cbd oil for neurodegenerative disorders

From Cannabis sativa to Cannabidiol: Promising Therapeutic Candidate for the Treatment of Neurodegenerative Diseases

Cannabis sativa, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects. Besides Δ9-tetrahydrocannabinol that is the principal psychoactive constituent of Cannabis, cannabidiol (CBD) is the most abundant nonpsychoactive phytocannabinoid and may represent a prototype for anti-inflammatory drug development for human pathologies where both the inflammation and oxidative stress (OS) play an important role to their etiology and progression. To this regard, Alzheimer’s disease (AD), Parkinson’s disease (PD), the most common neurodegenerative disorders, are characterized by extensive oxidative damage to different biological substrates that can cause cell death by different pathways. Most cases of neurodegenerative diseases have a complex etiology with a variety of factors contributing to the progression of the neurodegenerative processes; therefore, promising treatment strategies should simultaneously target multiple substrates in order to stop and/or slow down the neurodegeneration. In this context, CBD, which interacts with the eCB system, but has also cannabinoid receptor-independent mechanism, might be a good candidate as a prototype for anti-oxidant drug development for the major neurodegenerative disorders, such as PD and AD. This review summarizes the multiple molecular pathways that underlie the positive effects of CBD, which may have a considerable impact on the progression of the major neurodegenerative disorders.

Introduction

Oxidative stress (OS) plays a crucial role in aging and occurs manly when the activity of the anti-oxidants enzymes is not sufficient to counterbalance the generation of reactive oxygen species (ROS). In the latter condition, high production of ROS can alter the structure of proteins, lipids, nucleic acids, and matrix components leading to programmed cell death (Cassano et al., 2016). Different tissues present different susceptibility to OS. The central nervous system (CNS) is extremely sensitive to this type of damage for several reasons. To this regard, the CNS has a low level of antioxidant enzymes, a high content of oxidizable substrates, and a large amount of ROS produced during neurochemical reactions (Trabace et al., 2004; Uttara et al., 2009). In addition to several other environmental or genetic factors, OS contributes to neurodegeneration since free radicals attack neural cells. Therefore, neurons suffer a functional or sensory loss during the neurodegenerative process. Even if oxygen is indispensable for life, an unbalanced metabolism and an excess production of ROS ends up in a series of pathological conditions, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and many other neural disorders. Free radicals cause lesions to protein and DNA, activate inflammatory process and subsequent cell apoptosis (Cassano et al., 2012).

In the last years, there is an urgent need to discover new drug targets that can effectively combat cell alteration caused by the stress of cell membranes. In this perspective, the endocannabinoid (eCB) system has attracted considerable interest due to the current interplay between eCB and different redox-dependent signaling pathways. The two well-characterized eCBs are N-arachidonoyl-ethanolamine or anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which are synthesized on demand in response to elevations of intracellular calcium (Howlett et al., 2002; Di Marzo et al., 2005) and respectively metabolized by fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MAGL) (Piomelli, 2003; Di Marzo, 2008; Kunos et al., 2009). Cannabinoid (CB) receptors exist in two different subtypes: type 1 (CB1) and type 2 (CB2) (Matsuda et al., 1990; Munro et al., 1993; Howlett et al., 2002). The CB1 receptors, first cloned in 1990, are widely distributed in the body and in the CNS are distributed at the level of basal ganglia, cerebellum, hippocampus, caudate nucleus, putamen, hypothalamus, amygdala, and spinal cord (Matsuda et al., 1990). The CB2 receptors, cloned in 1993, are mainly located in cells of the immune system with high density in the spleen, T lymphocytes, and macrophages (Munro et al., 1993). Their anatomical distribution correlates them to the actions for which they are responsible: the activation of the CB1 receptors has euphoric effects and an antioxidant, antiemetic, analgesic, antispasmodic, and appetite stimulating actions. As for CB2 receptors, their stimulation is attributable to the anti-inflammatory and immunomodulatory actions of CB (Cassano et al., 2017).

Converging evidence strongly suggests that eCBs act as retrograde synaptic messengers (Kano et al., 2002; Freund et al., 2003). This phenomenon is initiated postsynaptically by an elevation of cytoplasmic calcium concentration that induces the production and release into the synaptic space of eCBs. Thereafter, eCBs activate CB1 receptors at presynaptic levels and block the release from the terminals of neurons of different transmitters, such as gamma-aminobutyric acid (GABA), glutamate, dopamine (DA), noradrenaline, serotonin, and acetylcholine (Howlett et al., 2002; Pertwee and Ross, 2002; Szabo and Schlicker, 2005). These mechanisms mediated by the activation of presynaptic CB1 receptors are termed depolarization-induced suppression of inhibition (DSI) and excitation (DSE), respectively when are involved the inhibitory (GABA) or excitatory (glutamate) synaptic transmissions (Kano et al., 2002; Freund et al., 2003). Likewise, CB2 receptors can modulate the production and function of certain inflammatory cytokines at multiple levels by activating the immune cells and modulating their migration both within and outside the CNS (Freund et al., 2003; Walter and Stella, 2004). Antioxidant enzymes can be modulated by eCBs, not only acting on the CB1 and CB2 receptors, but also through the transient receptor potential vanilloid-1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPAR-alpha), and the orphan receptors N-arachidonyl glycine receptor or G-protein-coupled receptors 18 (GPR18) GPR19 and GPR55 (Piomelli, 2003; McHugh et al., 2010; Howlett et al., 2011; McHugh, 2012). Therefore, the direct and/or indirect modulation of pathways through which the eCBs damper the OS may represent a promising strategy for reducing the damage caused by a redox imbalance (Gallelli et al., 2018). Moreover, antioxidants are now seen as a convincing therapy against severe neurodegeneration, as they have the ability to fight it by blocking the OS. Diet and medicinal herbs are an important source of antioxidants. The recognition of antioxidant therapy upstream and downstream of OS has proven to be an effective tool to improve any neuronal damage as well as to eliminate free radicals. Antioxidants have a wide field of application and can prevent OS interacting with the metal ions, which play an important role in the build-up of neuronal plaque (Uttara et al., 2009).

In the last decade there are increasing evidences that secondary plant metabolites, extracted from medicinal herbs, may represent lead compounds for the production of medications against inflammation and OS, protecting from neuronal cell loss (Giudetti et al., 2018). Among these medicinal herbs, Cannabis sativa, commonly known as marijuana, contains a pool of secondary plant metabolites with therapeutic effects (Gugliandolo et al., 2018). In this context, cannabidiol (CBD) the nonpsychotropic CB extract from Cannabis sativa may represent a prototype for anti-inflammatory drug development for those human pathologies where both the inflammation and OS play a key role to their etiology and progression (Izzo et al., 2009). To this regard, therapies that effectively combat disease progression are still lacking in the field of neurodegenerative disorders, and mostly with AD. CBD, which modulates the eCB system, but has also CB receptor-independent mechanism, seems to be a prototype for anti-inflammatory drug development.

Therefore, the present review summarizes the main molecular mechanisms through which CBD exerts its beneficial effects that may have a considerable impact on the progression of the major neurodegenerative disorders.

Cannabis sativa

The medical and psychotropic effects of Cannabis sativa have been well known since long time. A multitude of secondary metabolites was extracted from this plant and most of them were used for therapeutic purpose by many cultures. So far more than 400 chemical compounds have been isolated from Cannabis sativa and among them more than 100 terpeno-phenol compounds named phytocannabinoids have been detected (Mechoulam and Hanus, 2000; Mechoulam et al., 2007). As such Cannabis sativa can be regarded as a natural library of unique compounds. The most abundant phytocannabinoid is the Δ9-tetrahydrocannabinol (delta-9-THC), responsible for the psychotropic effect associated with Cannabis consumption, and then the nonpsychoactive constituent CBD and cannabigerol (CBG) (Mechoulam and Hanus, 2000; Mechoulam et al., 2007; Gugliandolo et al., 2018). Table 1 shows the list of the most abundant nonpsychoactive phytocannabinoids isolated from Cannabis sativa. Phytocannabinoids mimic the effects of eCBs that regulate the transmission of nerve impulses in some synapses of the nerve pathways, causing in particular a reduction in the release of signals between the cells (Piomelli, 2003).

Table 1

Most abundant nonpsychoactive phytocannabinoids isolated from Cannabis sativa: chemical structures and pharmacological actions.

Phytocannabinoids Mechanisms Effects References
CB2 inverse agonist Anti-inflammatory effects Thomas et al., 2005
CB1, CB2 antagonist Antispasmodic effect
FAAH inhibition Reduces FAAH expression in the inflamed intestine Ligresti et al., 2006
TRPA1 agonist Analgesic effects De Petrocellis et al., 2008
TRPM8 antagonist Analgesic effects.
Potential role in prostate carcinoma
TRPV1 agonist Antipsychotic and analgesic effects
Adenosine uptake competitive inhibitor Anti-inflammatory effects Carrier et al., 2006
PPARγ agonist Vasorelaxation and stimulation of fibroblasts into adipocytes O’Sullivan et al., 2009
5HT1A agonist Anti-ischemic and anxiolytic properties Campos and Guimarães, 2008
Resstel et al., 2009
Ca 2+ channel Neuroprotective and antiepileptic properties Drysdale et al., 2006
Ryan et al., 2009
Suppressor of tryptophan degradation Potential role in pain, inflammation and depression Jenny et al., 2009
CB1 antagonist Increases central inhibitory neurotransmission Thomas et al., 2005
Dennis et al., 2008
Ma et al., 2008
CB2 partial agonist Stimulates mesenchymal stem cells Scutt and Williamson, 2007
TRPV1 agonist Potential role in analgesia Ligresti et al., 2006
TRPA1 agonist De Petrocellis et al., 2008
TRPM8 antagonist
TRPA1 partial agonist Potential role in analgesia De Petrocellis et al., 2008
TRPM8 antagonist
TRPA1 partial agonist De Petrocellis et al., 2008
TRPM8 antagonist Potential role in analgesia
TRPV1 agonist Ligresti, A., et al., 2006
COX-2 inhibitor Potential role in inflammation Takeda et al., 2008

Due to its high lipophilicity and its affinity for lipid membranes, delta-9-THC was supposed to bind non-specifically variety of cell membranes modifying their fluidity rather than to activate a specific receptor (Hillard et al., 1985). Later this first hypothesis was completely discarded and was demonstrated that delta-9-THC exerts its effects by combining with a selective receptor (Devane et al., 1988; Howlett et al., 1990; Matsuda et al., 1990). In fact, many authors have demonstrated that delta-9-THC exerts its psychoactive effects acting on CB1 receptors, whereas CDB and CBG, two nonpsychoactive CBs, have low affinity for both CB1 and CB2 receptors and inhibit FAAH, resulting in increased levels of eCBs, which in turn further activate the CB1 receptor (Devane et al., 1988; Howlett et al., 1990; Matsuda et al., 1990; Appendino et al., 2011). Among the nonpsychoactive phytocannabinoids, most of the evidences have focused on CBD, which possesses a high antioxidant and anti-inflammatory activity, together with neuroprotective, anxiolytic and anticonvulsant properties (Pellati et al., 2018).

Mechanisms of CBD Action

After delta-9-THC, CBD is the second most abundant phytocannabinoids and is one of the major nonpsychoactive CB constituents in the plant of Cannabis sativa representing up to 40% of Cannabis extract. Adams and colleagues first isolated the CBD, while Mechoulam and colleagues analyzed its structure and stereochemistry (reviewed in Pertwee, 2006). Therapeutically CBD is already available alone and in formulation with delta-9-THC (Booz, 2011). In particular, a drug containing only CBD (Epidiolex) is used for children affected by epilepsy resistant to other treatments, as well as in combination (1:1 ratio) with delta-9-THC (CBD/delta-9-THC, Sativex/Nabiximols) is currently used to treat the spasticity observed in patients affected by multiple sclerosis (Pertwee, 2008; Devinsky et al., 2016). Compared to delta-9-THC, CBD possess a better safety profile and it is well tolerated when administered at animals and patients even at high doses (up to 1,500 mg/day) (Bergamaschi et al., 2011). In fact, authors demonstrated that CBD did not alter cardiovascular parameters, body temperature, psychomotor, and psychological functions, as well as did not induce catalepsy like delta-9-THC (Bergamaschi et al., 2011). Unlike delta-9-THC, CBD does not target directly the CB receptors and this characteristic may justify its better safety profile compared to delta-9-THC (Pertwee, 2006; Thomas et al., 2007).

Although the pharmacodynamics of CBD is not fully clarified, different evidences have been accumulated showing that CBD seems to act throughout different pathways. To this regard, although CBD shows much lower affinity than delta-9-THC for CB1 and CB2 receptors, it is able to antagonize CB1/CB2 receptor agonists in vitro at reasonably low concentrations (nanomolar range) (Thomas et al., 2007). In particular, it has been shown by in vitro studies that CBD is able to act as CB1/CB2 receptors inverse agonist an action that underlies its antagonism of CP55940 and R-(+)-WIN55212 at the CB1/CB2 receptor (Thomas et al., 2007). It has been hypothesized that the anti-inflammatory actions of CBD might be due to its ability to act as a CB2 receptor inverse agonist (Pertwee, 2006). Besides CB receptors, CBD has been profiled also towards other pharmacological substrates. To this regard, CBD showed also affinity to the peroxisome proliferation-activated receptors (PPARs), which are a family of ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily. In humans, there are three PPAR isoforms PPARα, PPARβ/δ, and PPARγ that are encoded by separate genes and are differently expressed in organs and tissues (Michalik et al., 2006). CBD seems to activate the transcriptional activity of PPARγ, which play a primary role in the regulation of adipocyte formation, insulin sensitivity and activation of inflammatory response (O’Sullivan, 2007; O’Sullivan and Kendall, 2010; Hind et al., 2016; O’Sullivan, 2016). To this regard, CBD activates PPARγ receptors leading to a lower expression of proinflammatory genes, which were inhibited by PPARγ antagonists (Esposito et al., 2007; Esposito et al., 2011; O’Sullivan, 2016).

Moreover, CBD exerts a more potent antioxidant effects than other antioxidants, such as ascorbate or α-tocopherol, in in vitro study where cortical neurons were treated with toxic concentrations of glutamate (Hampson et al., 1998; Campos et al., 2016).

The neuroprotective effect was present regardless of whether the insult was due to the activation of N-methyl-D-aspartate (NMDA) receptor, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, or kainate receptors and, more interestingly, it was not mediated by CB receptors since the CB antagonist was unaffected (Hampson et al., 1998). The latter result suggests that CBD may be a potent antioxidant without psychotropic side effects, which are mediated by the direct action on CB receptors.

The anti-inflammatory effect of CBD is also mediated by the adenosine A2A (A2A) receptor whose activation dampers the immune system, leading to a reduction of the antigen presentation, immune cell trafficking, immune cell proliferation, production of the proinflammatory cytokine, and cytotoxicity (Magen et al., 2009). In fact, it has been shown that CBD enhances A2A receptor signaling by the inhibition of cellular update of an adenosine transporter leading to anti-inflammatory and antioxidant effects (Carrier et al., 2006). Likewise, CGS-21680, which is an agonist of the A2A receptor, mimics the actions of CBD that were suppressed by an A2A antagonist (i.e. ZM241,385) (Martín-Moreno et al., 2011).

The CBD neuroprotective property seems to be due also to the activation of 5-hydroxytryptamine subtypes 1A (5-HT1A) receptors, which are located in pre- and post-synaptic membranes in several brain regions (Hoyer et al., 1986). Russo and colleagues first demonstrated that CBD is able to activate the 5-HT1A receptors (Russo et al., 2005). Further support to this first observation was given by a recent study where the authors found that the effect of CBD was blocked by WAY-100135, a selective 5-TH1A receptor antagonist (Galaj et al., 2019).

Finally, it has been demonstrated that CBD has a direct effect on mitochondria (da Silva et al., 2018). To this regard, it has been widely accepted that mitochondrial dysfunction can contribute to neurodegeneration due to the overproduction of ROS and iron accumulation (Mills et al., 2010; Serviddio et al., 2011; Cassano et al., 2012; Cassano et al., 2016; Romano et al., 2017). In particular, iron overload induces several mitochondrial alterations, such as increased mitochondrial DNA (mtDNA) deletions and reduction of epigenetic mtDNA modulation, mitochondrial ferritin levels, and succinate dehydrogenase activity, which may altogether alter cellular viability leading to neurodegenerative process (da Silva et al., 2018). Interestingly, all these iron-induced mitochondrial alterations were completely reversed by CBD, which promotes neural cell survival (da Silva et al., 2018). Moreover, doxorubicin, a broad-spectrum chemotherapeutic drug, induces a dose-dependent cardiotoxicity through the dysregulation of various metabolic signaling pathways, including mitochondrial dysfunction (Hao et al., 2015). In particular, doxorubicin reduces the activity of myocardial mitochondrial complexes (I and II) and glutathione peroxidase leading to an increase of ROS generation (Hao et al., 2015). Interestingly, CBD significantly attenuated doxorubicin-induced cardiotoxicity and cardiac dysfunction by improving mitochondrial complex I activity and enhancing mitochondrial biogenesis (Hao et al., 2015).

Since CBD targets multiple substrates, it may be a good candidate as a multimodal drug for the major neurodegenerative disorders, such as PD and AD. Figure 1 shows the effects of CBD in PD and AD.

Effect of cannabidiol (CBD) in Parkinson’s disease and Alzheimer’ disease (AD). CBD antagonizes the action of cannabinoid receptors (CB1, CB2) acting as a reverse agonist and negative allosteric modulator of both receptors. CBD also inhibits fatty acid amide hydrolase (FAAH), resulting in increased levels of endocannabinoids (ECs). ECs activate the anti-oxidant and anti-inflammatory effects that are partially mediated by the actions of the CBD of transient receptor potential cation channel subfamily V member 1 (TRPV1) [1]. CBD binds the peroxisome proliferator-activated receptors (PPARs), antagonizes the action of nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), and reduces the expression of proinflammatory enzymes such as inducible nitric oxide synthases (iNOS), cyclooxygenase-2 (COX-2), and proinflammatory cytokines [2]. Activation of PPARγ by modulating the expression of proinflammatory mediators such as nitric oxide (NO), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 6 (IL-6), iNOS, and COX-2 [3]. The CBD downregulates the β- and γ-secretase genes leading to a reduction in amyloid-β (Aβ) production [4]. CBD is able to reduce the oxidative stress (OS) through the attenuation of mitochondrial dysregulation and reactive oxygen species (ROS) generation or by the decrease of the expression of several ROS generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoforms [5]. The stimulation of transient receptor potential vanilloid-1 (TRPV1) by CBD can activate phosphoinositide 3-kinases/protein kinase B (PI3K/Akt) signaling, which in turn inhibits glycogen synthase kinase 3 β (GSK-3β) by phosphorylation of Ser9, thus reducing tau phosphorylation [6]. CBD reduces the activity of p-GSK-3β, the active phosphorylated form of GSK3-β, and causes an increase in the Wnt/β-catenin pathway. The activation of this pathway can protect against OS and Aβ neurotoxicity in AD [7].

CBD and PD

PD is a progressive neurodegenerative disorder characterized manly by motor alterations, such as akinesia, bradykinesia, tremors, postural instability, and rigidity. Although the etiology of PD is still largely elusive, its pathophysiology is characterized by loss of midbrain substantia nigra DA neurons and overwhelming evidence indicates that OS is a central factor in PD pathophysiology (Hirsch et al., 1988; Branchi et al., 2010; Aureli et al., 2014). It has been demonstrated in animal model of PD that CBD exerts a neuroprotective effect as antioxidant compound acting through a mechanism that is CB receptor-independent (Fernández-Ruiz et al., 2013). In fact, in 6-hydroxydopamine-lesioned mice CBD was able to significantly reduce the DA depletion and to attenuate the OS increasing the expression of Cu,Zn-superoxide dismutase (SOD), which is an important endogenous mechanism that defences cell against OS (Fernández-Ruiz et al., 2013; Martinez et al., 2015). The latter evidence indicates that CBs having antioxidant CB receptor-independent properties attenuate the neurodegeneration of nigrostriatal dopaminergic fibers occurring in PD (García-Arencibia et al., 2007). This thesis is reinforced by the observation that CBD reduces the neuronal cell death in the striatum occurring after the administration of 3-nitropropionic acid (3NP), an inhibitor of mitochondrial complex II. In particular, the authors demonstrated that 3NP administration causes a reduction of both GABA levels and striatal atrophy of the GABAergic neurons as indicated by a depletion of mRNA levels of proenkephalin (PENK), substance P (SP), and neuronal-specific enolase (NSE). Moreover, the inhibition of mitochondrial complex II induced by 3NP reduces the mRNA expression of superoxide dismutase-1 (SOD-1) and -2 (SOD-2), which are endogenous defences against the OS. Interestingly, after 3NP administration CBD can completely abolish the atrophy of the GABAergic neurons and significantly increase the mRNA levels of SOD-2, as well as attenuate the reduction of mRNA levels of SOD-1 and PENK. Differently, after 3NP administration the administration of arachidonyl-2-chloroethylamide (ACEA) or HU-308, respectively agonist of CB1 and CB2 receptor, did not revert the striatal atrophy of the GABAergic neurons, as well as did not restore the endogenous defences against the OS induced by 3NP (Sagredo et al., 2007). Taken together, these results suggest that CBD exerts a neuroprotective role on the GABAergic neurons that project from the striatum to the substantia nigra and further confirm that its mechanism is CB receptor-independent (Sagredo et al., 2007). Furthermore, in another study authors explored whether CBD was able to attenuate the pathological symptoms of PD modulating the GPR55. In particular, mice were treated for 5 weeks with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTPp), which induced motor function impairment and loss of tyrosine hydroxylase-positive neurons and DA levels in the brain. This chronic mouse model of PD was treated with abnormal-CBD (Abn-CBD), a synthetic CBD isomer and GPR55 agonist. Authors found that the key features of PD induced by MPTPp were prevented by the pharmacological treatment, suggesting that the activation of GPR55 may be a good strategy for the treatment of PD (Celorrio et al., 2017).

CBD and AD

AD is the most common form of dementia affecting elderly people and its pathology is characterized by the accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles (NFTs) in the brain (Querfurth and LaFerla, 2010).

Although the etiology of AD appears to be linked to a multitude of mechanisms, inflammation seems to play a crucial role in its pathogenesis (Bronzuoli et al., 2018; Scuderi et al., 2018). Expected benefits of current therapies are limited (Sabbagh, 2009; Neugroschl and Sano, 2010), so that there is pressing demand for discovering new treatments able to slow disease progression or prevent its onset.

In this contest, the anti-inflammatory properties of CBD were evaluated by both in vitro and in vivo studies in an animal model of Aβ-induced neuroinflammation (Iuvone et al., 2004; Esposito et al., 2006; Esposito et al., 2007; Esposito et al., 2011). In particular, authors demonstrated that CBD reduces the tau protein hyperphosphorylation through the inhibition of Wingless-type MMTV integration site family member (Wnt) pathways and significantly attenuates all the markers of the Aβ-induced neuroinflammation, including the glial fibrillary acidic protein (GFAP) and inducible nitric oxide synthase (iNOS) protein expression, nitrite production, and interleukin 1 β (IL-1β) (Iuvone et al., 2004; Esposito et al., 2006; Esposito et al., 2007; Iuvone et al., 2009; Esposito et al., 2011). CBD pre-treatment induces a reduction of ROS production, lipid peroxidation, caspase-3 levels, and DNA fragmentation in PC12 cells stimulated by Aβ, an in vitro model of AD (Iuvone et al., 2004; Bedse et al., 2014; Gallelli et al., 2018).

The beneficial effects of CBD were further confirmed by another study where mice were chronically treated (for 3 weeks) with CBD after been injected intracerebroventricularly with fibrillar Aβ (Martín-Moreno et al., 2011). CBD counteracts the Aβ-induced microglial activation, the production of proinflammatory cytokine tumor necrosis factor α (TNF-α) and ameliorates the memory alterations observed in a spatial memory task (Martín-Moreno et al., 2011).

Moreover, Aβ can gradually accumulate in mitochondria, where it can cause reduction of both activity of the respiratory chain complexes and the rate of oxygen consumption leading to a free radical generation and oxidative damage (Caspersen et al., 2005; Lin and Beal, 2006; Manczak et al., 2006; Cassano et al., 2012). To this regard, CBD is able to counteract mitochondrial alterations by the reduction of ROS production induced by both the Aβ and nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase (NOX) (Hao et al., 2015; Vallée et al., 2017).

It is well know that tau hyperphosphorylation, mostly at serine (Ser) or threonine (Thr) residues, plays a crucial role in the pathogenesis of AD, thereby molecules that reduce phospho-tau aggregates may represent a good candidate for the AD treatment. To this regard, it has been demonstrated that CBD reduces the expression of genes, which encode kinases (GSK-3β, CMK, and MAPK) responsible for aberrant tau phosphorylation, leading to a reduction of tau hyperphosphorylation and subsequent NFT formation (Libro et al., 2016). Likewise, CBD activates the PI3K/Akt signaling through the TRPV1, which is able to inhibit the kinase GSK-3β, thereby decreasing tau phosphorylation (Libro et al., 2016). Finally, CBD downregulates β- and γ-secretase genes leading to a reduction of Aβ production (Libro et al., 2016).

Conclusion

The present review provided evidence that the nonpsychoactive phytocannabinoids CBD could be a potential pharmacological tool for the treatment of neurodegenerative disorders; its excellent safety and tolerability profile in clinical studies renders it a promising therapeutic agent.

The molecular mechanisms associated with CBD’s improvement in PD and AD are likely multifaceted, and although CBD may act on different molecular targets all the beneficial effects are in some extent linked to its antioxidant and anti-inflammatory profile, as observed in in vitro and in vivo studies. Therefore, this review describes evidence to prove the therapeutical efficacy of CBD in patients affected by neurodegenerative disorders and promotes further research in order to better elucidate the molecular pathways involved in the therapeutic potential of CBD.

Author Contributions

All authors have contributed to the writing, design, and preparation of figures. The senior authors TC and GS have carried out coordination of efforts.

Funding

This article was published with a contribution from the University of Foggia.

CBD For Neurodegeneration: How CBD Protects The Brain As We Age

Neurodegeneration is an umbrella term used to describe any progressive loss of neuron function.

CBD helps protect the brain from natural degeneration in four key ways — antioxidant, anti-inflammatory, immune-modulation, and sleep-support.

Article By

Neurodegenerative disorders are conditions involving a loss of neuron function in the brain and spinal cord. [1]

As neurons are lost, brain function begins to suffer. This produces problems with memory, concentration, attention, muscle coordination, and language. There are many causes of neurodegeneration, but the main risk factor is age.

Can CBD offer support for chronic neurodegenerative disorders?

Learn how CBD is used to support neurodegenerative disorders, and what the research says about its efficacy.

MEDICALLY REVIEWED BY

Carlos G. Aguirre, M.D., Pediatric Neurologist

Updated on October 20, 2021

Table of Contents
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The Benefits of CBD Oil For Brain Health

Neurodegenerative disorders are characterized by a gradual loss of neurons in particular regions of the nervous system. This cell loss causes a decline in cognitive ability and accounts for most of the symptoms experienced with this condition.

How CBD Protects the Brain & Neurons

  • Reducing brain inflammation
  • Preventing T-cell migration across the blood-brain barrier (prevents autoimmunity)
  • Antioxidant support (protects the DNA from damage)
  • Alleviates anxiety
  • May relieve depression
  • May improve muscle control & alleviate muscle tremors
  • My promote recovery of damaged neurons

CBD For Degenerative Brain Disorders

Cannabis may support neurodegenerative disorders including:

  • Alzheimer’s disease
  • Parkinson’s disease
  • Multiple sclerosis (MS)
  • Huntington’s Disease
  • Prion disease (minor improvement)
  • Lou Gehrig’s Disease (ALS)
  • Spinocerebellar Ataxia (SCA)
  • Spinal Muscular Atrophy (SMA)

1. Alzheimer’s Disease

Alzheimer’s disease is the most common form of neurodegeneration. It involves the buildup of toxic metabolites (TAU proteins or beta-amyloid plaque) around the neurons. Eventually, this results in neuron death and gradual cognitive debility. Alzheimer’s disease, like most other neurodegenerative disorders, is associated with excessive neuroinflammation [11, 12].

CBD offers benefits to this condition primarily through its anti-inflammatory effects.

2. Parkinson’s Disease

Parkinson’s disease is a neurodegenerative disorder affecting the basal ganglia where dopamine is manufactured. The result is a gradual loss of dopamine in the brain, causing muscle tremors, mood changes, and a gradual loss of cognitive function.

Like Alzheimer’s disease, Parkinson’s is considered to rely on excessive inflammatory processes in the brain [11, 12].

CBD, therefore, offers relief from this condition through its anti-inflammatory and neuroprotective actions.

3. Multiple Sclerosis (MS)

Multiple sclerosis is an autoimmune-driven neurodegenerative disorder. Widespread neuroinflammation causes immune cells to attack the myelin sheath on the nerve cells, causing a gradual loss of neuron function.

CBD is very beneficial to this condition through its immunomodulatory and anti-inflammatory effects — both of which are primary factors involved with the progression of MS [15].

Additionally, CBD may provide direct benefits to some of the most common side-effects of MS, including muscle spasticity [16] and loss of bladder control [17].

4. Huntington’s Disease

Huntington’s disease is a neurodegenerative disorder with similar characteristics to Alzheimer’s disease. It’s a genetic disorder involving dysfunction in the gene encoding for a protein called huntingtin. People with Huntington’s disease manufacture huntingtin proteins that are too long. They fracture into smaller pieces and become tangled around the neurons — leading to their gradual death. As Huntington builds up, it causes widespread inflammation throughout the brain and loss of cognitive function over time.

There is no cure for Huntington’s disease, but CBD has been shown to offer significant benefits — slowing progression and alleviating many of the most common symptoms [14].

5. Creutzfeldt-Jakob Disease (CJD) and Other Prion Diseases

Prion diseases such as CJD aren’t common but bring devastating side effects as the disease progresses. It involves a misfolded, protease-resistant protein (PrPres) entering the brain and replicating. Being resistant to protease means that the brain cells cannot break down and remove this protein from the brain. Therefore, as these proteins replicate and build up in the brain, they begin to interfere with healthy brain function. Currently, there’s no cure for prion diseases.

Although inflammation is a primary factor involved with prion disease progression, CBD has only been shown to have minor benefits on the condition by resisting the buildup of PrPres [13].

6. Amyotrophic Lateral Sclerosis (ALS)

Lou Gehrig’s Disease (ALS) is a neurodegenerative disease causing gradual — and ultimately fatal — disruption in signals controlling voluntary muscles throughout the body.

There is no cure for ALS, but CBD has been shown to offer significant benefits.

7. Spinocerebellar Ataxia (SCA)

SCA is a progressive, inherited neurodegenerative disease affecting the cerebellum — the part of the brain associated with coordination and muscle movement. There is no cure for the disease, and it’s often fatal.

Treatment is focused on alleviating symptoms such as muscle tremors, depression, and insomnia — all of which CBD is well-known to help.

8. Spinal Muscular Atrophy (SMA)

SMA is a rare neurodegenerative disorder affecting the motor neurons controlling the muscles. Eventually, the disease causes loss of muscle function and muscle wasting. Like many other neurodegenerative disorders, the condition is caused by a dysfunction in producing a particular protein in the brain. Over time, these dysfunctional proteins build-up, resulting in the death of the neurons. There is no cure for this condition.

It’s unclear whether CBD is beneficial to those with SMA. The majority of side-effects of this condition involve muscle weakness — something CBD isn’t thought to improve.

How to Use CBD Oil For Brain Health

Tips for Getting the Most Out of Using CBD for Neurodegenerative Disorders:

  1. Use a full-spectrum extract (THC also offers benefits for these conditions)
  2. Incorporate improvements of diet and lifestyle choices at the same time as CBD supplementation
  3. If there is an environmental cause (such as heavy metal exposure), make sure this is removed immediately
  4. Be consistent with dosing — it can take up to three months before any changes are experienced when it comes to neurodegenerative disorders

What’s Are The Best CBD Products For Brain Health?

Neurodegenerative disorders are a combination of many different neurological and systemic issues working together to produce a gradual loss of neurons.

Therefore, treating these conditions isn’t as straightforward as just addressing one of these issues at a time — it relies on addressing several of them at the same time.

CBD oils and other cannabis products should, therefore, be combined with other treatments and lifestyle and dietary changes for best results.

So, when searching for the best oils for neurodegenerative disorders, there are two things to consider:

  1. Has the CBD product been proven to be free from contaminants such as heavy metals or pesticides?
  2. Does the potency of the CBD product match the recommended dose? In the case of neurodegenerative disorders, this usually means using a high-potency extract.

It’s also useful to opt for a full-spectrum CBD extract rather than an isolate if you want to leverage the neuroprotective benefits of some of the other cannabinoids. However, if this isn’t possible, or you’ve decided you like a company selling CBD isolates, that’s okay. It will still work but just isn’t the best CBD oil for the job.

What Dose Of CBD Should I Use For Neurodegenerative Disease?

Most of the research involving CBD and other cannabinoids for neurodegenerative disorders involve very high doses — usually in the realm of around 500 mg per day.

Although it may not be totally necessary to use a dose this high, it does suggest that the heavy end of the dosage range is the most beneficial.

Use our CBD oil dosage calculator below to find the best dose for you based on your weight.

Remember to start low and build up over time. Everyone reacts differently to CBD, so it’s therefore important that you take a conservative approach to find the right dose to avoid any negative side effects.

Recommended strength for neurodegenerative disorders: medium to high strength

CBD Dosage Calculator

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How Long Will It Take To Notice Improvement?

Neurodegenerative disorders are long-term medical conditions — and most of them have no cure. CBD can be used to slow the progression of the disease and alleviate common side effects but isn’t going to cure the condition.

Therefore, it’s helpful to track the progress of the disease over time to identify whether the CBD is working or if the dose needs to be increased.

You can do this by taking detailed notes about your symptoms. Then, you can go back and see if there have been any improvements over time. Additionally, in the case of progressive neurodegenerative disorders, you can track the rate of progression of the disease.

What Is Neurodegenerative Disease?

Neurodegeneration is an umbrella term for a series of unrelated medical conditions that result in a loss of neuron function.

The primary cause for this condition is dementia, including Alzheimer’s disease — accounting for up to 70% of cases around the world, according to JPND Research.

These disorders are generally progressive, worsening in severity and rate of degeneration over time. This can take any time from a few months to a few decades. However, the process of neurodegeneration usually begins long before symptoms start to appear.

Evidence in recent years has pointed the finger at inflammation in the brain as one of the primary drivers of neurodegeneration [8]. The problem with this is that it’s also necessary for resisting neurological damage — prompting researchers to regard neuroinflammation as the “double-edged sword” of neurodegeneration.

When something causes damage to the neurons in the brain — for which there are too many potential causes to count — local immune cells start the inflammatory process.

In the early stages, this is beneficial — even necessary — for eliminating toxic materials. This is because inflammation speeds the recovery of the neurons by boosting blood flow to the area and bringing in defensive immune cells to remove any infectious materials.

The problem is that, in many cases, this inflammation goes out of control, causing a cascade of devastating, long-term inflammation in the brain. Excessive inflammation causes the microglia to release toxic substances into the brain, ultimately leading to the death of the neurons. These microglia are tasked with keeping the neurons safe [9, 10].

The whole process goes from a typical inflammatory response to a devastating, self-perpetuating process of degeneration and loss of neurons.

What Causes Degenerative Brain Disease?

  1. Environmental toxic exposure(such as heavy metal exposure)
  2. Nutritional deficiencies
  3. Stroke
  4. Cancer
  5. Oxidative damage
  6. Genetic factors

When to Avoid Using CBD or Cannabis-Related Products

Even though CBD is very safe, there are some instances when you must first consult with an experienced medical professional before taking it:

  • If you have psychosis
  • If you have bipolar disorder (caution advised)
  • Whenever taking antipsychotics or certain antidepressants

Key Takeaways: How Does CBD Support Brain Health?

Researchers are still disputing exactly how CBD and other cannabinoids are effective for slowing the progression of neurodegenerative disorders.

The interaction between CBD and the nervous system is complex — involving multiple separate processes going on at the same time.

However, the general idea is that CBD supports the homeostasis of the nervous system. This means it supports the balance of various factors involved with neurological function, including inflammation, pain transmission, nerve excitability, and immune function.