title: Dronabinol in severe, enduring anorexia nervosa: a randomized controlled trial. Blood Levels of the Endocannabinoid Anandamide are Increased in Anorexia Nervosa and in Binge-Eating Disorder, but not in Bulimia Nervosa Effect of dronabinol therapy on physical activity in anorexia nervosa: a randomised, controlled trial Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial. A double-blind trial of delta 9-tetrahydrocannabinol in primary anorexia nervosa. How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review
abstract: OBJECTIVE The evidence for pharmacological treatment of severe , longst and ing anorexia nervosa ( AN ) is sparse and the few controlled pharmacologic studies have focused on a narrow range of drugs . The aim of the present study was to investigate the effects of treatment with a synthetic cannabinoid agonist on body weight and eating disorder-related psychopathological personality traits in women with severe , enduring AN . METHOD This add-on , prospect i ve , r and omized , double blind , controlled crossover study was conducted between 2008 and 2011 at a specialized care center for eating disorders . Twenty-five women over 18 years with AN of at least 5 years duration were r and omized to treatment with either dronabinol-placebo or placebo-dronabinol .  In addition to the st and ardized baseline therapeutic regime , the participants received dronabinol , 2.5 mg twice daily for 4 weeks and matching placebo for 4 weeks , separated by a 4-week wash-out period . Primary outcome was the mean change in body weight . Secondary outcome was score changes on the Eating Disorder Inventory-2 ( EDI-2 ) . Data were analyzed for the 24 patients who completed the trial . RESULTS During dronabinol treatment , participants gained 0.73 kg ( t = 2.86 , df = 22 , p < 0.01 ) above placebo without significant psychotropic adverse events . Dronabinol significantly predicted weight gain in a multiple linear regression including EDI-2 body dissatisfaction score and leptin . EDI-2 subscale scores showed no significant changes over time . DISCUSSION Dronabinol therapy was well tolerated . During four weeks of exposure it induced a small but significant weight gain in the absence of severe adverse events The endocannabinoid system , consisting of two cannabinoid receptors ( CB1 and CB2 ) and the endogenous lig and s an and amide ( arachidonoylethanolamide ( AEA ) ) and 2-arachidonoylglycerol ( 2-AG ) , has been shown to control food intake in both animals and humans , modulating either rewarding or quantitative aspects of the eating behavior . Moreover , hypothalamic endocannabinoids seem to be part of neural circuitry involved in the modulating effects of leptin on energy homeostasis . Therefore , alterations of the endocannabinoid system could be involved in the pathophysiology of eating disorders , where a deranged leptin signalling has been also reported . In order to verify this hypothesis , we measured plasma levels of AEA , 2-AG , and leptin  in 15 women with anorexia nervosa ( AN ) , 12 women with bulimia nervosa ( BN ) , 11 women with binge-eating disorder ( BED ) , and 15 healthy women .  Plasma levels of AEA result ed significantly enhanced in both anorexic and BED women , but not in bulimic patients . No significant change occurred in the plasma levels of 2-AG in all the patients ' groups . Moreover , circulating AEA levels were significantly and inversely correlated with plasma leptin concentrations in both healthy controls and anorexic women . These findings show for the first time a derangement in the production of the endogenous cannabinoid AEA in drug-free symptomatic women with AN or with BED . Although the pathophysiological significance of this alteration awaits further studies to be clarified , it suggests a possible involvement of AEA in the mediation of the rewarding aspects of the aberrant eating behaviors occurring in AN and BED Purpose The level of physical activity is inappropriately high in up to 80 % of the patients suffering of anorexia nervosa ( AN ) , as a result of conscious efforts to lose weight , affect regulation and biological adaptive changes to starvation induced by hypothermia and neuroendocrine mechanisms . The purpose s of this paper were to ( 1 ) assess the effect of dronabinol — a synthetic cannabinoid agonist — on physical activity in patients with chronic and stable AN , and to ( 2 ) unravel the role of leptin and cortisol in this process . Methods This prospect i ve , r and omised , double-blind , crossover study was conducted at a specialised care centre for eating disorders . Twenty-four adult women with AN of at least 5-year duration received either the dronabinol-placebo or placebo-dronabinol sequence .  Physical activity was monitored during the fourth week of each intervention . Body weight , leptin and urinary free cortisol excretion were measured repeatedly during the trial . Changes in behavioural dimensions related to AN were assessed by Eating Disorder Inventory-2 . Results The total duration of physical activity did not change , while its average intensity increased by 20 % ( P = 0.01 ) during dronabinol therapy , result ing in an increased energy expenditure with 68.2 kcal/day ( P = 0.01 ) above placebo . Conclusions This r and omised , double-blind study revealed that cannabinoid agonist treatment was associated with a modest increase in physical activity in adult women with severe and longst and ing AN . Additionally , we detected a strong relationship between the circulating levels of leptin and physical activity in these chronically undernourished patients OBJECTIVE Anorexia nervosa ( AN ) is characterised by complex neuroendocrine disturbances due to severe underweight , physical hyperactivity and purging behaviour . Cannabinoid agonists are used to palliate cachexia of various causes , but their interactions with the hormonal systems that are involved in energy metabolism have not been previously described in humans . Therefore we found it of interest to assess interactions between the synthetic cannabinoid agonist dronabinol and insulin-like growth factor I ( IGF-I ) , urinary free cortisol ( UFC ) and adipokines in patients with chronic AN . DESIGN This was a prospect i ve , double-blind r and omised crossover study , conducted at a specialised care centre for eating disorders . The results are based on twenty-four adult women with chronic AN , who completed the study . The participants received dronabinol ( oral capsules , 5 mg daily ) and matching placebo over four weeks , separated by a four-week washout period . Bioactive IGF was determined by a cell-based bioassay , whereas total IGF-I , IGFBP-2 and -3 and the two adipokines leptin and adiponectines were measured by immunoassays . The UFC excretion was determined by mass spectrometry . RESULTS As previously reported , dronabinol treatment caused a small , yet significant increase in BMI as compared to placebo ( + 0.23 kg/m(2 ) ; P = 0.04 ) . This modest weight gain predicted a corresponding increase in bioactive IGF-I , while the amount of daily energy expenditure due to physical activity had a comparable but opposite effect . Nevertheless , neither IGF-I , bioactive IGF nor the IGFBPs levels changed significantly during dronabinol intervention as compared to placebo . Adiponectin also remained unaffected by the weight gain , whereas plasma leptin showed a transient increase at three weeks ( P < 0.05 ) . UFC levels were decreased during dronabinol intervention . CONCLUSION Our results showed that low-dosage therapy with the synthetic cannabinoid agonist dronabinol affected neither the concentration nor the activity of the circulating IGF-system in women with severe and chronic AN . However , our results suggest that such treatment may alleviate the increased hypothalamic-pituitary-adrenal axis activity seen in these patients Δ9-Tetrahydrocannabinol ( Δ9-THC ) , the most prominent psychoactive cannabinoid in Cannabis sativa L. ( marijuana ) , has been reported to have properties of appetite stimulation , promotion of weight gain , and antiemetic efficacy in selected patient population s. In this 4-week , double-blind , crossover study , 11 female patients with primary anorexia nervosa ( PAN ) were evaluated on Δ9-THC and on an active placebo , diazepam . All patients participated in a st and ardized behavior modification treatment program . The following data were obtained : ( 1 ) daily weight , ( 2 ) daily caloric intake , and ( 3 ) weekly psychiatric assessment s. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales . The only significant differences found between the changes over time on Δ9-THC versus diazepam were more pathology on Δ9-THC for somatization , interpersonal sensitivity , and sleep disturbance . Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during Δ9-THC administration . One week after the study ended , each subject was given the highest dose level of Δ8-THC achieved in the study , and periodic blood sample s were obtained coincident with self-rated “ subjective high ” assessment s and pulse measurements . Quantitative analyses of these sample s indicated peak times of 1 to 5 hours postdose for Δ9- THC and for its primary active metabolite , 11-hydroxy-THC , which generally coincided with peak times for “ subjective high ” and pulse rate . The results of this clinical investigation suggest that Δ9-THC is not efficacious , in short-term administration , in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients We conducted a review of systematic review s ( SRs ) and r and omized-controlled trials ( RCTs ) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders . Five data bases were systematic ally search ed ( 2006—August 2018 ) ; 4 SRs ( of 11 RCTs ) and 14 RCTs ( 1629 participants ) were included . Diagnoses were : dementia , cannabis and opioid dependence , psychoses/schizophrenia , general social anxiety , posttraumatic stress disorder , anorexia nervosa , attention-deficit hyperactivity disorder , and Tourette`s disorder . Outcome variables were too heterogeneous to conduct a meta- analysis . A narrative synthesis method was applied . The study quality was assessed using the risk-of-bias tool and SIGN-checklists . THC- and CBD-based medicines , given as adjunct to pharmaco- and psychotherapy , were associated with improvements of several symptoms of mental disorders , but not with remission . Side effects occurred , but severe adverse effects were mentioned in single cases only . In order to provide reliable treatment recommendations , more and larger RCTs with follow-up assessment s , consistent outcome measures and active comparisons are needed
target: The only properly design ed , low bias and highly powered study found a weight increasing effect  of dronabinol in AN , while the other , using Δ9-THC at a high dose , found no effect and where the dose may have counteracted the weight gaining effects due to adverse events .
background: Anorexia nervosa ( AN ) is a psychiatric disorder with a high mortality and unknown etiology , and effective treatment is lacking .
  For decades , cannabis has been known to cause physical effects on the human body , including increasing appetite , which may be beneficial in the treatment of AN .
  To systematic ally review the literature for evidence of an effect of cannabinoids on ( 1 ) weight gain , and ( 2 ) other outcomes , in AN .