European Urology

1. Cannabis and cannabis-based medicinal extracts: clinical evidence of a bladder effect

Recent years have seen a wealth of publications on the endocannabinoid system and its association with the regulation of micturition. Interest has grown since published reports from patients with multiple sclerosis (MS) suggested a beneficial effect of smoked cannabis on symptoms associated with bladder dysfunction, particularly urinary urgency, urgency incontinence, and even hesitancy in initiating micturition. Those symptoms were improved in 64%, 55%, and 59%, respectively, of participants in a questionnaire-based survey [1]. To date, a small number of open-label and placebo-controlled studies have demonstrated that orally administered cannabinoid modulators may alleviate neurogenic overactive bladder (OAB) symptoms refractory to first-line treatment. Mostly in patients with advanced MS, preparations containing delta-9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD) appeared to effectively ameliorate clinical parameters such as urgency incontinence episodes, daytime frequency, nocturia, and pad weight [2], [3], and [4]. Patient-associated outcomes, such as the Patient's Global Impression of Change, also improved significantly more in patients treated with the active component than in the placebo arm of studies [4]. Symptomatic improvements, however, could not be reflected to robust urodynamic changes [3] and [4].

2. The cannabinoid receptor system: What do we know?

Cannabis-based medicinal extracts (CBMEs) exert their effects via the cannabinoid receptors. Two types, CB1 and CB2, have been well described, whereas an orphan G-protein coupled receptor, GPR55, was recently claimed to be a novel cannabinoid receptor responding to ligands such as cannabidiol [5]. Both CB1 and CB2 have been identified in the central nervous system, although CB2 is more prominent in peripheral tissues [5]. Both receptors were recently identified in all layers of the human bladder [6] and [7]; their expression in the urothelium was found to be significantly higher than in the detrusor, and the expression of CB1 was higher than CB2 [6]. CB2 receptors were also identified in sensory suburothelial nerves expressing the transient receptor potential vanilloid 1 (TRPV1) receptor and calcitonin gene-related peptide as well as in cholinergic neurons in the detrusor [7].

The functional implications of these findings have yet to be fully elucidated. Activation of CB1 peripherally has been associated with vasodilation and motility changes via suppression of release of neurotransmitters, whereas activation of CB2 appears to induce anti-inflammatory, antinociceptive, and immunosuppressive actions [5]. Animal bladder experiments suggested a modulatory role of CB2 receptors in both afferent signalling and cholinergic nerve activity [7]. Their activation produced a decrease in the nerve-evoked contractions of the bladder tissue and an increase in the micturition intervals and the bladder pressure. In an animal model of partial bladder outlet obstruction, intravesical application of a selective CB2 agonist reduced the number of nonvoiding contractions and increased bladder compliance and opening detrusor pressures. Furthermore, detrusor strips from treated animals demonstrated increased sensitivity to nerve stimulation [8].

Bladder CB1 receptors are also thought to be functional [6]. Local CB1 receptor activation could modulate the bladder afferent activity [9]. It is possible that such effects are mediated via interaction between the CB1 and TRPV1 receptors; CB1 was also found to colocalise on bladder afferents with TRPV1 [9]. A counterbalance appears to exist between the two receptors, since inflammatory mediators, such as bradykinin, and potent endogenous cannabinoids, such as arachidonyl-ethanolamide (anandamide), may simultaneously sensitise TRPV1 and inhibit CB1, resulting in release of neuropeptides and induction of neurogenic inflammation and detrusor overactivity [10].

Further evidence for a role of the endocannabinoid system in bladder mechanosensation has been provided by the codistribution of fatty acid amide hydrolase (FAAH), the key enzyme for the degradation of anandamide, with CB2 in the human bladder urothelium [11]. Both systemic and intravesical administration of an FAAH antagonist induced afferently mediated urodynamic changes, which were thought to be mediated mainly via CB2 activation. It was thus proposed that urothelial and suburothelial CB2 may represent targets for FAAH substrates [11].

3. Mechanism of action in the bladder: Do oral cannabinoid modulators exert a local bladder effect?

Because oral uptake of CBMEs may be followed by central side effects [2], [3], and [4] but also may improve OAB symptoms, which are known to be afferently mediated, the question arises of whether the latter beneficial effects are centrally mediated or whether a local bladder component via an action on the afferent bladder pathways plays a role. The possibility of a local effect on bladder afferents is only partially supported by animal studies in which both systemic and intravesical administration of endocannabinoid modulators improves parameters associated with bladder overactivity [8] and [9]. Robust human data do not exist to date. Indirect evidence has been provided by a single immunohistochemical study that has shown increased CB1 expression in the suburothelium and detrusor of patients diagnosed with idiopathic detrusor overactivity [12]. Levels of CB1-expressing suburothelial nerve fibres were found to correlate with the degree of the patients’ sensation of urgency. A recent short report of human bladder biopsies from MS patients participating in a placebo-controlled trial using a sublingual endocannabinoid modulator (Sativex; GW Pharmaceuticals, Wiltshire, UK) comprising THC and CBD in a 1:1 ratio, implied that bladder CB2 receptors (mainly urothelial and suburothelial) may mediate the effect of oral cannabinoid agonists [13]. CB2 messenger RNA expression was found to be increased in MS patient bladders when compared with controls; CB2 expression was decreased after active but not after placebo treatment, whereas CB1 expression remained unchanged after treatment with the active component [13]. Previously, animal data had also suggested that the beneficial effect of cannabinoid agonists in bladder function may be due to a peripheral action on cannabinoid receptors located in the spine, the bladder, or both [14].

4. The future

Modulation of the endocannabinoid system is currently being investigated for a wide range of potential therapeutic applications including smoking cessation, treatment of obesity, immune system regulation, and pain relief as well as for possible anticancer effects. Similarly, the future for the use of cannabinoids in lower urinary tract (LUT) dysfunction will certainly be intriguing. The proposed role of cannabinoids in bladder mechanosensation supports their therapeutic potential in conditions of bladder overactivity, whereas a body of evidence already exists for their role in bladder inflammation [9], [10], [12], and [15]. Novel findings of functional CB receptors in the animal and human prostate also suggest a role for CB-mediated modulation of autonomic neurotransmission in the prostate [16]. Clearly, further research is needed to investigate the role of peripheral cannabinoid receptors and their exogenous modulators on LUT control.

Conflicts of interest

Apostolos Apostolidis is an investigator for GSK, Pharmaserve-Lilly, Pfizer, Astellas, and Allergan; is a consultant for Astellas and Allergan; and has received honoraria from Pfizer, Astellas, and Allergan.