Cannabinoids, the Blood–Brain Barrier, and Neurodegeneration: Mechanisms, Dysregulation, and Therapeutic Perspectives
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel; yludmila@post.bgu.ac.il (L.Y.); kaunitz@post.bgu.ac.il (N.S.); taima@post.bgu.ac.il (T.Z.-A.); shirdayan09@gmail.com (S.D.); boriskh83@gmail.com (B.K.)
*Correspondence: sbs@bgu.ac.il (S.B.-S.); fleisher@bgu.ac.il (S.F.-B.); Tel.: +972-54-599-1056 (S.B.-S.); +972-8-6477377 (S.F.-B.)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.
1. Introduction
The comprehensive analysis of the influence of natural compounds on the proper functioning of living organisms and their use in disease treatment is one of the most important and advanced areas in medical sciences today. Particular attention is paid in these studies to cannabinoids. The classification of cannabinoids includes three large groups according to their origin: endocannabinoids, synthetic cannabinoids, and phytocannabinoids [1].
Endocannabinoids (or endogenous cannabinoids) are endogenous lipid signaling molecules that activate cannabinoid receptors [2].
Phytocannabinoids were first discovered in Cannabis sativa L. [3]; later, these compounds were also found in Rhododendron species, some legumes, the genus Radula, and some fungi [4]. From a chemical viewpoint, phytocannabinoids are meroterpenoids with a resorcinol core containing isoprenyl, alkyl, or aralkyl side chains (Figure 1) as a general rule [5]. More than 120 phytocannabinoids were identified in Cannabis sativa L. The parental molecule is cannabigerolic acid (CBGA) (Figure 1) from which many cannabinoids are synthesized; the dominant compounds tend to be Δ9-tetrahydrocannabinolic acid (Δ9-THCA) and cannabinolic acid (CBDA) [6].
More than 450 synthetic cannabinoids are known; they are structurally similar to phytocannabinoids and endocannabinoids [7].
Pharmacological studies have shown that cannabinoids possess anti-inflammatory, immunosuppressive, and antioxidant properties [8]. From the research and clinical perspectives, these properties are very important with regard to neurodegenerative diseases because the fundamental mechanisms underlying their development include aging, neuroinflammation, oxidative stress, mitochondrial dysfunction, apoptosis, protein disorders, and so on [9]. These diseases are a large and complex group of neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, amyotrophic lateral sclerosis, and so on, which adversely affect the physical and mental health of millions of people globally.
Although cannabinoids are promising agents for the treatment of neurodegenerative diseases [10,11], they may cause various short- and long-term side effects [12]. There is still a growing interest in the use of cannabinoids in this regard because neurodegenerative diseases have no cure at present, and only symptomatic treatment is available [8]. Progress in the development of cannabinoid-based drugs is impossible without a deep knowledge of the endocannabinoid system (ECS), cannabinoids, the blood–brain barrier (BBB), and neurodegeneration.
Therefore, understanding how cannabinoids, the blood–brain barrier, and neurodegeneration are interrelated and affect one another is vitally important for treating neurodegenerative diseases. Another important issue in this review is the endocannabinoid system. Its dysregulation plays a pivotal role in the pathophysiology of neurodegenerative diseases by facilitating neuroprotection and modulating the immune response. This review aims to provide an overview of the ECS at the neurovascular interface, alterations and dysregulation in the ECS during neurodegenerative diseases, phytocannabinoids interactions with the BBB, and their therapeutic potential in the context of neurodegeneration. The findings could inform the targeting of cannabinoids for various aspects of these multifactorial diseases.
2. Methods
We performed a structured literature search using several electronic databases (Science Direct, Google Scholar, PubMed, and Scopus). The search strategy was designed to determine the relationship between the ECS, BBB, and cannabinoids in the context of neurodegeneration on the basis of multiple criteria sorting methods [13]. The keywords were searched alone or in combination with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis. The manuscripts published between 2000 and 2025 were chosen for possible inclusion in the present work. Narrative reviews, case reports or case series with 5 patients or fewer, letters, and editorials were excluded. A set of original research publications was obtained, and a comprehensive analysis of the interrelationship between cannabinoids, the blood–brain barrier and neurodegeneration were performed.
4. Dysregulation of the Endocannabinoid System in Neurodegenerative Diseases
Mechanisms involving endocannabinoid levels, the upregulation and degradation of CB1 and CB2 receptors upregulation and degradation, and the main catabolic enzymes, namely two types of hydrolases—fatty acid amidohydrolases and monoacylglycerol lipase—play an important role in the pathophysiology of neurodegenerative diseases [51]. Various molecular processes (suppressing pro-inflammatory factors, promoting neuronal survival, shifting polarization of microglial cells, and so on) are modulated by CB1 [52]. CB2 may regulate inflammatory responses and maintain immune homeostasis [53].
It is known that the increased content of endocannabinoids is initiated by direct stimulation of the receptor by an endocannabinoid agonist or antagonist, and as a result, inhibitors of FAAH and MAGL raise the excitability of the ECS by decreasing the hydrolysis of endocannabinoids [54]. Although the comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on neurodegeneration remain poorly understood, the majority of experimental studies on the basis of models of multiple sclerosis, Alzheimer’s, Parkinson’s, and Huntington’s diseases demonstrate their protective effect against neurodegenerative diseases [55,56]. Thus, FAAH and MAGL are promising therapeutic targets due to their roles in modulating endocannabinoid levels and in the regulation of neuroinflammation and neuroprotection.
Figure 3 illustrates the interactions between hydrolase inhibition and various pathways. According to Figure 3, the effects of repeated FAAH inhibition have been investigated on the following biochemical indicators: the corticosterone (CORT) [57], the cyclooxygenase (COX) [58], prostaglandin E2 (PGE2) [59], nitric oxide (NO) [60], 3,4-dihydroxyphenylalanine (DOPA) [61] and brain-derived neurotrophic factor (BDNF) [62]. Figure 3 shows that short-term pharmacological inhibition of MAGL influences the CORT level [63], cytokine expression [64], DOPA response [65] and Glial cell line-derived neurotrophic factor (GDNF) expression [66].
In addition, GDNF is of decisive importance for the maintenance of the nigrostriatal system [67] and an upregulation of GDNF acts against neurotoxicity in Parkinson’s disease [68].
CB1 and CB2 modulations cause a decrease in microglial activation and inflammatory cytokines IL-2 and IL-6 in Alzheimer’s disease [69].
The inhibition of MAGL and FAAH is a potential possibility to suppress inflammation, prevent neurodegeneration, improve synaptic plasticity, and boost spatial learning [70]. The comparable effects of FAAH, MAGL, and dual FAAH/MAGL inhibitors on neurodegeneration remain poorly understood.
It is interesting that MAGL but not FAAH inactivation inhibits neuroinflammation and allows for avoidance of neurodegeneration in a mouse model of Parkinson’s disease [65]. MAGL inhibition promotes normalization of arachidonic acid (AA) and 2-AG dynamics in various models of multiple sclerosis, Parkinson’s disease, and Alzheimer’s disease [71]. Perhaps inhibition of MAGL adjusts prostaglandin production and diminishes inflammation in neurodegenerative diseases [72].
Overexpression of CB2 and FAAH enzymes has been found after postmortem analysis of brains from Alzheimer’s disease patients, and increased amyloid beta plaque formations have been recorded [73].
According to the in vivo study, the MAGL inhibitor is not able to change cognitive deficits associated with sporadic Alzheimer’s disease, but it improves some biochemical properties [74]. Systemic administration of MAGL/FAAH inhibitory compounds improves memory impairments in rodent models of Alzheimer’s disease [75].
Future studies should focus on the catalytic mechanisms and regulation of both hydrolases to develop effective inhibitors.
6. Neuroprotective and Therapeutic Roles of Phytocannabinoids
Neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, share a prominent component of chronic neuroinflammation [94,95].
Microglial cells and astrocytes play key roles in regulating neuroinflammatory processes [96]. Glial cells also contribute to the formation and maintenance of the impermeable blood–brain barrier, which prevents potentially toxic blood-borne substances from entering the brain [97].
Cannabinoids can beneficially modulate these neuroimmune responses and may contribute to the preservation of BBB integrity under inflammatory conditions, thereby supporting their potential relevance in neuroprotective strategies rather than establishing direct therapeutic efficacy [23,98,99,100].
At this neurovascular interface, the endocannabinoid system becomes particularly relevant. Endogenous cannabinoids such as anandamide and 2-AG are synthesized locally by endothelial cells, astrocytes, and microglia, enabling rapid modulation of tight junction dynamics, vascular tone, and leukocyte trafficking [23,98,99,100].
In models of LPS-induced and ischemia-related inflammation, cannabinoid treatment preserves tight-junction structure and reduces BBB permeability. Furthermore, CBD or selective CB2 agonists decrease endothelial expression of ICAM-1 and VCAM-1, thereby limiting leukocyte adhesion and trans-endothelial migration, while increasing trans-endothelial electrical resistance, a functional marker of tight-junction reinforcement. These findings suggest that CBD may exert protective and beneficial effects in inflammatory diseases of the nervous system, including epilepsy, psychiatric disorders, and neurodegenerative conditions. These vascular effects involve not only receptor activation but also suppression of NF-κB-dependent transcriptional programs within endothelial cells. Additionally, cannabinoids modulate the RhoA/ROCK signaling pathway, a pathway that regulates cytoskeletal tension and tight junction stability, providing a mechanistic link between ECS activation and structural BBB preservation [80].
During inflammatory activation, microglial CB2 receptor expression increases, allowing cannabinoids to selectively modulate pro-inflammatory (M1-like) phenotypes while sparing or enhancing protective, phagocytic functions (M2-like). This selective immunomodulation distinguishes cannabinoids from broad immunosuppressants [101,102].
Accordingly, microglial activation is a regulatable process and has emerged as a therapeutic target in neurodegenerative diseases. Chronic and dysregulated microglial activation is a hallmark of several neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, where sustained production of pro-inflammatory cytokines contributes to progressive neuronal damage. Nicotinic acetylcholine receptors (nAChRs) expressed in neurons, as well as microglia and astrocytes, participate in the cholinergic anti-inflammatory pathway activated by vagus nerve stimulation [103,104,105]. This pathway has been implicated in limiting neuroinflammation-driven neurodegeneration by suppressing innate immune activation within the CNS. Experimental studies show that stimulating these receptors attenuates LPS-induced cytokine production in macrophages and microglial cells [106,107,108]. For example, activation of the α7 nAChR by nicotine markedly reduces the ischemia-induced expression of TNF-α and IL-1β, indicating α7 nAChR-dependent suppression of microglial activation. Given the overlap between ischemia-induced inflammation and inflammatory mechanisms observed in chronic neurodegenerative diseases, modulation of α7 nAChR signaling may represent a potential strategy for attenuating microglia-mediated neurodegeneration [109].
Building on this concept, selective α7 nAChR agonists, such as GTS-21, demonstrate anti-inflammatory and neuroprotective effects in mouse models of neuroinflammation. In LPS-induced Parkinsonian inflammation and in MPTP-based PD models, GTS-21 reduces the expression of iNOS and pro-inflammatory cytokines. At the same time, it increases the levels of the anti-inflammatory mediator TGF-β. These effects coincide with the suppression of NF-κB signaling and the activation of PPARγ-dependent pathways. In MPTP-treated mice, GTS-21 alleviates motor deficits and reduces microglial activation, linking cholinergic modulation of microglia to structural and functional neuroprotection in dopaminergic degeneration [95].
Astrocytes maintain CNS homeostasis by regulating cerebral blood flow, supporting neuronal metabolism, and modulating neuronal function through cytokine secretion [97]. Under inflammatory conditions, astrocytes become reactive and produce molecules that inhibit axonal regeneration, while releasing cytokines and chemokines that shape CNS immune responses [110]. Astrocytes also prevent glutamate-mediated excitotoxicity by rapidly clearing synaptic glutamate, thus avoiding excessive glutamate receptor activation, pathological Ca2+ influx, and ionic imbalance [97,111]. In neurodegenerative diseases such as Alzheimer’s disease, Huntington’s disease, and amyotrophic lateral sclerosis, failure of this astrocyte-dependent glutamate buffering system promotes sustained excitotoxic stress and progressive neuronal loss [112].
Reactive astrocytes comprise functionally distinct subtypes. Pro-inflammatory A1 astrocytes are induced by microglia-derived cytokines and exhibit neurotoxic properties, impairing neuronal development and promoting the death of both neurons and oligodendrocytes, whereas A2 astrocytes support neuronal survival and repair mechanisms. Modulation of astrocytic phenotypes therefore represents a potential mechanism through which cannabinoids may influence neuroinflammatory environments in diseases such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis [113]. CB1 has an important role in modulating stress responses in vivo models. Understanding the beneficial endocannabinoid-related adaptations within the BBB can represent a promising strategy for developing innovative therapies for neurodegenerative diseases [22].
Cannabinoids modulate excitotoxicity by regulating glutamate release through CB1 receptors on presynaptic terminals. CB1 signaling controls excessive neurotransmitter release partly by influencing voltage-gated calcium channels. Additionally, CB1-mediated inhibition of mitochondrial respiration in axonal terminals may reduce metabolic stress during inflammatory insults, thereby providing further protection against excitotoxic damage [114,115].
Neuroinflammation also induces excessive production of reactive oxygen and nitrogen species, creating oxidative stress that damages membrane lipids, proteins, nucleic acids, and mitochondria, ultimately promoting cell death. In multiple sclerosis (MS), cannabinoids may protect against oxidative injury by limiting nitric oxide production in macrophages/microglia and astrocytes [116,117,118,119].
Phytocannabinoids, particularly CBD, reduce the generation of reactive species while enhancing endogenous antioxidant defenses and mitochondrial resilience. CBD activates the Nrf2 pathway and upregulates downstream targets, such as heme oxygenase-1 (HO-1), thereby strengthening the cell’s antioxidant capacity. In the brain, Nrf2 further contributes to neuroprotection by mitigating neuroinflammation triggered by harmful stimuli commonly observed in neurodegenerative diseases. Through modulation of pathways such as the NLRP3 inflammasome, Nrf2 plays a central defensive role against oxidative stress, gliosis, protein aggregation, and inflammatory damage, thereby reinforcing the neuroprotective potential of CBD in disorders such as Alzheimer’s and Parkinson’s disease. By stabilizing mitochondrial membrane potential and reducing cytochrome c-dependent caspase activation, CBD further attenuates apoptosis under conditions of oxidative and neuroinflammatory stress, adding an additional mechanistic layer to its neuroprotective profile [120,121,122].
Accumulating evidence indicates that phytocannabinoids, such as CBG, Δ9-THC, and CBD, interact with multiple targets in the ECS and beyond. In addition to CB1 and CB2 receptors, they modulate TRP channels (TRPV, TRPA, and TRPM), GPR55, voltage-gated calcium and sodium channels, and transcriptional regulators, including NF-κB [123,124]. Through modulation of NF-κB and these ion channels, phytocannabinoids can attenuate neuroinflammatory signaling and reduce the expression of pro-inflammatory cytokines and chemokines, processes that are critically involved in the pathogenesis of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. NF-κB serves as a key regulator of immune function by driving the expression of pro-inflammatory genes, including those encoding cytokines and chemokines, and by controlling the activation, differentiation, and effector functions of innate immune cells and inflammatory T cells [125].
Another important non-cannabinoid target is PPARγ, which represses pro-inflammatory gene expression and counteracts NF-κB activity. PPARα and PPARγ agonism is therefore of growing interest as a therapeutic mechanism through which phytocannabinoids may act in neuroinflammatory conditions [123,124,126,127,128]. In this context, CBD acts as a PPARγ agonist, attenuating NF-κB signaling. PPARγ enhances lipid accumulation in both mice and humans and is involved in the pro-apoptotic and tumor-regressive effects of CBD. CBD induces an increase in COX-2–dependent prostaglandin levels, promoting PPARγ translocation to the nucleus and consequently triggering apoptotic cell death. PPARγ represents a critical factor in CBD’s ability to modulate inflammatory responses [129,130].
Based on the role in modulating neuroinflammation and stabilizing the BBB, both preclinical and clinical studies have evaluated phytocannabinoids in neurodegenerative disorders, such as AD, PD, Huntington’s disease, ALS and MS. Studies show that Δ9-THC reduces pro-inflammatory cytokines, including IFN-γ and TNF-α, and suppresses T-cell proliferation, whereas CBD and CBG reduce inflammation and pain and improve motor function [131,132].
In AD models, studies demonstrated that various phytocannabinoids, including CBD, THC, and CBG, reduce neuroinflammation and protect against intracellular amyloid-β (Aβ) toxicity, promote the breakdown of aggregates, decrease the expression of TNF-α, COX-2, and IL-6, and contribute to improved cognitive performance. Moreover, CBD was found to reduce oxytosis, a cell death pathway associated with oxidative stress. Mechanistically, phytocannabinoids exert these neuroprotective effects not only through classical CB1 and CB2 receptor-mediated signaling but also by modulating oxidative stress responses, mitochondrial function, and proteostasis pathways. In particular, CBD and cannabigerol (CBG) have been shown to enhance cellular antioxidant defenses, reduce the accumulation of reactive oxygen species (ROS), and preserve mitochondrial bioenergetics in neurons exposed to Aβ-induced toxicity. Additionally, these compounds enhance protein clearance mechanisms, thereby mitigating proteotoxic stress and reducing the accumulation of misfolded Aβ aggregates, which may support neuronal survival and function. Collectively, these findings indicate that phytocannabinoids act through a multifaceted neuroprotective network, making them promising candidates for therapeutic intervention in Alzheimer’s disease [133,134,135,136]. In a recent study, CBG, CBDV, and acidic cannabinoids have been demonstrated to have neuroprotective properties in PC12 cells; these compounds inhibit amyloid β-evoked neurotoxicity [137]. Another computational and biochemical research investigating Alzheimer’s disease in vivo revealed that repeated treatment with CBDA and CBGA may prevent aggregation of β-amyloid fibrils and restore the expression level of TRPM7 according to the β-arrestin assay on GPR109A and qPCR [138].
In Parkinson’s disease models, CBD reduces dopaminergic degeneration, shifts microglial activity toward an anti-inflammatory state, and improves motor performance. Additionally, CBD increases TRPV1 expression in astrocytes, which may support repair processes [139].
In models of Huntington’s disease, Δ9-THC has been shown to attenuate motor coordination deficits and reduce both striatal degeneration and the accumulation of huntingtin protein aggregates in R6/2 transgenic mice. Cannabigerol (CBG) has demonstrated neuroprotective effects in multiple Huntington’s disease models, including a 3-nitropropionate-induced model and transgenic mice. In the 3-nitropropionate model, CBG significantly decreased neuronal death; lowered the levels of pro-inflammatory mediators, including COX-2, inducible nitric oxide, TNF-α, and IL-6; and improved motor performance. In transgenic mice, CBG treatment produced modest improvements in motor coordination, partially normalized genes dysregulated in Huntington’s disease, and enhanced the expression of anti-inflammatory mediators, including PPARγ [140,141,142].
In ALS models, CBD and CBG reduce neuroinflammation and suppress the NF-κB pathway while increasing IL-10 and IL-37 expression [143].
In multiple sclerosis models, a combined treatment of CBD and THC suppresses T cells, reduces the secretion of pro-inflammatory cytokines (IL-17, IFN-γ, and TNF-α), and increases the secretion of anti-inflammatory cytokines (IL-4, IL-10, and TGF-β). These effects are dependent on CB1/CB2 receptors [89].
Most evidence comes from preclinical models, but no animal models of neurodegenerative diseases fully imitate human diseases. Therefore, clinical trials are extremely important in pharmaceutical applications of phytocannabinoids. To systematically illustrate the evidence obtained from these studies, Table 2 summarizes their findings from clinical studies in various neurodegenerative diseases, including the type of cannabinoid, study model, main effects, and mechanisms [90].
Collectively, clinical evidence indicates that phytocannabinoids such as CBD and Δ9-THC may provide symptomatic relief in neurodegenerative disorders, including improvements in pain, spasticity, sleep disturbances, and agitation (Table 2). Nevertheless, well-controlled, large-scale clinical trials are required to determine their long-term safety, efficacy, and potential role beyond symptomatic management [90].
7. Side Effects
Adverse effects of cannabinoid intake on almost all body systems are well known; their durations and severity depend on many factors, for example, age, sex, concentrations of cannabinoids, and so on [152]. Acidic cannabinoids show mild side effects, while neutral cannabinoids are associated with severe side effects, including psychoactivity [153]. For example, side effects of THC may include various psychoactive effects, tachycardia, dry mouth, red eyes, etc. [154].
It is mostly unclear whether cannabinoids crossing the BBB pose a specific risk to the BBB. In fact, it has been demonstrated in cell and animal models that THC induces BBB damage, which is partly associated with CB1 activation and triggering the oxidative stress response [17].
All adverse events reported in clinical trials are reflected in Table 2.
8. Future Directions: Targeting the BBB-ECS Axis
Another key challenge is the strong context dependence of ECS signaling within the NVU. The effects of ECS components on BBB integrity vary depending on the cell type. For example, astrocytic CB1 protects against claudin-5 loss during stress [22], while endothelial CB1 induces oxidative stress and tight junction breakdown [17]. This highlights the importance of studying ECS modulation in a cell-specific and time-dependent manner.
Despite growing interest in the role of phytocannabinoids and the ECS in regulating the BBB, important gaps in knowledge remain. Most mechanistic studies on BBB regulation have focused on CBD and THC. In contrast, acidic phytocannabinoids such as THCA, CBDA, and CBGA have been studied mainly for their pharmacokinetics and general neuroprotective effects [81,92,155]. Multicellular BBB models and in vivo studies are necessary to better understand how these acidic compounds affect tight junction organization, transporter function, and neurovascular signaling, particularly given their lower penetration through the BBB compared to neutral counterparts.
Future research should consider combined strategies that target both ECS components and related pathways involved in neuroinflammation and oxidative stress, such as PPAR signaling. Since MAGL and FAAH inhibitors, CB2 activation, and phytocannabinoids like CBD and CBG influence overlapping molecular pathways, rational polypharmacology may provide better protection of BBB integrity and neuronal function than single-target approaches. Moreover, ECS and phytocannabinoids may indirectly influence BBB permeability, NVU function, and neurodegeneration [8]. Changes in microbial metabolites, alteration of circulating cytokine profiles, and modulation of peripheral immune cells may indirectly alleviate BBB stress and enhance barrier integrity and function [156]. This mechanism remains incompletely investigated regarding the endocannabinoid system and phytocannabinoids in neurodegenerative disease models.
The known neurodegenerative disease models require further improvement because the existing models may not allow for the complicated interaction between cellular pathologies and their associated clinical syndromes.
9. Conclusions
All the above findings refer to the important roles of the ECS, cannabinoids, BBB, and neurodegeneration in the pathophysiology of neurodegenerative diseases. The various neuroprotective properties of cannabinoids through many cellular and molecular pathways in neurodegenerative diseases have been demonstrated. CBD and THC have been researched much more extensively than many other phytocannabinoids. For example, CBG, CBDV, and acidic cannabinoids have great potential for the treatment of neurodegenerative diseases due to their chemical diversity and ability to interact with various targets. However, they have not been investigated deeply.
Permeability assays, in vivo BBB evaluation studies, and formulation strategies to improve delivery are urgently required to define the full therapeutic promise of THCA, CBDA, and other acidic forms of cannabinoids at the BBB.
Outstanding progress has been made in understanding the multifaceted activities of cannabinoids through various mechanisms. However, major gaps still remain, particularly with regard to the imperfect preclinical models and limited clinical studies, with difficulties due to inconsistent methods and small sample sizes. Future investigations of endocannabinoid hydrolytic enzymes should give priority to considering the kinetics of enzyme-catalyzed hydrolysis and search for novel inhibitors or activators; modulating CB1 and CB2 for re-generating balance in neurons and glial cells; reducing degenerative and inflammatory damage; and elucidating the potential mechanisms of cannabinoids for maintaining and increasing BBB integrity.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
No new data were created or analyzed in this study. Data sharing is not applicable to this article.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
Abbreviations
The following abbreviations are used in this manuscript: Δ9-THCAΔ9-Tetrahydrocannabinolic acid2-AG2-ArachidonoylglycerolAβAmyloid-βAEAAnandamideADAlzheimer’s diseaseALSAmyotrophic lateral sclerosisAQP4Aquaporine-4BBBBlood–brain barrierBDNFBrain-derived neurotrophic factorCB1Cannabinoid receptor 1CB2Cannabinoid receptor 2CBDACannabidiolic acidCBDVCannabidivarinCBGCannabigerolCBGACannabigerolic acidCNSCentral nervous systemCORTCorticosteroneCOX-2Cyclooxygenase-2DAGLαDiacylglycerol lipase αDOPA3,4-dihydroxyphenylalanineEAEExperimental autoimmune encephalomyelitisECSEndocannabinoid systemFAAHFatty acids amide hydrolaseGDNFGlial cell line-derived neurotrophic factorGPR55G-protein-coupled receptor 55GTS-213-(2,4-dimethoxy-benzylidene) anabaseineHO 1Heme oxygenase 1ICAM-1Intercellular adhesion molecule 1IFN-γInterferon gammaIL-2Interleukin-2IL-6Interleukin-6iNOSInducible nitric oxide synthaseLDHLactate dehydrogenaseLPSLipopolysaccharideM1-likeMacrophages 1-likeM2-likeMacrophages 2-likeMAGLMonoacylglycerol lipaseMAGLiMonoacylglycerol lipase inhibitorMSMultiple SclerosisMPTP1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinenAChRsNicotinic acetylcholine receptorsNAPE-PLDN-acyl phosphatidylethanolamine phospholipase DNF-κBNuclear Factor kappa-light-chain-enhancer of activated B cellsNONitric OxideNVUNeurovascular unitOGDOxygen-glucose deprivationPDParkinson’s diseasePEAN-palmitoyl-ethanolaminePGE2Prostaglandin E2PPARγPeroxisome proliferator-activated receptor γRhoARas homolog family member AROCKRho-associated, coiled-coil containing protein kinaseTBITraumatic brain injuryTJTight junctionTNF-αTumor necrosis factor-αTRPTransient receptor potentialTRPATransient receptor potential subfamily ATRPMTransient receptor potential melastatinTRPVTransient receptor potential vanilloidVCAM-1Vascular cell adhesion protein 1VE-cadherinVascular endothelial cadherinVEGFVascular endothelial growth factorZO-1Zonula occludens-1
| Component | Expression at NVU | Main Effects on BBB Structure and Function | Clinical Findings |
|---|---|---|---|
| CB1 receptor | Brain endothelial cells, pericytes, and glial cells [23,25,38] | Modulates tight junction proteins, vascular tone, and oxidative stress [23,38] | CB1 can either preserve or disrupt the BBB; CB1 activation led to downregulation of tight junction proteins [17,26]. Other studies reported that CB1 is upregulated in response to BBB disruption and is responsible for BBB integrity [22,25]. |
| CB2 receptor | Brain endothelial cells, pericytes [23,25], and glial cells [23,47]. | Reduces leukocyte adhesion, preserves tight junctions, and limits the release of neurotoxic mediators [21,23]. | CB2 activation attenuates BBB leakage and neuroinflammation [21]. |
| GPR55 | Brain endothelial cells [27] and glial cells [48]. | GPR55 activation leads to transient disruption and reorganization of tight and adherent junction proteins in brain microvascular endothelial cells [27]. | Activation of GPR55 reduces BBB integrity and increases BBB permeability in vivo [27]. |
| Endocannabinoids (AEA, 2-AG) | Produced by brain endothelial cells, astrocytes, and microglia [15]. | Under basal conditions, it may impair endothelial repair, and under injury, it increases claudin-5 and ZO-1 [15,32,39]. | Reduced AEA/2-AG levels with elevated degrading enzymes associated with BBB breakdown after traumatic brain injury [42]. AEA/2-AG treatment limits inflammation and preserves BBB integrity in vitro [15,39]. |
| Synthetic enzymes (NAPE-PLD, DAGLα/β) | Brain endothelial and glial cells [22,43,47,49]. | increases ECS tone in the brain; DAGLα-derived 2-AG maintains VE-cadherin and ZO-1 in brain endothelial cells [44]. | DAGLα inhibition compromises endothelial monolayers and facilitates BBB disruption [44]. |
| Degrading enzymes (FAAH, MAGL) | Brain endothelial, pericytes, and glial cells [22,46,50]. | Control 2-AG/AEA and arachidonic acid levels; preserved BBB integrity via anti-oxidative and anti-inflammatory pathways. | MAGL inhibitor protects BBB integrity in an ischemic model [46]; FAAH inhibitor protects the permeability of brain microvascular endothelial cells in vitro [50]. |
| Endocannabinoid-like mediators (PEA, OEA, oleamide) | Brain endothelial and glial cells [29,30,33,34]. | PEA and OEA have anti-inflammatory effects on BBB via PPAR signaling; PEA enhances the effects AEA and 2-AG [35]; oleamide inhibits gap-junction communication in glial and microvascular endothelial cells [29,31,32,33,34]. | PEA and OEA enhance BBB integrity in vitro and in vivo [33,34]. Oleamide increases BBB permeability in vivo [31,32]. |
| Disease | Phytocannabinoid | Study Design | Sample Size | Dose | Duration | Phytocannabinoid Effects | Endocannabinoids Modulation | Clinical Findings | Adverse Effects |
|---|---|---|---|---|---|---|---|---|---|
| Multiple Sclerosis | Δ9-THC + CBD (Sativex) [144] | Randomized, double-blind, placebo-controlled crossover trial | 57 patients | Capsules: 2.5 mg THC + 0.9 mg CBD standardized (escalated to max ~30 mg THC/day) | 14 days | May reduce spasticity, alleviates pain, improves sleep | CBD may increase anandamide levels | CB1/CB2-mediated anti-inflammatory modulates glutamatergic neurotransmission | Minor adverse events slightly more frequent in active phase; generally mild toxicity symptoms |
| Alzheimer’s Disease | Δ9-THC/Dronabinol [145] | Randomized, double-blind, placebo-controlled, crossover | 12 patients | Oral Dronabinol 2.5 mg twice daily | 6 weeks | Increased body weight overall; improved behavior and reduced disturbed behavior more during dronabinol periods | - | CB1/CB2 agonist | Seizure (one patient) |
| Nabilone [146] | Randomized, double-blind, placebo-controlled | 39 patients | Oral 0.5–1 mg/day | 6 weeks | Reduces agitation | - | Improvement in agitation scores compared with placebo | Mild sedation, somnolence | |
| CBD [147,148] | Randomized, double-blind, placebo-controlled | 13 patients | Oral 600 mg/day | 4 weeks | Potential neuro-protective and anti-inflammatory effects | Increase anandamide via FAAH inhibition and transport restriction | Antioxidant, anti-inflammatory effects, | Mild gastrointestinal upset, fatigue | |
| Huntington’s Disease | Δ9-THC + CBD (Sativex) [149] | Randomized, double-blind, placebo-controlled, crossover pilot clinical trial | 24 patients | Oromucosal spray: up to 12 sprays/day | 12 weeks | No significant motor, cognitive, behavioral or functional improvement vs. placebo | Not specifically evaluated Increase anandamide via FAAH inhibition and transport restriction | Trial showed safety and tolerability but no significant symptomatic benefit at the prescribed dose | No severe adverse events; well tolerated |
| Parkinson’s Disease | CBD [150] | Exploratory double-blind trial | 21 patients | Oral 150–400 mg/day | Improved non-motor symptoms: sleep disturbances, psychosis; no significant motor improvement | Possible anandamide enhancement, anti-inflammatory | Non CB1/CB2-mediated; antioxidant, anti-inflammatory | Mild somnolence, diarrhea | |
| CBD [151] | Open-label trial | 6 patients | Oral 150–400 mg/day | 4 weeks | Reduced psychosis and agitation | Improvement in psychotic symptoms without worsening motor function | No serious adverse events |