Abstract
Restless legs syndrome (RLS) is a chronic sensorimotor disorder characterized by an urge to move the legs. This urge is often accompanied by pain or other uncomfortable and unpleasant sensations, it either occurs or worsens during rest, particularly in the evening and/or at night, and temporarily improves with activity. Affecting nearly 3% of the North American and European populations in its moderate-to-severe form, RLS has a considerable negative impact on the quality of life, and sleep and is associated with significant morbidity. Although new developments have deepened our understanding of the disorder, yet, the corresponding pathophysiologic features that underlie the sensorimotor presentation are still not fully understood. Usually, symptoms respond well to dopamine agonists (DA), anticonvulsants, or opiates, used either alone or in any combination, but still, a subset of patients remains refractory to medical therapy and serious side effects such as augmentation and impulse control disorder may occur in patients with RLS under DA. Convincing treatment alternative are lacking but recently patients’ spontaneous reports of a remarkable and total remission of RLS symptoms following cannabis use has been reported. The antinociceptive effect of marijuana has been documented in many painful neurological conditions and the potential benefit of cannabis use in patients with refractory RLS should, therefore, be questioned by robust clinical trials. Here, we review basic knowledge of RLS and the putative mechanisms by which cannabis may exert its analgesic effects.
Keywords
- Restless legs syndrome
- Cannabis
- Treatment
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Abrams DI (2018) The therapeutic effects of Cannabis and cannabinoids: an update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med 49:7–11
Akpinar S (1982) Treatment of restless legs syndrome with levodopa plus benserazide. Arch Neurol 39(11):739
Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ (2001) MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56(2):263–265
Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ et al (2005) Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 165(11):1286–1292
Allen RP, Connor JR, Hyland K, Earley CJ (2009) Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med 10(1):123–128
Allen RP, Ondo WG, Ball E, Calloway MO, Manjunath R, Higbie RL et al (2011) Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med 12(5):431–439
Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW et al (2014) Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance. Sleep Med 15(8):860–873
Allen RP, Picchietti DL, Auerbach M, Cho YW, Connor JR, Earley CJ et al (2018) Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med 41:27–44
Ashkenazi R, Ben-Shachar D, Youdim MB (1982) Nutritional iron and dopamine binding sites in the rat brain. Pharmacol Biochem Behav 17(Suppl 1):43–47
Axel EK (1945) Restless legs: a clinical study. Acta Medica Scand Suppl 158(158):1–123
Barker D, Saito M (1981) Autonomic innervation of receptors and muscle fibres in cat skeletal muscle. Proc R Soc Lond B Biol Sci 212(1188):317–332
Barraud Q, Obeid I, Aubert I, Barriere G, Contamin H, McGuire S et al (2010) Neuroanatomical study of the A11 diencephalospinal pathway in the non-human primate. PLoS One 5(10):e13306
Barriere G, Cazalets JR, Bioulac B, Tison F, Ghorayeb I (2005) The restless legs syndrome. Prog Neurobiol 77(3):139–165
Beard JL, Chen Q, Connor J, Jones BC (1994) Altered monamine metabolism in caudate-putamen of iron-deficient rats. Pharmacol Biochem Behav 48(3):621–624
Benarroch E (2007) Endocannabinoids in basal ganglia circuits: implications for Parkinson disease. Neurology 69(3):306–309
Benarroch EE (2014) Synaptic effects of cannabinoids: complexity, behavioral effects, and potential clinical implications. Neurology 83(21):1958–1967
Ben-Shachar D, Finberg JP, Youdim MB (1985) Effect of iron chelators on dopamine D2 receptors. J Neurochem 45(4):999–1005
Berger K, Kurth T (2007) RLS epidemiology–frequencies, risk factors and methods in population studies. Movement Disorders 22(Suppl 18):S420–S423
Bianco LE, Wiesinger J, Earley CJ, Jones BC, Beard JL (2008) Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats. J Neurochem 106(1):205–215
Bloomfield MA, Morgan CJ, Egerton A, Kapur S, Curran HV, Howes OD (2014) Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol Psychiatry 75(6):470–478
Chenini S, Arnulf I, Monaca CC, Ghorayeb I (2018) French consensus: pharmacoresistant restless legs syndrome. Rev Neurol 174(7–8):522–531
Chokroverty S (2014) Therapeutic dilemma for restless legs syndrome. N Engl J Med 370(7):667–668
Chokroverty S (2015) Opioid-induced hyperalgesia and dopamine-induced augmentation in an intractable and refractory case of RLS. Sleep Med 16(10):1304
Clemens S, Rye D, Hochman S (2006) Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 67(1):125–130
Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG et al (2003) Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61(3):304–309
Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ et al (2004) Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 62(9):1563–1567
Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT et al (2009) Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain J Neurol 132(Pt 9):2403–2412
Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ (2011) Profile of altered brain iron acquisition in restless legs syndrome. Brain J Neurol 134(Pt 4):959–968
Durgin T, Witt EA, Fishman J (2015) The humanistic and economic burden of restless legs syndrome. PLoS One 10(10):e0140632
Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP (2000) Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 54(8):1698–1700
Earley CJ, Barker PB, Horska A, Allen RP (2006) MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med 7(5):458–461
Earley CJ, Kuwabara H, Wong DF, Gamaldo C, Salas R, Brasic J et al (2011) The dopamine transporter is decreased in the striatum of subjects with restless legs syndrome. Sleep 34(3):341–347
Earley CJ, Kuwabara H, Wong DF, Gamaldo C, Salas RE, Brasic JR et al (2013) Increased synaptic dopamine in the putamen in restless legs syndrome. Sleep 36(1):51–57
Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC et al (2014) Altered brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis-Ekbom Disease). Sleep Med 15(11):1288–1301
Erikson KM, Jones BC, Beard JL (2000) Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 130(11):2831–2837
Erikson KM, Jones BC, Hess EJ, Zhang Q, Beard JL (2001) Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav 69(3–4):409–418
Ferre S, Fredholm BB, Morelli M, Popoli P, Fuxe K (1997) Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci 20(10):482–487
Ferre S, Garcia-Borreguero D, Allen RP, Earley CJ (2018) New insights into the neurobiology of restless legs syndrome. Neuroscientist 1073858418791763
Garcia-Borreguero D, Guitart X, Garcia Malo C, Cano-Pumarega I, Granizo JJ, Ferre S (2018) Treatment of restless legs syndrome/Willis-Ekbom disease with the non-selective ENT1/ENT2 inhibitor dipyridamole: testing the adenosine hypothesis. Sleep Med 45:94–97
Garraway SM, Hochman S (2001) Modulatory actions of serotonin, norepinephrine, dopamine, and acetylcholine in spinal cord deep dorsal horn neurons. J Neurophysiol 86(5):2183–2194
Ghorayeb I, Gamas A, Mazurie Z, Mayo W (2017) Attention-deficit hyperactivity and obsessive-compulsive symptoms in adult patients with primary restless legs syndrome: different phenotypes of the same disease? Behav Sleep Med:1–8
Happe S, Reese JP, Stiasny-Kolster K, Peglau I, Mayer G, Klotsche J et al (2009) Assessing health-related quality of life in patients with restless legs syndrome. Sleep Med 10(3):295–305
Hauser W, Fitzcharles MA (2018) The perils of overestimating the efficacy of cannabis-based medicines for chronic pain management. Pain Physician 21(1):E79–E80
Heim B, Djamshidian A, Heidbreder A, Stefani A, Zamarian L, Pertl MT et al (2016) Augmentation and impulsive behaviors in restless legs syndrome: coexistence or association? Neurology 87(1):36–40
Hyacinthe C, De Deurwaerdere P, Thiollier T, Li Q, Bezard E, Ghorayeb I (2015) Blood withdrawal affects iron store dynamics in primates with consequences on monoaminergic system function. Neuroscience 290:621–635
Koppel BS, Brust JC, Fife T, Bronstein J, Youssof S, Gronseth G et al (2014) Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82(17):1556–1563
Kushida C, Martin M, Nikam P, Blaisdell B, Wallenstein G, Ferini-Strambi L et al (2007) Burden of restless legs syndrome on health-related quality of life. Qual Life Res Int J Qual Life Asp Treat Care Rehab 16(4):617–624
Lanza G, Bachmann CG, Ghorayeb I, Wang Y, Ferri R, Paulus W (2017) Central and peripheral nervous system excitability in restless legs syndrome. Sleep Med 31:49–60
Lee HB, Hening WA, Allen RP, Kalaydjian AE, Earley CJ, Eaton WW et al (2008) Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci 20(1):101–105
Li X, Allen RP, Earley CJ, Liu H, Cruz TE, Edden RA et al (2016) Brain iron deficiency in idiopathic restless legs syndrome measured by quantitative magnetic susceptibility at 7 tesla. Sleep Med 22:75–82
Limousin N, Flamand M, Schroder C, Charley Monaca C (2018) French consensus: treatment of newly diagnosed restless legs syndrome. Rev Neurol 174(7–8):515–521
Megelin T, Ghorayeb I (2017) Cannabis for restless legs syndrome: a report of six patients. Sleep Med 36:182–183
Meiser J, Weindl D, Hiller K (2013) Complexity of dopamine metabolism. Cell Commun Signal 11(1):34
Mendiguren A, Aostri E, Pineda J (2018) Regulation of noradrenergic and serotonergic systems by cannabinoids: relevance to cannabinoid-induced effects. Life Sci 192:115–127
Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J (2005) CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14(1):43–47
Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lesperance P (1997) Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Movement Disorders 12(1):61–65
Moreno E, Chiarlone A, Medrano M, Puigdellivol M, Bibic L, Howell LA et al (2018) Singular location and signaling profile of adenosine A2A-Cannabinoid CB1 receptor heteromers in the dorsal striatum. Neuropsychopharmacology 43(5):964–977
Nelson C, Erikson K, Pinero DJ, Beard JL (1997) In vivo dopamine metabolism is altered in iron-deficient anemic rats. J Nutr 127(12):2282–2288
Ohayon MM, O’Hara R, Vitiello MV (2012) Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev 16(4):283–295
Ondo WG (2005) Methadone for refractory restless legs syndrome. Movement Disorders 20(3):345–348
Picchietti DL, Bruni O, de Weerd A, Durmer JS, Kotagal S, Owens JA et al (2013) Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group. Sleep Med 14(12):1253–1259
Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE (2004) Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. Movement Disorders 19(6):695–699
Quiroz C, Gulyani S, Ruiqian W, Bonaventura J, Cutler R, Pearson V et al (2016) Adenosine receptors as markers of brain iron deficiency: implications for restless legs syndrome. Neuropharmacology 111:160–168
Saletu M, Anderer P, Saletu-Zyhlarz G, Prause W, Semler B, Zoghlami A et al (2001) Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. Eur Neuropsychopharmacol 11(2):153–161
Salminen AV, Garrett L, Schormair B, Rozman J, Giesert F, Niedermeier KM et al (2017) Meis1: effects on motor phenotypes and the sensorimotor system in mice. Dis Model Mech 10(8):981–991
Silver N, Allen RP, Senerth J, Earley CJ (2011) A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med 12(5):440–444
Starowicz K, Finn DP (2017) Cannabinoids and pain: sites and mechanisms of action. Adv Pharmacol 80:437–475
Trenkwalder C, Chaudhuri KR, Martinez-Martin P, Rascol O, Ehret R, Valis M et al (2015) Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson’s disease (PANDA): a double-blind, randomised, placebo-controlled trial. Lancet Neurol 14(12):1161–1170
Vigil JM, Stith SS, Adams IM, Reeve AP (2017) Associations between medical cannabis and prescription opioid use in chronic pain patients: a preliminary cohort study. PLoS One 12(11):e0187795
Walters AS (1995) Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Movement Disorders 10(5):634–642
Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV et al (2015) Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 313(24):2456–2473
Winkelman JW, Redline S, Baldwin CM, Resnick HE, Newman AB, Gottlieb DJ (2009) Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. Sleep 32(6):772–778
Winkelmann J, Prager M, Lieb R, Pfister H, Spiegel B, Wittchen HU et al (2005) “Anxietas tibiarum”. Depression and anxiety disorders in patients with restless legs syndrome. J Neurol 252(1):67–71
Winkelmann J, Allen RP, Hogl B, Inoue Y, Oertel W, Salminen AV et al (2018) Treatment of restless legs syndrome: evidence-based review and implications for clinical practice (Revised 2017) (section sign). Movement Disorders 33(7):1077–1091
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Ghorayeb, I. (2021). Cannabis for Restless Legs Syndrome. In: Monti, J.M., Pandi-Perumal, S.R., Murillo-Rodríguez, E. (eds) Cannabinoids and Sleep. Advances in Experimental Medicine and Biology, vol 1297. Springer, Cham. https://doi.org/10.1007/978-3-030-61663-2_13
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