An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis

Abstract

The majority of patients with multiple sclerosis (MS) develop troublesome lower urinary tract symptoms (LUTS). Anecdotal reports suggest that cannabis may alleviate LUTS, and cannabinoid receptors in the bladder and nervous system are potential pharmacological targets. In an open trial we evaluated the safety, tolerability, dose range, and efficacy of two whole-plant extracts of Cannabis sativa in patients with advanced MS and refractory LUTS. Patients took extracts containing delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD; 2.5 mg of each per spray) for eight weeks followed by THC-only (2.5 mg THC per spray) for a further eight weeks, and then into a long-term extension. Assessments included urinary frequency and volume charts, incontinence pad weights, cystometry and visual analogue scales for secondary troublesome symptoms. Twenty-one patients were recruited and data from 15 were evaluated. Urinary urgency, the number and volume of incontinence episodes, frequency and nocturia all decreased significantly following treatment (PB/0.05, Wilcoxon’s signed rank test). However, daily total voided, catheterized and urinary incontinence pad weights also decreased significantly on both extracts. Patient self-assessment of pain, spasticity and quality of sleep improved significantly (PB/0.05, Wilcoxon’s signed rank test) with pain improvement continuing up to median of 35 weeks. There were few troublesome side effects, suggesting that cannabis-based medicinal extracts are a safe and effective treatment for urinary and other problems in patients with advanced MS.

Keywords

cannabidiol cannabis delta-9-tetrahydrocannabinol multiple sclerosis neurogenic detrusor overactivity neuropathic pain sleep disorder spasticity urinary incontinence

Get full access to this article

View all access options for this article.

References

Koldewijn E , Hommes O , Lemmens W , Debruyne F , van Kerrebroeck P. Relationship between lower urinary tract abnormalities and disease-related parameters in multiple sclerosis . J Urol 1995; 154: 169-173 .

Consroe P , Musty R , Rein J , Tillery W , Pertwee R. The perceived effects of smoked cannabis on patients with multiple sclerosis . Eur Neurol 1997; 38: 44-48 .

Wade DT , Robson P , House H , Makela P , Aram J. A preliminary controlled study to determine whether whole-plant cannabis extracts can improve intractable neurogenic symptoms . Clin Rehabil 2003; 17: 21-29 .

Jaggar SI , Sellaturay S , Rice AS. The endogenous cannabinoid anandamide, but not the CB2 ligand palmitoylethanolamide, prevents the viscero-visceral hyper-reflexia associated with inflammation of the rat urinary bladder . Neurosci Lett 1998; 253: 123-126 .

Pertwee RG , Fernando SR. Evidence for the presence of cannabinoid CB1 receptors in mouse urinary bladder . Br J Pharmacol 1996; 118: 2053-2058 .

Dmitrieva N , Berkley KJ. Contrasting effects of WIN 55212-2 on motility of the rat bladder and uterus . J Neurosci 2002; 22: 7147-7153 .

Martin RS , Luong LA , Welsh NJ , Eglen RM , Martin GR , MacLennan SJ. Effects of cannabinoid receptor agonists on neuronally-evoked contractions of urinary bladder tissues isolated from rat, mouse, pig, dog, monkey and human . Br J Pharmacol 2000; 129: 1707-1715 .

Glass M , Dragunow M , Faull RL. Cannabinoid receptors in the human brain: a detailed anatomical and quantitative auto-radiographic study in the fetal, neonatal and adult human brain . Neuroscience 1997; 77: 299-318 .

Notcutt W , Price M , Miller R , Newport S , Phillips C , Simmons S et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 ‘N of 1’ studies . Anaesthesia 2004; 59: 440-452 .

10.

Whittle BA , Guy GW , Robson P. Prospects for new cannabis-based prescription medicines . J Cannabis Ther 2001; 1: 183-205 .

11.

Robson PJ , Guy GW. Clinical studies of cannabis medicines. In Cannabis and cannabinoids as medicines. London: Pharmaceutical Press , 2004.

12.

Folstein MF , Folstein SE , McHugh PR. ‘Mini-mental state’. A practical method for grading the cognitive state of patients for the clinician . J Psychiatr Res 1975; 12: 189-198 .

13.

Capasso R , Izzo AA , Fezza F , Pinto A , Capasso F , Mascolo N et al. Inhibitory effect of palmitoylethanolamide on gastrointestinal motility in mice . Br J Pharmacol 2001; 134: 945-950 .

14.

Bartocci C , Evandri MG , Tucci P , Bolle P. Interactions between A-9THC and capsaicin on isolated lamb bladder detrusor . Farmaco 2001; 56: 349-351 .

15.

Christopoulos A , Wilson K. Interaction of anandamide with the M(1) and M(4) muscarinic acetylcholine receptors . Brain Res 2001; 915: 70-78 .

16.

Lagalwar S , Bordayo EZ , Hoffmann KL , Fawcett JR , Frey WH, 2nd . Anandamides inhibit binding to the muscarinic acetylcholine receptor . J Mol Neurosci 1999; 13: 55-61 .

17.

Coutts AA , Pertwee RG. Inhibition by cannabinoid receptor agonists of acetylcholine release from the guinea-pig myenteric plexus . Br J Pharmacol 1997; 121: 1557-1566 .

18.

Wiseman OJ , Fowler CJ , Landon DN. The role of the human bladder lamina propria myofibroblast . BJU Int 2003; 91: 89-93 .

19.

Smart D , Gunthorpe MJ , Jerman JC , Nasir S , Gray J , Muir AI et al. The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1) . Br J Pharmacol 2000; 129: 227-230 .

20.

Szallasi A , Fowler CJ. After a decade of intravesical vanilloid therapy: still more questions than answers . Lancet Neurol 2002; 1: 167-172 .

21.

Brady CM , Apostolidis A , Harper M , Yiangou Y , Beckett A , Jacques TS et al. Parallel changes in bladder suburothelial vanilloid receptor TRPV1 and pan-neuronal marker PGP9.5 immunoreactivity in patients with neurogenic detrusor over-activity (NDO) after intravesical resiniferatoxin treatment . BJU Int 2004; 93: 770-776 .

22.

Jaggar SI , Hasnie FS , Sellaturay S , Rice AS. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain . Pain 1998; 76: 189-199 .

23.

Athwal B , Berkley K , Hussain I , Brennan A , Craggs M , Sakakibara R et al. Brain responses to changes in bladder volume and urge to void in healthy men . Brain 2001; 124: 369-377 .

24.

Killestein J , Hoogervorst EL , Reif M , Kalkers NF , Van Loenen AC , Staats PG et al. Safety, tolerability, and efficacy of orally administered cannabinoids in MS . Neurology 2002; 58: 1404-1407 .

25.

Stewart AL , Ware JE. Measuring functioning and well being: the medical outcomes study approach. London: Duke University Press , 1992.

26.

Zigmond AS , Snaith RP. The hospital anxiety and depression scale . Acta Psychiatr Scand 1983; 67: 361-370 .

27.

Hobart J , Lamping D , Fitzpatrick R , Riazi A , Thompson A. The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure . Brain 2001; 124: 962-973 .

28.

Mahoney FI , Barthel DW. Functional evaluation: The Barthel Index . Md State Med J 1965; 14: 61-65 .

29.

Donovan JL , Abrams P , Peters TJ , Kay HE , Reynard J , Chapple C et al. The ICS-‘BPH’ Study: the psychometric validity and reliability of the ICSmale questionnaire . Br J Urol 1996; 77: 554-562 .

30.

Jackson S , Donovan J , Brookes S , Eckford S , Swithinbank L , Abrams P. The Bristol Female Lower Urinary Tract Symptoms questionnaire: development and psychometric testing . Br J Urol 1996; 77: 805-812 .

31.

Ashworth B. Preliminary trial of carisoprodol in multiple sclerosis . Practitioner 1964; 192: 540-542 .