Changes in IGF-I, urinary free cortisol and adipokines during dronabinol therapy in anorexia nervosa: Results from a randomised, controlled trial
Introduction
The cannabinoid system is suggested to promote orexigenic and metabolic effects via both central and peripheral actions [1]. Accordingly, during the past decades, synthetic cannabinoid receptor 1 (CBR1) agonists have emerged as a novel treatment approach of severe underweight [2], [3], [4].
In contrast to other somatic conditions associated with chronic cachexia, anorexia nervosa (AN) is a purely psychiatric disease associated with multiple and profound neuroendocrine disturbances. The long, often chronic and relapsing periods of severe underweight affect nearly all endocrine axes and results in a severe catabolic condition, which in combination with an increased protein turnover has been referred to as auto-cannibalism. Dronabinol – a synthetic cannabinoid agonist – has been associated with a minor weight gain in patients with chronic AN [5]. Intriguingly, levels of physical activity were also modestly increased [6], while the parameters assessing eating disorder related behaviour and symptomatology remained unchanged during treatment. These apparently contradictory observations suggest that dronabinol exerted metabolic rather than psychoactive effects. However, the potential impact of CBR1 stimulation on the impaired hormonal systems involved in energy homeostasis has not been previously investigated in this group of patients.
The regulation of IGF-I is a pivotal process in AN, both in adaptation to chronic starvation and in regenerative processes during nutritional restoration. Chronic AN patients develop a nutritionally acquired resistance to GH, resulting in a decreased hepatic production of IGF-I and low circulating levels of total, free [7] and bioactive [8] IGF levels. The CBR1 has been found in hypothalamic regions secreting somatostatin as well as GH releasing hormone, and a biphasic response of GH to tetrahydrocannabinol exposure was described in previous reports [9]. Furthermore, animal studies report that both cannabinoid agonists [10] and marijuana smoke condensate [11] induce a significant increase in IGF-I gene expression. However, the evidence regarding interaction between the cannabinoid system and GH–IGF-I axis in humans is extremely sparse.
Hypercortisolemia is present in many adults and adolescents with AN [12]. The anatomic cohabitation of the CBR1 and the corticotropin-releasing hormone (CRH) expression in the hypothalamus [13] supports the existence of a close interaction between the endocannabinoid system and the activity of the hypothalamic–pituitary–adrenal (HPA). In animal models, CBR1 signalling leads to a negative modulation of stress-induced HPA activation [14]. However, the evidence of such a relationship in humans remains limited [15].
The amount of adipose tissue is usually extremely low in patients with AN and consequently, circulating levels of adipose tissue-derived factors, commonly referred to as adipokines, are profoundly altered. Among these, leptin is the primary signalling hormone through which the hypothalamus senses the nutritional state and modulates food intake and energy balance accordingly [16], and indeed hypoleptinemia has been proposed to serve as a diagnostic marker of AN [17]. Being a long-term integrative signal of energy storage, leptin has been reported to increase with weight gain in AN patients [18] and conversely, to decrease with weight loss in obese subjects [19]. Besides BMI and body fat, levels of leptin are highly correlated with IGF-I [20] and urinary free cortisol (UFC) [21], suggesting that the physiological regulation of leptin is complex. Data from cannabis smoking HIV-infected adult men suggest that the secretion of leptin might also be modulated though the endogenous cannabinoid receptors [22]. In addition to leptin, adiponectin is an insulin-sensitising cytokine produced by adipose tissue, but in contrast to leptin, plasma adiponectin is normally decreased in obese subjects and elevated in lean subjects. However, in AN, adiponectin levels have been reported to be elevated [23], [24], reduced [25] or unchanged [26] in comparison to levels in normal-weight controls.
In vitro data suggest that endocannabinoids may stimulate adipocyte proliferation [27], leading to fat accumulation, independently of the amount of food ingested [27]. Furthermore, adiponectin decreased during CBR1 receptor stimulation in vitro [28], while it increased during CBR1 antagonist stimulation in vitro as well as in vivo [29], [30]. According to our current information, the effects of CBR1 stimulation on the endogenous adipokine secretion have not previously been documented in patients with AN.
The aim of the present study was to assess the pathways affected by CBR1 stimulation in patients with AN. To this end, we studied the circulating IGF-system and serum levels of leptin and adiponectin as well as the UFC following 4 weeks of treatment with dronabinol vs. placebo in patients with severe, long-standing AN.
Section snippets
Trial design
Twenty-four adult women with chronic AN participated in this double-blinded, randomised, controlled, crossover study conducted at Odense University Hospital in Denmark [5].
The participants attended both psychiatric and somatic therapy as inpatients or outpatients at our centre and fulfilled the diagnostic criteria for AN according to the Diagnostic and Statistical Manual of Mental Disorders (fourth edition, text revision) for at least five years.
The baseline therapeutic regime was kept
Results
The participants were Caucasian women with a median age of 28 (23.5–42.0) years and median disease duration of 10.5 (7–18) years prior to inclusion. Baseline BMI was 15.7 ± 1.7 kg/m2 and the patients weighted 74.7 ± 8.1% of their ideal body weight. Both body weight and the estimated energy expenditure due to physical activity were modestly increased during dronabinol compared to placebo, as recently described [5], [6]. Although modest, the change in body weight led to a statistically significant BMI
Discussion
The orexigenic effect of cannabinoid agonist therapy has been widely documented in patients with cachexia associated with cancer, AIDS and Alzheimer's [2], [3], [4]. However, the interactions between cannabinoid agonists and the IGF system and other main metabolic systems involved in energy metabolism have not previously been investigated in humans. This study investigated the impact of the synthetic cannabinoid agonist dronabinol on several hormone systems involved in energy homeostasis in
Conflict of interest statement
This research was carried out independently by the Department of Endocrinology, Center for Eating Disorders, Odense University Hospital and was monitored by The Regional Unit for Good Clinical Practice, being approved by The Danish Medical Agency (journal number: 2612–3699), The Regional Committee for Medical Ethics (project id: S-20080016), and The Danish Data Protection Agency. The authors followed the guidelines by the European Medical Writers' Association. To our knowledge, all previously
Acknowledgements
We thank the patients who participated in the trial. Charlotte Olsen and Lone Hansen, are thanked for helping with sample collection. Laboratory technicians Merete Møller, Hanne Pedersen, Susanne Sørensen, Kirsten Nyborg Rasmussen, Lone Kvist, Elsebeth Hornemann og Lisa Buus are thanked for helping with the hormone measurements. Claire Gudex is thanked for language editing of the final manuscript.
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