment resulted in a mean increase in weight (0.1 kg) whereas the placebo group had a mean loss of 0.4 kg.

Safety:                  Overall dronabinol was well tolerated.

Incidence of nervous system events: 35% in dronabinol group vs 9% in placebo group. The adverse events (AEs) were mostly mild to moderate and resolved without discontinuation of treatment.

Most common nervous system AEs in the dronabinol group were (i) euphoria (n = 9), (ii) dizziness (n = 5), (iii) thinking abnormalities (n = 5), and (iv) somnolence (n = 4).

Conclusion:         Dronabinol was deemed a safe and effective treatment for anorexia in patients with AIDS.

Long-Term Efficacy and Safety of Dronabinol for Acquired Immunodeficiency Syndrome Associated Anorexia. (Beal et al, 1997).

 

Objective:           A multicentre, open-label, follow up study to investigate the long-term effect of synthetic THC for anorexia associated with weight loss in patients with AIDS.

Cohort:                 Patients were eligible if they had previously taken part in a 6-week placebo vs synthetic THC study (Beal et al 1995). In current study, all patients were treated with synthetic THC treatment (90% received 2.5 mg dronabinol bd, remaining 10% received 2.5 mg once daily). Of these, 38% modified their own dose by either increasing or decreasing the dose.

Total enrolled n = 94 (previously received: synthetic THC n = 46, placebo n = 48).

Completed full 12 months n = 22

Average duration of therapy: 5.8 ±4.38 months

Results:                Using the visual analogue scale for hunger (VASH), dronabinol treatment was associated with improvement in mean appetite.

Patients previously treated with dronabinol or placebo exhibited improvement in mean appetite as measured by VASH (previous dronabinol: percent change from baseline of 48.6 – 76.1% at each month, previous placebo: percent change from baseline of 27.3% to 69.9%).

Safety:                  At least 1 treatment related AE was reported in 44% of participants. Most AEs were mild to moderate, while 2 patients reported a severe AE.

Central nervous system related AEs occurred in 38% of patients, these included anxiety, confusion, depersonalization, dizziness, euphoria, somnolence, and thinking abnormality).

 

Comparison of Orally Administered Cannabis Extract and Delta-9-Tetrahydrocannabinol in Treating Patients With Cancer-Related Anorexia-Cachexia Syndrome: A Multicentre, Phase III, Randomized, Double-Blind, Placebo-Controlled Clinical Trial From the Cannabis-In- Cachexia-Study-Group (Strasser et al, 2006).

 

Objective:           To compare the effects of whole plant cannabis extract (CE), THC and placebo on appetite and QoL in patients with cancer-related anorexia-cachexia syndrome.

Cohorts:               Completed treatment (6 weeks): total n = 164 (out of 243).

Completed placebo n = 33 (out of 48).

Completed CE (2.5mg THC, 1mg CBD bd) n = 66 (out of 95).

Completed THC (2.5mg bd) n = 65 (out of 100).

Results:                Treatment was not found to significantly increase appetite in comparison to placebo, however, a large placebo affect was also noted (increased appetite was reported by 69% in the placebo arm, 73% in the CE arm and 58% in the THC arm).

Safety:                  Both CE and THC treatments were well tolerated.

 

 

A Phase II Study of Delta-9-tetrahydrocannabinol for Appetite Stimulation in Cancer-associated Anorexia (Nelson et al. 1994).

 

Objective:           To investigate the appetite stimulation properties of THC in advanced cancer related anorexia.

Cohort:                 Total n =18 (THC 2.5 mg three times a day.)

Results:                Overall 13 out of 18 participants reported an improvement in appetite (slight improvement n = 10, major improvement n = 3).

Of the 6 patients weighed pre- and post-study, 3 gained weight, 2 maintained weight while 1 patient lost weight.

Safety: Four patients reported side effects (grade I) and 3 withdrew from the study.

 

Unknown or expected adverse effects, risks and safety issues & related toxicology:

 

A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.

 

According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration

(2017): Cannabis is not appropriate for patients who:

• Are under the age of 25 (with the exception of intractable epilepsy or severe pain syndrome)
• Have a personal history or strong family history of psychosis
• Have a current or past cannabis use disorder, or active substance use disorder
• Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)
• Are pregnant, planning to become pregnant, or

Breastfeeding.

Cannabis should be authorized with caution in patients who:

• Smoke tobacco
• Have risk factors for cardiovascular disease
• Are heavy users of alcohol
• Are taking sedating medications or any other medication metabolized by the CYP450 pathway
• At risk or have liver disease

 

Potential drug interactions

Increasing THC concentration:

Examples of inhibitors:

– Antidepressants (e.g. Fluoxetine, Fluvoxamine)

– Proton Pump Inhibitors (e.g. Omeprazole)

– Cimetidine

– Macrolides (Clarithromycin, Erythromycin)

– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)

– Calcium Antagonists (e.g. Diltiazem, Verapamil)

– HIV protease inhibitors (e.g. Ritonavir)

– Amiodarone

– Isoniazid

– Grapefruit juice

Increasing CBD concentration:

– Metabolized by CYP 2C19 and CYP 3A4

– Bioavailability could be increased by many of the same substances as for THC

Decreasing THC and CBD concentration:

• CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism
• Examples of inducers:

– Rifampicin

– Primidone

– Carbamazepine

– Phenobarbital

– Phenytoin

– Rifabutin

– Saint John’s Wort

 

Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex.) and commonly used antiepileptic

drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).

• Caution with blood thinners like Warfarin, Heparin,

Clopidogrel (Plavix)

• Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia,

hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).

 

Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.