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Volume 23, Issue 5
  • ISSN: 1570-159X
  • E-ISSN: 1875-6190

Abstract

With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms. Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS. Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control. This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs).

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2024-09-13
2025-03-27

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References

  1. McGinleyM.P. GoldschmidtC.H. Rae-GrantA.D. Diagnosis and treatment of multiple sclerosis.JAMA2021325876577910.1001/jama.2020.2685833620411
     [Google Scholar]
  2. FilippiniG. MinozziS. BorrelliF. CinquiniM. DwanK. Cannabis and cannabinoids for symptomatic treatment for people with multiple sclerosis.Cochrane Libr.202255CD01344410.1002/14651858.CD013444.pub235510826
     [Google Scholar]
  3. TorriC.V. BrambillaL. PolitiP.L. ViggianiF. MercurioS. ToniettiS. RonzoniM. CrisafulliS.G. AntozziC. TramacereI. RedemagniC. ConfalonieriP. Nabiximols oromucosal spray in patients with multiple sclerosis-related bladder dysfunction: A prospective study.Mult. Scler. Relat. Disord.20237410471110.1016/j.msard.2023.10471137062198
     [Google Scholar]
  4. WiendlH. SpelmanT. ButzkuevenH. KapposL. TrojanoM. SuR. CampbellN. HoP.R. LicataS. Real-world disability improvement in patients with relapsing–remitting multiple sclerosis treated with natalizumab in the Tysabri Observational Program.Mult. Scler.202127571972810.1177/135245852092686932579430
     [Google Scholar]
  5. Piasecka-StryczyńskaK. KaczyńskiŁ. RolkaM. HomaM. StaśkiewiczW. PaczwaP. WójcikR. KaczorM.P. RejdakK. Systematic review and network meta-analysis (NMA) for cladribine tablets in achieving sustained disability improvement (SDI) in multiple sclerosis.Neurol. Neurochir. Pol.202256648048910.5603/PJNNS.a2022.006836421066
     [Google Scholar]
  6. BrunoA. DolcettiE. CentonzeD. Theoretical and therapeutic implications of the spasticity-plus syndrome model in multiple sclerosis.Front. Neurol.20221280291810.3389/fneur.2021.80291835197915
     [Google Scholar]
  7. ChanA. SilvánC.V. Evidence-based management of multiple sclerosis spasticity with nabiximols oromucosal spray in clinical practice: A 10-year recap.Neurodegener. Dis. Manag.202212314115410.2217/nmt‑2022‑000235377770
     [Google Scholar]
  8. PattiF. ChisariC.G. FernándezÓ. SarrocaJ. Ferrer-PicónE. HernándezV.F. Vila SilvánC. A real‐world evidence study of nabiximols in multiple sclerosis patients with resistant spasticity: Analysis in relation to the newly described ‘spasticity‐plus syndrome’.Eur. J. Neurol.20222992744275310.1111/ene.1541235590453
     [Google Scholar]
  9. FernándezÓ. Costa-FrossardL. Martínez-GinésM. MonteroP. PrietoJ.M. RamióL. The broad concept of “spasticity-plus syndrome” in multiple sclerosis: A possible new concept in the management of multiple sclerosis symptoms.Front. Neurol.20201115210.3389/fneur.2020.0015232256440
     [Google Scholar]
  10. VaneyC. Heinzel-GutenbrunnerM. JobinP. TschoppF. GattlenB. HagenU. SchnelleM. ReifM. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled, crossover study.Mult. Scler.200410441742410.1191/1352458504ms1048oa15327040
     [Google Scholar]
  11. ZajicekJ.P. SandersH.P. WrightD.E. VickeryP.J. IngramW.M. ReillyS.M. NunnA.J. TeareL.J. FoxP.J. ThompsonA.J. Cannabinoids in multiple sclerosis (CAMS) study: Safety and efficacy data for 12 months follow up.J. Neurol. Neurosurg. Psychiatry200576121664166910.1136/jnnp.2005.07013616291891
     [Google Scholar]
  12. BraleyT.J. WhibleyD. AlschulerK.N. EhdeD.M. ChervinR.D. ClauwD.J. WilliamsD. KratzA.L. Cannabinoid use among Americans with MS: Current trends and gaps in knowledge.Mult. Scler. J. Exp. Transl. Clin.202063205521732095981610.1177/205521732095981633014410
     [Google Scholar]
  13. NovotnaA. MaresJ. RatcliffeS. NovakovaI. VachovaM. ZapletalovaO. GasperiniC. PozzilliC. CefaroL. ComiG. RossiP. AmblerZ. StelmasiakZ. ErdmannA. MontalbanX. KlimekA. DaviesP. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis.Eur. J. Neurol.20111891122113110.1111/j.1468‑1331.2010.03328.x21362108
     [Google Scholar]
  14. CollinC. EhlerE. WaberzinekG. AlsindiZ. DaviesP. PowellK. NotcuttW. O’LearyC. RatcliffeS. NovákováI. ZapletalovaO. PikováJ. AmblerZ. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis.Neurol. Res.201032545145910.1179/016164109X1259051868566020307378
     [Google Scholar]
  15. PattiF. MessinaS. SolaroC. AmatoM.P. BergamaschiR. BonavitaS. BrunoB.R. BresciaM.V. CostantinoG.F. CavallaP. CentonzeD. ComiG. CottoneS. DanniM. FranciaA. GajofattoA. GasperiniC. GhezziA. IudiceA. LusG. ManiscalcoG.T. MarrosuM.G. MattaM. MirabellaM. MontanariE. PozzilliC. RovarisM. SessaE. SpitaleriD. TrojanoM. ValentinoP. ZappiaM. Efficacy and safety of cannabinoid oromucosal spray for multiple sclerosis spasticity.J. Neurol. Neurosurg. Psychiatry201687994495110.1136/jnnp‑2015‑31259127160523
     [Google Scholar]
  16. FlacheneckerP. HenzeT. ZettlU.K. Long-term effectiveness and safety of nabiximols (tetrahydrocannabinol/cannabidiol oromucosal spray) in clinical practice.Eur. Neurol.2014721-29510210.1159/00036028524943098
     [Google Scholar]
  17. TurriM. TeatiniF. DonatoF. ZanetteG. TugnoliV. DeottoL. BonettiB. SquintaniG. Pain modulation after oromucosal cannabinoid spray (SATIVEX®) in patients with multiple sclerosis: A study with quantitative sensory testing and laser-evoked potentials.Medicines2018535910.3390/medicines503005929933552
     [Google Scholar]
  18. RussoM. NaroA. LeoA. SessaE. D’AleoG. BramantiP. CalabròR.S. Evaluating Sativex® in neuropathic pain management: A clinical and neurophysiological assessment in multiple sclerosis.Pain Med.2016176pnv08010.1093/pm/pnv08026764336
     [Google Scholar]
  19. LangfordR.M. MaresJ. NovotnaA. VachovaM. NovakovaI. NotcuttW. RatcliffeS. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regimen, in the relief of central neuropathic pain in patients with multiple sclerosis.J. Neurol.2013260498499710.1007/s00415‑012‑6739‑423180178
     [Google Scholar]
  20. ConteA. BettoloC.M. OnestiE. FrascaV. IacovelliE. GilioF. GiacomelliE. GabrieleM. AragonaM. TomassiniV. PantanoP. PozzilliC. InghilleriM. Cannabinoid‐induced effects on the nociceptive system: A neurophysiological study in patients with secondary progressive multiple sclerosis.Eur. J. Pain200913547247710.1016/j.ejpain.2008.05.01418603457
     [Google Scholar]
  21. KaviaR.B.C. De RidderD. ConstantinescuC.S. StottC.G. FowlerC.J. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis.Mult. Scler.201016111349135910.1177/135245851037802020829244
     [Google Scholar]
  22. ManiscalcoG.T. AponteR. BruzzeseD. GuarcelloG. ManzoV. NapolitanoM. MoreggiaO. ChiarielloF. FlorioC. THC/CBD oromucosal spray in patients with multiple sclerosis overactive bladder: A pilot prospective study.Neurol. Sci.20183919710210.1007/s10072‑017‑3148‑629052091
     [Google Scholar]
  23. MusellaA. SepmanH. MandolesiG. GentileA. FresegnaD. HajiN. ConradA. LutzB. MaccarroneM. CentonzeD. Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.Neuropharmacology20147956757210.1016/j.neuropharm.2014.01.00724440366
     [Google Scholar]
  24. ChiurchiùV. van der SteltM. CentonzeD. MaccarroneM. The endocannabinoid system and its therapeutic exploitation in multiple sclerosis: Clues for other neuroinflammatory diseases.Prog. Neurobiol.20181608210010.1016/j.pneurobio.2017.10.00729097192
     [Google Scholar]
  25. CentonzeD. BariM. RossiS. ProsperettiC. FurlanR. FezzaF. De ChiaraV. BattistiniL. BernardiG. BernardiniS. MartinoG. MaccarroneM. The endocannabinoid system is dysregulated in multiple sclerosis and in experimental autoimmune encephalomyelitis.Brain2007130102543255310.1093/brain/awm16017626034
     [Google Scholar]
  26. RossiS. BozzaliM. BariM. MoriF. StuderV. MottaC. ButtariF. CercignaniM. GravinaP. MastrangeloN. CastelliM. MancinoR. NucciC. SottileF. BernardiniS. MaccarroneM. CentonzeD. Association between a genetic variant of type-1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis.PLoS One2013812e8284810.1371/journal.pone.008284824391723
     [Google Scholar]
  27. PryceG. AhmedZ. HankeyD.J.R. JacksonS.J. CroxfordJ.L. PocockJ.M. LedentC. PetzoldA. ThompsonA.J. GiovannoniG. CuznerM.L. BakerD. Cannabinoids inhibit neurodegeneration in models of multiple sclerosis.Brain2003126102191220210.1093/brain/awg22412876144
     [Google Scholar]
  28. TadijanA. VlašićI. VlainićJ. ĐikićD. OršolićN. Jazvinšćak JembrekM. Intracellular molecular targets and signaling pathways involved in antioxidative and neuroprotective effects of cannabinoids in neurodegenerative conditions.Antioxidants20221110204910.3390/antiox1110204936290771
     [Google Scholar]
  29. CorreaF. Hernangómez-HerreroM. MestreL. LoríaF. DocagneF. GuazaC. The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: Evidence for a cross-talk between IL-12p70/IL-23 axis and IL-10 in microglial cells.Brain Behav. Immun.201125473674910.1016/j.bbi.2011.01.02021310228
     [Google Scholar]
  30. HernangómezM. MestreL. CorreaF.G. LoríaF. MechaM. IñigoP.M. DocagneF. WilliamsR.O. BorrellJ. GuazaC. CD200‐CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation.Glia20126091437145010.1002/glia.2236622653796
     [Google Scholar]
  31. LourbopoulosA. GrigoriadisN. LagoudakiR. TouloumiO. PolyzoidouE. MavromatisI. TascosN. BreuerA. OvadiaH. KarussisD. ShohamiE. MechoulamR. SimeonidouC. Administration of 2-arachidonoylglycerol ameliorates both acute and chronic experimental autoimmune encephalomyelitis.Brain Res.2011139012614110.1016/j.brainres.2011.03.02021406188
     [Google Scholar]
  32. KozelaE. LevN. KaushanskyN. EilamR. RimmermanN. LevyR. Ben-NunA. JuknatA. VogelZ. Cannabidiol inhibits pathogenic T cells, decreases spinal microglial activation and ameliorates multiple sclerosis‐like disease in C57BL/6 mice.Br. J. Pharmacol.201116371507151910.1111/j.1476‑5381.2011.01379.x21449980
     [Google Scholar]
  33. Moreno-MartetM. FeliúA. Espejo-PorrasF. MechaM. Carrillo-SalinasF.J. Fernández-RuizJ. GuazaC. de LagoE. The disease-modifying effects of a Sativex-like combination of phytocannabinoids in mice with experimental autoimmune encephalomyelitis are preferentially due to Δ-tetrahydrocannabinol acting through CB1 receptors.Mult. Scler. Relat. Disord.20154650551110.1016/j.msard.2015.08.00126590655
     [Google Scholar]
  34. FeliúA. Moreno-MartetM. MechaM. Carrillo-SalinasF.J. de LagoE. Fernández-RuizJ. GuazaC.A. Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis.Br. J. Pharmacol.2015172143579359510.1111/bph.1315925857324
     [Google Scholar]
  35. MoriF. LjokaC. NicolettiC.G. KusayanagiH. ButtariF. GiordaniL. RossiS. FotiC. CentonzeD. CB1 receptor affects cortical plasticity and response to physiotherapy in multiple sclerosis.Neurol. Neuroimmunol. Neuroinflamm.201414e4810.1212/NXI.000000000000004825520956
     [Google Scholar]
  36. BaioneV. BelvisiD. CorteseA. CettaI. TartagliaM. MillefioriniE. BerardelliA. ConteA. Cortical M1 plasticity and metaplasticity in patients with multiple sclerosis.Mult. Scler. Relat. Disord.20203810149410.1016/j.msard.2019.10149431715502
     [Google Scholar]
  37. StampanoniB.M. IezziE. CentonzeD. Multiple sclerosis: Inflammation, autoimmunity and plasticity.Handb. Clin. Neurol.2022184457470
     [Google Scholar]
  38. HoffmanA.F. HwangE.K. LupicaC.R. Impairment of synaptic plasticity by cannabis, Δ9-THC, and synthetic cannabinoids.Cold Spring Harb. Perspect. Med.2021115a03974310.1101/cshperspect.a03974332341064
     [Google Scholar]
  39. KochG. MoriF. CodecàC. KusayanagiH. MonteleoneF. ButtariF. FioreS. BernardiG. CentonzeD. Cannabis-based treatment induces polarity-reversing plasticity assessed by theta burst stimulation in humans.Brain Stimul.20092422923310.1016/j.brs.2009.03.00120633421
     [Google Scholar]
  40. StampanoniB.M. LeocaniL. ComiG. IezziE. CentonzeD. Can pharmacological manipulation of LTP favor the effects of motor rehabilitation in multiple sclerosis?Mult. Scler.201824790290710.1177/135245851772135828735565
     [Google Scholar]
  41. MoriF. KusayanagiH. NicolettiC.G. WeissS. MarcianiM.G. CentonzeD. Cortical plasticity predicts recovery from relapse in multiple sclerosis.Mult. Scler.201420445145710.1177/135245851351254124263385
     [Google Scholar]
  42. RossiS. FurlanR. ChiaraV.D. MuzioL. MusellaA. MottaC. StuderV. CavasinniF. BernardiG. MartinoG. CravattB.F. LutzB. MaccarroneM. CentonzeD. Cannabinoid CB1 receptors regulate neuronal TNF-α effects in experimental autoimmune encephalomyelitis.Brain Behav. Immun.20112561242124810.1016/j.bbi.2011.03.01721473912
     [Google Scholar]
  43. StampanoniB.M. IezziE. PavoneL. MandolesiG. MusellaA. GentileA. GilioL. CentonzeD. ButtariF. Modeling resilience to damage in multiple sclerosis: Plasticity meets connectivity.Int. J. Mol. Sci.201921114310.3390/ijms2101014331878257
     [Google Scholar]
  44. GajofattoA. CardobiN. GobbinF. CalabreseM. TurattiM. BenedettiM.D. Resting-state functional connectivity in multiple sclerosis patients receiving nabiximols for spasticity.BMC Neurol.202323112810.1186/s12883‑023‑03171‑036991352
     [Google Scholar]
  45. TomassiniV. OnestiE. TinelliE. FrascaV. AntonilliL. AragonaM. LopergoloD. CapuaG. PozzilliC. PantanoP. InghilleriM. Assessing the neurophysiological effects of cannabinoids on spasticity in multiple sclerosis.J. Neurosci. Rehabil.2014121310.17653/2374‑9091.SS0005
     [Google Scholar]
  46. SchwarzK. SchmitzF. Synapse dysfunctions in multiple sclerosis.Int. J. Mol. Sci.2023242163910.3390/ijms2402163936675155
     [Google Scholar]
  47. MandolesiG. BullittaS. FresegnaD. GentileA. De VitoF. DolcettiE. RizzoF.R. StrimpakosG. CentonzeD. MusellaA. Interferon-γ causes mood abnormalities by altering cannabinoid CB1 receptor function in the mouse striatum.Neurobiol. Dis.2017108455310.1016/j.nbd.2017.07.01928757328
     [Google Scholar]
  48. Robledo-MenendezA. VellaM. GrandesP. Soria-GomezE. Cannabinoid control of hippocampal functions: The where matters.FEBS J.202228982162217510.1111/febs.1590733977665
     [Google Scholar]
  49. PetsasN. De GiglioL. González-QuintanillaV. GiulianiM. De AngelisF. TonaF. CarmelliniM. MaineroC. PozzilliC. PantanoP. Functional connectivity changes after initial treatment with fingolimod in multiple sclerosis.Front. Neurol.20191015310.3389/fneur.2019.0015330967828
     [Google Scholar]
  50. RossiS. Lo GiudiceT. De ChiaraV. MusellaA. StuderV. MottaC. BernardiG. MartinoG. FurlanR. MartoranaA. CentonzeD. Oral fingolimod rescues the functional deficits of synapses in experimental autoimmune encephalomyelitis.Br. J. Pharmacol.2012165486186910.1111/j.1476‑5381.2011.01579.x21740406
     [Google Scholar]
  51. MusellaA. MandolesiG. GentileA. RossiS. StuderV. MottaC. SepmanH. FresegnaD. HajiN. PaolilloA. MatareseG. CentonzeD. Cladribine interferes with IL-1β synaptic effects in experimental multiple sclerosis.J. Neuroimmunol.20132641-281310.1016/j.jneuroim.2013.08.00924045165
     [Google Scholar]
  52. MoriF. KusayanagiH. ButtariF. CentiniB. MonteleoneF. NicolettiC.G. BernardiG. Di CantognoE.V. MarcianiM.G. CentonzeD. Early treatment with high-dose interferon beta-1a reverses cognitive and cortical plasticity deficits in multiple sclerosis.Funct. Neurol.201227316316823402677
     [Google Scholar]
  53. TurC. Carbonell-MirabentP. Cobo-CalvoÁ. Otero-RomeroS. ArrambideG. MidagliaL. CastillóJ. Vidal-JordanaÁ. Rodríguez-AcevedoB. ZabalzaA. GalánI. NosC. SalernoA. AugerC. ParetoD. ComabellaM. RíoJ. Sastre-GarrigaJ. RoviraÀ. TintoréM. MontalbanX. Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis.JAMA Neurol.202380215116010.1001/jamaneurol.2022.465536534392
     [Google Scholar]
  54. NazariM. KeshavarzS. RafatiA. NamavarM.R. HaghaniM. Fingolimod (FTY720) improves hippocampal synaptic plasticity and memory deficit in rats following focal cerebral ischemia.Brain Res. Bull.20161249510210.1016/j.brainresbull.2016.04.00427066884
     [Google Scholar]
  55. RussoM. DattolaV. LogiudiceA.L. CiurleoR. SessaE. De LucaR. BramantiP. BramantiA. NaroA. CalabròR.S. The role of Sativex in robotic rehabilitation in individuals with multiple sclerosis.Medicine20179646e882610.1097/MD.000000000000882629145345
     [Google Scholar]
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Disease-Modifying Symptomatic Treatment (DMST) Potential of Cannabinoids in Patients with Multiple Sclerosis
Curr. Neuropharmacol. 23, 503 (2025); https://doi.org/10.2174/011570159X329058240820070701
/content/journals/cn/10.2174/011570159X329058240820070701
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  • Article Type:     Research Article
Keyword(s): Cannabinoid; disease modifying therapies; multiple sclerosis; neuroprotective effects; spasticity plus syndrome; symptomatic therapies

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