# Cannabinoids, the Blood–Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives **Authors:** Shimon Ben-Shabat, Ludmila Yarmolinsky, Nitzan Sharon, Taima Zeadnaa-Aldda, Shir Dayan, Boris Khalfin, Sigal Fleisher-Berkovich PMC · DOI: 10.3390/biom16020225 · Biomolecules · 2026-02-02 ## TL;DR This paper reviews how cannabinoids might help treat neurodegenerative diseases by interacting with the blood-brain barrier and the endocannabinoid system. ## Contribution It systematically explores the interplay between cannabinoids, the blood-brain barrier, and neurodegeneration. ## Key findings - The endocannabinoid system is altered in neurodegenerative diseases. - Phytocannabinoids interact with the blood-brain barrier. - Cannabinoids show therapeutic potential for neurodegeneration. ## Abstract Neurodegenerative diseases are a large and complex group of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and so on, which adversely affect the physical and mental health of millions of people globally. Unfortunately, these diseases currently have no cure; only symptomatic treatment is available. Therefore, there is still a growing interest in using cannabinoids to treat neurodegenerative diseases. This systematic review examines the interrelationship between cannabinoids, the blood–brain barrier, and neurodegeneration, and their mutual effects. The objective of this review is to provide an overview of the endocannabinoid system at the neurovascular interface, the alterations and dysregulation of the ECS in neurodegenerative diseases, the interactions of phytocannabinoids with the blood–brain barrier, and their therapeutic potential in the context of neurodegeneration. The findings may facilitate the targeted application of cannabinoids to address multiple aspects of neurodegenerative diseases. ## Linked entities - **Diseases:** Alzheimer’s disease (MONDO:0004975), Parkinson’s disease (MONDO:0005180), Huntington’s disease (MONDO:0007739), multiple sclerosis (MONDO:0005301) ## Full-text entities - **Genes:** App (amyloid beta precursor protein) [NCBI Gene 54226] {aka Abeta}, Faah (fatty acid amide hydrolase) [NCBI Gene 14073], IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, Htt (huntingtin) [NCBI Gene 15194] {aka C430023I11Rik, Hd, Hdh, IT15}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, Ppara (peroxisome proliferator activated receptor alpha) [NCBI Gene 19013] {aka 4933429D07Rik, Nr1c1, PPAR-alpha, PPARalpha, Ppar}, Cnr2 (cannabinoid receptor 2) [NCBI Gene 57302] {aka CB-2, CB2, CB2C, CNR2C, rCB2}, MGLL (monoglyceride lipase) [NCBI Gene 11343] {aka HU-K5, HUK5, MAGL, MGL}, HMOX1 (heme oxygenase 1) [NCBI Gene 3162] {aka HMOX1D, HO-1, HSP32, bK286B10}, COX8A (cytochrome c oxidase subunit 8A) [NCBI Gene 1351] {aka COX, COX8, COX8-2, COX8L, MC4DN15, VIII}, Dagla (diacylglycerol lipase, alpha) [NCBI Gene 269060] {aka Nsddr}, PPARG (peroxisome proliferator activated receptor gamma) [NCBI Gene 5468] {aka CIMT1, FPLD3, GLM1, NR1C3, PPARG1, PPARG2}, Hcar2 (hydroxycarboxylic acid receptor 2) [NCBI Gene 353250] {aka Gpr109a, Gpr109b, Hm74, Hm74b, Niacr1, Pumag}, CNR1 (cannabinoid receptor 1) [NCBI Gene 1268] {aka CANN6, CB-R, CB1, CB1A, CB1K5, CB1R}, Ptgs2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 29527] {aka COX-2, Cox2, PGHS-2, PHS II, Pghs2}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, AQP4 (aquaporin 4) [NCBI Gene 361] {aka MIWC, MLC4, WCH4, hAQP4}, GFAP (glial fibrillary acidic protein) [NCBI Gene 2670] {aka ALXDRD}, VCAM1 (vascular cell adhesion molecule 1) [NCBI Gene 7412] {aka CD106, INCAM-100}, CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, FAAH (fatty acid amide hydrolase) [NCBI Gene 2166] {aka FAAH-1, FAAH1, PSAB}, Gpr55 (G protein-coupled receptor 55) [NCBI Gene 227326] {aka CTFL, Gm218, Lpir1}, Trpm7 (transient receptor potential cation channel, subfamily M, member 7) [NCBI Gene 679906] {aka Chak, LTrpC-7, Ltrpc7, Trp-plik}, Nos2 (nitric oxide synthase 2, inducible) [NCBI Gene 18126] {aka MAC-NOS, NOS-II, Nos-2, Nos2a, i-NOS, iNOS}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, TPSG1 (tryptase gamma 1) [NCBI Gene 25823] {aka PRSS31, TMT, trpA}, Tgfb1 (transforming growth factor, beta 1) [NCBI Gene 21803] {aka TGF-beta1, TGFbeta1, Tgfb, Tgfb-1}, IL17A (interleukin 17A) [NCBI Gene 3605] {aka CTLA-8, CTLA8, IL-17, IL-17A, IL17, ILA17}, IL37 (interleukin 37) [NCBI Gene 27178] {aka FIL1, FIL1(ZETA), FIL1Z, IL-1F7, IL-1H, IL-1H4}, Tnf (tumor necrosis factor) [NCBI Gene 21926] {aka DIF, TNF-a, TNF-alpha, TNFSF2, TNFalpha, Tnfa}, PPARA (peroxisome proliferator activated receptor alpha) [NCBI Gene 5465] {aka NR1C1, PPAR, PPAR-alpha, PPARalpha, hPPAR}, NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 114548] {aka AGTAVPRL, AII, AVP, C1orf7, CIAS1, CLR1.1}, CNR2 (cannabinoid receptor 2) [NCBI Gene 1269] {aka CB-2, CB2, CX5}, Tjp1 (tight junction protein 1) [NCBI Gene 21872] {aka ZO1}, Il6 (interleukin 6) [NCBI Gene 24498] {aka ILg6, Ifnb2}, MAPT (microtubule associated protein tau) [NCBI Gene 4137] {aka DDPAC, FTD1, FTDP-17, MAPTL, MSTD, MTBT1}, GDNF (glial cell derived neurotrophic factor) [NCBI Gene 2668] {aka ATF, ATF1, ATF2, HFB1-GDNF, HSCR3}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, RHOA (ras homolog family member A) [NCBI Gene 387] {aka ARH12, ARHA, EDFAOB, RHO12, RHOH12}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 7422] {aka L-VEGF, MVCD1, VEGF, VPF}, CLDN5 (claudin 5) [NCBI Gene 7122] {aka AWAL, BEC1, CPETRL1, TMDVCF, TMVCF}, Mgll (monoglyceride lipase) [NCBI Gene 23945] {aka Magl, Mgl}, GPR55 (G protein-coupled receptor 55) [NCBI Gene 9290] {aka LPIR1}, Gpr18 (G protein-coupled receptor 18) [NCBI Gene 110168], NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, NAPEPLD (N-acyl phosphatidylethanolamine phospholipase D) [NCBI Gene 222236] {aka C7orf18, FMP30, NAPE-PLD}, CYCS (cytochrome c, somatic) [NCBI Gene 54205] {aka CYC, HCS, THC4}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 17709], BDNF (brain derived neurotrophic factor) [NCBI Gene 627] {aka ANON2, BULN2}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 4513] {aka COII, MTCO2}, Chrna7 (cholinergic receptor, nicotinic, alpha polypeptide 7) [NCBI Gene 11441] {aka Acra7, alpha7, nAChR7, nAchR}, TRPV1 (transient receptor potential cation channel subfamily V member 1) [NCBI Gene 7442] {aka VR1}, HTR1A (5-hydroxytryptamine receptor 1A) [NCBI Gene 3350] {aka 5-HT-1A, 5-HT1A, 5HT1a, ADRB2RL1, ADRBRL1, G-21}, IL1B (interleukin 1 beta) [NCBI Gene 3553] {aka IL-1, IL1-BETA, IL1F2, IL1beta}, Vegfa (vascular endothelial growth factor A) [NCBI Gene 22339] {aka L-VEGF, Vegf, Vpf}, Nfkb1 (nuclear factor of kappa light polypeptide gene enhancer in B cells 1, p105) [NCBI Gene 18033] {aka NF-KB1, NF-kappaB, NF-kappaB1, p105, p50, p50/p105}, PTGS2 (prostaglandin-endoperoxide synthase 2) [NCBI Gene 5743] {aka COX-2, COX2, GRIPGHS, PGG/HS, PGHS-2, PHS-2}, Cnr1 (cannabinoid receptor 1) [NCBI Gene 25248] {aka CB-R, CB1, CB1R, SKR6R}, Tnf (tumor necrosis factor) [NCBI Gene 24835] {aka RATTNF, TNF-alpha, Tnfa} - **Diseases:** endotoxin (MESH:D012772), MS (MESH:D009103), ALS (MESH:D008113), motor (MESH:D000068079), memory impairments (MESH:D008569), cognitive deficits (MESH:D003072), EAE (MESH:D004681), dry mouth (MESH:D014987), dopaminergic degeneration (MESH:D009410), beta-amyloid (MESH:C000718787), mesial temporal lobe epilepsy (MESH:C566903), ischemic injury (MESH:D017202), agitation (MESH:D011595), encephalomyelitis (MESH:D004679), toxicity (MESH:D064420), striatal degeneration (MESH:C537500), amyotrophic lateral sclerosis (MESH:D000690), epilepsy (MESH:D004827), gliosis (MESH:D005911), motor coordination deficits (MESH:D001259), ischemia (MESH:D007511), neurological disorders (MESH:D009461), excitotoxic damage (MESH:D020263), tachycardia (MESH:D013610), tumor (MESH:D009369), Huntington's disease (MESH:D006816), inflammatory damage (MESH:D018746), neurotoxic (MESH:D020258), AD (MESH:D000544), psychiatric disorders (MESH:D001523), Neuroinflammation (MESH:D000090862), red eyes (MESH:D005134), edema (MESH:D004487), TBI (MESH:D000070642), Parkinsonian inflammation (MESH:D007249), shock (MESH:D012769), spasticity (MESH:D009128), injury to (MESH:D014947), Neurodegeneration (MESH:D019636), diseases (MESH:D004194), mitochondrial dysfunction (MESH:D028361), Alzheimer's and Parkinson's diseases (MESH:D010300), sleep disturbances (MESH:D012893), pain (MESH:D010146) - **Chemicals:** ROS (MESH:D017382), Cannabinoids (MESH:D002186), CBD (MESH:D002185), glucose (MESH:D005947), CBGA (MESH:C100679), Endocannabinoids (MESH:D063388), lipid (MESH:D008055), 3-nitropropionate (MESH:C015392), MPTP (MESH:D015632), LPS (MESH:D008070), nicotine (MESH:D009538), 3,4-dihydroxyphenylalanine (MESH:D004295), 2-AG (MESH:C094503), Delta9-THCA (MESH:C025351), AEA (-), CBDV (MESH:C580853), cannabinolic acid (MESH:C045780), glutamate (MESH:D018698), anandamide (MESH:C078814), CBG (MESH:C037036), GTS-21 (MESH:C088936), Oleamide (MESH:C029407), NO (MESH:D009569), phospholipids (MESH:D010743), water (MESH:D014867), amides (MESH:D000577), PGE2 (MESH:D015232), AA (MESH:D016718), THC (MESH:D013759), prostaglandin (MESH:D011453), resorcinol (MESH:C031389), N-oleoyl-ethanolamine (MESH:C000707817), CORT (MESH:D003345), oxygen (MESH:D010100), N-palmitoyl-ethanolamine (MESH:C005958) - **Species:** Rattus norvegicus (brown rat, species) [taxon 10116], Homo sapiens (human, species) [taxon 9606], Cannabis sativa (species) [taxon 3483], Mus musculus (house mouse, species) [taxon 10090] - **Mutations:** A2A - **Cell lines:** PC12 — Rattus norvegicus (Rat), Rat adrenal gland pheochromocytoma, Cancer cell line (CVCL_0481), bEnd.3 — Mus musculus (Mouse), Transformed cell line (CVCL_0170), hCMEC/D3 — Homo sapiens (Human), Transformed cell line (CVCL_U985), R6/2 — Mus musculus (Mouse), Hybridoma (CVCL_9233) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12938789/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12938789/full.md ## References 156 references — full list in the complete paper: https://tomesphere.com/paper/PMC12938789/full.md --- Source: https://tomesphere.com/paper/PMC12938789