Canna~Fangled Abstracts

The impact of phyto- and endo-cannabinoids on central nervous system diseases：A review

By January 12, 2023January 23rd, 2023No Comments

 2023 Jan; 13(1): 30–38.
Published online 2022 Oct 12. doi: 10.1016/j.jtcme.2022.10.004
PMCID: PMC9845650
PMID: 36685079
Shan-Shan Zhang,a,b Niu-Niu Zhang,b Tian-Tian Guo,b Lee-Yan Sheen,c Chi-Tang Ho,d,∗∗ and Nai-Sheng Baib,∗
Author information Article notes Copyright and License information Disclaimer

Associated Data

Supplementary Materials

Abstract

Background and aim

Cannabis sativa L. is a medicinal plant with a long history. Phyto-cannabinoids are a class of compounds from C. sativa L. with varieties of structures. Endocannabinoids exist in the human body. This article provides an overview of natural cannabinoids (phyto-cannabinoids and endocannabinoids) with an emphasis on their pharmacology activities.

Experimental procedure

The keywords “Cannabis sativa L″, “cannabinoids”, and “central nervous system (CNS) diseases” were used for searching and collecting pieces of literature from PubMed, ScienceDirect, Web of Science, and Google Scholar. The data were extracted and analyzed to explore the effects of cannabinoids on CNS diseases.

Result and conclusion

In this paper, schematic diagrams are used to intuitively show the phyto-cannabinoids skeletons’ mutual conversion and pharmacological activities, with special emphasis on their relevant pharmacological activities on central nervous system (CNS) diseases. It was found that the endocannabinoid system and microglia play a crucial role in the treatment of CNS diseases. In the past few years, pharmacological studies focused on Δ9-THC, CBD, and the endocannabinoids system. It is expected to encourage new studies on a more deep exploration of other types of cannabinoids and the mechanism of their pharmacological activities in the future.

Keywords: Cannabinoids, Chemical structures, Endocannabinoid system, CNS diseases

Graphical abstract

Image 1

 

List of abbreviations

CBN
Cannabinol
THC
Tetrahydrocannabinol
CBD
Cannabidiol
AEA
Anandamide
2-AG
2-arachidonoylglycerol
CB
Cannabinoid receptor
CNS
Central nervous system
CBC
Cannabichromene
CBG
Cannabigerol
CBL
Cannabicyclol
CBE
Cannabielsoin
CBT
Cannabitriol
ECS
Endocannabinoid system
AD
Alzheimer’s disease
GSH-Px
Glutathione peroxidase
HD
Huntington’s disease
Aβ
Amyloid β-peptide
LRP-1
Lipoprotein receptor-related protein 1
LPS
lipopolysaccharide
ERK
Extra-cellular signal-regulated kinase
iNOS
Inducible nitric oxide synthase
IL-1β
Interleukin 1β
PD
Parkinson’s disease
MAGL
Monoacylglycerol lipase
FAAH
Fatty acid amide hydrolase
TNF-α
Tumor necrosis factor-α
PGE2
Prostaglandin E2
NO
Nitric oxide
ENT-1
Equilibrate nucleoside transporter 1
TRPV1
Transient receptor potential vanilloid 1 receptor
MS
Multiple sclerosis
EAE
Experimental autoimmune encephalomyelitis
TLR4
Toll Like Receptor 4

1. Introduction

As one of the oldest plants in the world, Cannabis sativa L. has been used in textiles and medicinals for thousands of years. The Chinese invented hemp paper in about 2000 BC, which is the earliest record of the application of hemp. Cannabinoids are a class of compounds naturally exist in C. sativa L. and animal’s central nervous and immune systems with multiple pharmacological activities. Cannabinoids exhibit a terpenophenolic skeleton, and they can be divided by sources as the endocannabinoids, the synthetic cannabinoids, and the phyto-cannabinoids. The phyto-cannabinoids are isolated from C. sativa L. They are the main active ingredients of C. sativa L., and work by imitating endocannabinoids to activate specific receptors in human. The main phyto-cannabinoids are Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD). In addition to C. sativa L. a series of cannabinoid analogs were also discovered in Echinacea species, Helichrysum umbraculigerum, and Radula species.

Endocannabinoids play an immunoregulatory role in the immune system and modulate the excitability of the central nervous system. AEA (anandamide, N-arachidonoylethanolamide) and 2-AG (2-arachidonoylglycerol) are the two major endocannabinoids. To date, hundreds of cannabinoids have been isolated and identified. The cannabinoid receptors are a class of G protein-coupled receptor proteins, and the recognized cannabinoid receptors are cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2). CB1 is mainly distributed in the nervous system and expressed in brain tissue, which plays a role in regulating neurotransmitter transmission. The CB1 pathway is involved in metabolic syndrome and related symptoms, such as atherosclerosis, type 2 diabetes, and others. CB2 primarily distributes in immune tissues and cells, and plays an immunomodulatory role. Cannabinoids can act on the immune system through CB2, while CB2 is only active in specific cell populations. Numerous studies showed that cannabinoids have multiple pharmacological activities, such as reducing inflammation, pain modulation, treating sleep disorders, depressants, anti-epilepsy and other central nervous system (CNS) disorders., , , 

Neuroinflammation is considered a critical process in the development of the central nervous system. The CNS diseases include neurodegenerative diseases, depression, sleep disorders, epilepsy, stroke, multiple sclerosis, and pain. The CNS disease was associated with inflammation, especially neuroinflammation. Therefore, the prevention of neuroinflammation seems to be one of the most effective treatments for these disorders.

This review will cover studies in the field up to 2022 focusing on chemical structure diversities and pharmacological activities of natural cannabinoids. It will provide a comprehensive inventory of cannabinoids of different origins and outline the pharmacological activities on CNS diseases.

2. Chemical structures of cannabinoids

2.1. Phyto-cannabinoids

The phyto-cannabinoids are classified according to three-part skeletal structure differences, which are the isoprenyl residue, the resorcinyl core, and the side chain. Δ9-tetrahydrocannabinol (THC)-type compounds are the largest number of phyto-cannabinoids. Δ9-THC-type compounds are sensitive to air and temperature and are prone to oxidation and degradation. Oxidative degradation of Δ9-THC caused by heating, light exposure, or aging will lead to CBN, and acid isomerization will generate Δ8-tetrahydrocannabinol (Δ8-THC) (Fig. 1). Both Δ9-THC-type and Δ8-THC-type belong to tetrahydrocannabinol-type (THC-type) compounds. Δ9-THC is the main active ingredient of Cannabis, used for antiemetic and analgesic for cancer patients, anti-anxiety, anti-inflammatory, and other medical purposes.

Fig. 1

The reciprocal transformation of the skeletal structure of the major cannabinoids.

Other major phyto-cannabinoids in Cannabis are CBD-type compounds. Although the structures of CBD and Δ9-THC show certain similarities, the two compounds have different biological properties. Other phyto-cannabinoids type contains Cannabicyclol (CBL)-type, Cannabielsoin (CBE)-type, Cannabinol (CBN)-type, and Cannabitriol (CBT)-type are also shown here. Δ9-THC, Cannabidiol (CBD), Cannabichromene (CBC), Cannabigerol (CBG), and Cannabinol (CBN) are the main phyto-cannabinoids. Cannabichromene (CBC) is also one of the most abundant phyto-cannabinoids in Cannabis spp. Cannabigeroids are one of the most diverse types of phyto-cannabinoids in chemical structure and are isomers with some structural changes based on isoprenyl. The structure of Cannabigerol (CBG)-type compounds are linear isoprenyl skeleton. Also, there are some cannabinoids with monocyclic (CBC and CBD) or bicyclic (CBE, CBL, and CBN) structures (Fig. 1). The chemical structures of phyto-cannabinoids were listed in the Supplementary files.

2.2. Endocannabinoids

Anandamide (AEA) and 2-arachidonoylglycerol (2-AG) are two major endocannabinoids. N-arachidonoyldopamine (NADA), O-arachidonoylethanolamide (VA), and 2-arachidonoylglycerol ether (2-AGE) derived from n-3 polyunsaturated fatty acids are also considered endocannabinoids. Endocannabinoids, receptors, and enzymes (synthesize and degrade endocannabinoids) constitute the endocannabinoid system (ECS, Fig. 2). The ECS is a neuromodulation network that participates in the development of the central nervous system and plays an important role in the homeostasis maintenance of cognition, behavior, emotion, development, and various physiological processes. Studies have shown that the endocannabinoid system is the foundation of emotional homeostasis and cognitive function.

Fig. 2

Schematic of the endocannabinoid system. The main endocannabinoids AEA and 2-AG are synthesized after postsynaptic cell stimulation. 2-AG is degraded by monoacylglycerol lipase (MAGL) which is expressed in the presynaptic terminal. While fatty acid amide hydrolase (FAAH) is localized to postsynaptic cells, which predominantly degrades AEA. AEA and 2-AG are transported across the membrane and respectively act on cannabinoid receptors (CB1 and CB2) which are expressed on presynaptic terminals, to exhibit the corresponding therapeutic effects.

3. Pharmacological activities

Many studies have shown that cannabinoids have a variety of pharmacological activities. These have aroused the interest of the scientific community to find therapeutic effects in different aspects. The central nervous system (CNS) is huge and complex. In the past few decades, pieces of evidence have shown that a series of CNS diseases are related to neuroinflammation, including neurodegenerative diseases, depression, sleep disorders, and epilepsy. The endocannabinoid system is widespread in the CNS and participates in the control of many neurophysiological processes such as pain, motor function, depression and cognition.

3.1. Neurodegenerative diseases

Neuroinflammation involves the activation of microglia and astrocytes, resulting in the secretion of proinflammatory cytokines, which can activate a series of pathways. Neuroinflammation is a critical process in the development of CNS diseases. Therefore, the prevention of neuroinflammation remains one of the effective methods in the treatment of these diseases. Many research have been devoted to study the neuroprotective properties of cannabinoids. They found that cannabinoids can provide neuroprotection for various neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). This protective effect is thought to inhibit the release of glutamate at synapses because the addition of extracellular glutamate can damage neurons. The endocannabinoid system expressed in basal neural stem cells is an effective target for motor dysfunction treatment, which can regulate the release of neurotransmitters and motor activity., As the course of AD and PD progresses, the ECS may be permanently over-activated, which could even contribute to the suppression of motor activity and loss of memory (Fig. 3).

Fig. 3

Schematic representation of mechanisms of neuroinflammation in CNS diseases. Neuroinflammatory is caused by proinflammatory cytokines, pathogenic molecules (e.g. LPS), Aβ and other infections, injury, etc. Amyloid β-peptide (Aβ) is produced by aging or senescence, which can be transported from blood to the brain via the low density lipoprotein receptor-related protein 1 (LRP-1). Lipopolysaccharide (LPS) works through toll Like Receptor 4 (TLR4). The activation of microglia leads to proinflammatory cytokines (IL-1β, IL-4, TNF-α, NO, ROS) synthesis and cytotoxic effect, which causes neuroinflammatory related to CNS diseases.

 

3.1.1. Alzheimer’s disease (AD)

The ECS has an important neuroprotection role in neurodegenerative diseases. Alzheimer’s disease (AD) is a neurodegenerative disease associated with Aβ accumulation, oxidation, neuroinflammatory, and age. High levels of AEA could exhibit neuroprotective effects. In the kainic acid-induced seizures mice model, it was shown that as age increased, AEA levels decreased and 2-AG levels increased. It was shown that the treatment of THC (0.75 mg/kg·bw, i.p.), CBD (0.75 mg/kg·bw, i.p.), or a mix of △9-THC and CBD (0.75 mg/kg·bw each botanical extract, i.p.) could reduce cognitive impairment in AD model mice. A combination of △9-THC and CBD could significantly decrease microgliosis and the expression of several cytokines, thereby reducing the pro-inflammatory response of ERK 1/2 (extra-cellular signal-regulated kinase) to Aβ. △9-THC and CBD have a therapeutic effect on AD. It was reported that △9-THC directly interacted with Aβ inhibiting its aggregation, whereas CBD reduced Aβ production by activating PPARγ. The aggregation of Aβ in the brain is one of the triggers of AD. Limited clinical evidence showed that cannabinoids had beneficial effects on AD patients, and almost no other side effects were observed during treatment with △9-THC (1.5 mg twice daily), except for euphoria, drowsiness, or fatigue. It was reported that Aβ42 accumulation and plaque deposition induced the expression of CB2. Though CB2 receptor activation played an important role in controlling the microglia responses to Aβ accumulation that the mechanism remains to be elucidated. Despite the limited clinical evidence clarifying the therapeutic effect of cannabinoids in AD, assessment of cognitive profiles and neurodegenerative markers is still lacking, which will encourage additional clinical trials to clarify the potential therapeutic effect of cannabinoids in AD.

 

3.1.2. Parkinson’s disease (PD)

Parkinson’s disease (PD) is the most common neurodegenerative disease after Alzheimer’s disease. The symptoms of PD include muscle rigidity, movement disorder, tremor, psychological symptoms, cognitive impairment, sleep disorder, somatoform autonomic dysfunction, and others. In PD models, CB2 receptor expression increased and microglia activation indicated the dysregulation of the cannabinoid system. The CB2 receptor expression increased while the CB1 receptor remained in PD patients. Substantial evidence suggests that CB2 receptors play an important role more than CB1 receptors in the regulation of neuroinflammation associated with PD. It is reported that cannabinoids show a reduction of l-dopa-induced dyskinesia via CB1 receptor activation. Increased expression of CB1 and CB2 receptors was observed in MPTP-induced macaques, but a low expression in dyskinetic animals was indicated due to the prolonged use of l-dopa. Intrastriatal injection of LPS in mice led to microglia activation and the expression of CD68, which induced an inflammatory response. Furthermore, the activation of the CB2 receptor impaired LPS-induced CD68 expression in the striatum, while decreasing the regulation of tyrosine hydroxylase and striatal iNOS. On the contrary, exacerbated functional deficits and increased microglial activation were developed after LPS injection in CB2-deficient mice. THC was proven to relieve LPS-induced neuroinflammation in mice and have a potential neuroprotective effect via PPARγ activation. l-dopa will increase dynorphin and ERK phosphorylation. In PD mice study, it was found that △9-THC (3 mg/kg·bw, i.p.) and CBD (3 mg/kg·bw, i.p.) had neuroprotective action. THC activating PPARγ will decrease dynorphin and ERK phosphorylation. And the activation of PPARα by oleoylethanolamide could down-regulate the expression of FosB and pAcH3, which could also relieve l-dopa dyskinesia. The CB1-CB2 heteromer levels were increased in 6-OHDA model mice, which recovered in l-dopa treatment mice. This might be due to the cannabinoids’ compensatory neuroprotective mechanism, or the overexpression of the CB1-CB2 heteromer contributes to movement disorder. Together, the modulation of cannabinoid receptors on microglia may provide an effective treatment target for PD, further study of the mechanism of cannabinoid receptors for treating PD is needed, which will contribute to the development of potential new therapies of cannabinoid for treating PD.

 

3.1.3. Huntington’s disease (HD)

Huntington’s disease (HD) is a neurodegenerative disease caused by the accumulation of mutant huntingtin protein in neurons and glial cells. Mutant huntingtin protein will cause inflammatory responses in glial cells, which will increase the levels of pro-inflammatory cytokines such as IL-6 and tumor necrosis factor-α (TNF-α). It was reported that the increasing level of IL-6 can be detected in HD gene carriers’ plasma which can predict onset more than a decade ahead of time. The microglial activation associated with cognitive function was also related to the HD onset. It was reported that the activation of the CB2 receptor could alleviate inflammation response and neuron injury. The downregulation of the CB1 receptor has been detected in early HD patients. CB1 could inhibit the release of glutamate. The downregulation of the CB1 receptor will lead to a high level of glutamate and aggravate its damage to nerve cells. Multiple studies have shown that the down-regulation of CB1 may also aggravate cytotoxicity like oxidative stress. The neuroprotective effect of CBG has also been evaluated in R6/2 and 3 – nitropropionate-lesioned mice, and the neuroprotective effect of CBG might not be mediated by CB1/2, it might be mediated by other targets like PPARs. The inflammation, brain edema, movement disorder, and neuronal loss in HD model mice were reduced after the administration of CB2 receptor select agonists. Based on previous studies, cannabinoids can bind to CB1/2 receptors to alleviate neurotoxicity, oxidation injury, and inflammation, such as △9-THC (10 mg/kg·bw) and CBD (10 mg/kg·bw), which were considered a new therapeutic way for HD. A clinical evaluation is still required before cannabinoids be used as a treatment for HD, and Sativex® (△9-THC + CBD) might be a good choice.

3.2. Pain

According to the length of duration, pain can be divided into acute pain and chronic pain. In the light of the cause of the pain, it can be divided into nociceptive, inflammatory, neuropathic, and oncological. Compared to nociceptive pain, short-term acute pain is easier to treat. Inflammatory and neuropathic pain may shift into a lasting chronic pain that is difficult to treat. For centuries, preparations of cannabis have been used as analgesics. Studies have found that the analgesic components in cannabis are mainly two active cannabinoids: △9-THC and CBD. In the past two decades, many drugs affecting the ECS have been developed for pain relief. There are currently three drugs that can activate cannabinoid receptors as commercial products: Cesamet® (nabilone), Marinol® (△9-THC + dronabinol), and Sativex® (△9-THC + CBD), they can be used for the analgesic treatment of cancer, neuropathic and spasticity associated with multiple sclerosis. However, phyto-cannabinoids have some side effects and should be carefully considered before use. Of particular concern is that patients with a history of mental illness should refrain from phyto-cannabinoids drugs like Sativex® (△9-THC + CBD), which might lead to transient mental illness episode onset or recurrence. The endocannabinoid system is largely involved in the regulation of pain and inflammation. Endocannabinoids are generated on demand and mainly produce short-term anti-nociceptive effects through binding to CB1 receptors in nociceptive neurons. The inhibitory effect of MAGL on acute pain appears to be predominantly CB1-mediated, whereas CB2-mediated has been found in models of inflammatory and neuropathic pain. The current findings indicate that cannabis analgesics have a therapeutic effect on chronic pain especially neuropathic pain, and further mechanistic research is necessary.

3.3. Epilepsy

Epilepsy is a chronic neurological disease characterized by recurrent and spontaneous seizures. Cannabis has a long history of anti-epileptic effects. In recent years, people have studied the anti-epileptic effects of cannabinoid compounds and found that the phyto-cannabinoids △9-THC, △9-THCV, CBD, CBDV, endocannabinoids, and synthetic cannabinoids all have anti-epileptic effects in animal models. Currently, cannabinoids used clinically to treat epilepsy in mice models include THC (△9-THC, 1–100 mg/kg·bw, i.p.) and CBD (5–400 mg/kg·bw, i.p.), and mainly CBD. △9-THC depends on the activation of CB1 and CB2 receptors, and the anti-epileptic mechanism of CBD is still unclear. Some studies believe that CBD has a low affinity for CB1 and CB2 receptors and may interfere with other targets in the brain including TRPV1, voltage-gated potassium, sodium channels, GPR55, etc. In the past few years, the use of CBD to treat epilepsy has increased dramatically. Cases have shown that treatment with a high CBD/THC ratio can effectively reduce the frequency of seizures. Scientific evidence suggested that CBD had a significant effect on reducing seizures. CBD was an agonist on TRP channels, especially in TRPV1, which was responsible for regulating the Ca2+ channel. However, current evidence is insufficient to explain the mechanism of the antiepileptic action of CBD. More data are needed to explain the antiepileptic mechanism of cannabinoids.

3.4. Depression

Depression is one of the most common neuropsychiatric diseases. Studies have found that the ECS is partially involved in the control of emotional behavior and emotions through the functional coupling of the monoamine system in the brain. Studies have shown that the endocannabinoid system plays a key role in the pathogenesis of depression and the regulation of the effects of antidepressants. The level of serum endocannabinoids in patients with major depression will also change. Some studies have found that patients with depression have lower levels of endocannabinoid AEA and 2-AG. Besides, 2-AG levels are lower in patients with longer depressive episodes, while patients with mild depression have higher levels. Therefore, depression can be improved by increasing the content of endocannabinoid 2-AG. Studies have found that aerobic exercise can increase the content of 2-AG in the body., In addition to adjusting the ECS, the use of phyto-cannabinoids to treat depression is also considered. Studies have pointed out that when CBC is used in combination with other cannabinoids such as CBD (0.2 ng/nL, intracranial infusions) and THC (0.2 ng/nL, intracranial infusions), it has an effect on improving insomnia and antidepressants., However, some research pointed out that cannabis has two opposite effects on depression. On the one hand, the heavy use of cannabis is associated with a higher incidence of depression. On the other hand, the main active ingredient of cannabis △9-THC as an agonist of CB1 and CB2 can reduce depressive behavior. Increased CB1 levels could be detected in the dorsolateral prefrontal cortex of depressed patients, whereas did not affect CB1 immune response in the dorsolateral prefrontal cortex. However, the changes in CB2 levels were not been detected in the dorsolateral prefrontal cortex. The increased CB1 expression and a lack of CB1-induced Gi/o proteins activation could be detected in anti-depression treated studies. Pieces of evidence have shown that CBD had anti-depression and anxiolytic properties which were not related to the action of CBD on CB1 and CB2,51 while the mechanism of CBD acting on anti-depression was not clear.

3.5. Sleep disorders

Sleep is regulated by circadian rhythm. Disorders of circadian rhythm cause sleep disorders. The sleep disorder can be primary or can be triggered by brain diseases such as multiple sclerosis, mental diseases, and other conditions. It is reported that about 30–35% of the population is under sleep deprivation. In an animal study, sleep disorder was associated with increased IL-6 level and microglia activation, and injury of hippocampal associated with learning and memory was observed. It is reported that sleep disorder was associated with IL-1β, IL-6, TNF-α, and CRP levels increasing. Another report has shown that sleep disorder was associated with NF-κB activation and the increasing levels of TNF-α and IL-1β in the hippocampus. Sleep disorder will increase the microglia activation and Aβ level, which may promote brain injury., Pieces of evidence showed that circadian rhythm and sleep disorder were related to the increasing levels of proinflammatory cytokines. However, the pathophysiology mechanism is unclear.

△9-THC and CBD interact with the endocannabinoid system and other systems to influence mood and sleep, which are increasingly used to regulate sleep disorders. Previous studies have revealed that an endocannabinoid concentration changes the circadian rhythm. The inhibition of MAGL and increasing level of 2-AG were found in mice brains, which had a wake-promoting effect. Preclinical evidence has shown that AEA has a sleep-promoting effect. THC is a partial agonist at CB1receptor to promote sleep like AEA. It is also reported that CBD can inhibit FAAH to increase the level of AEA, which could be a mechanism for CBD’s sleep-promoting effect. Evidence has shown that nabiximols® (THC and CBD) have an effective improvement to sleep disorders caused by pain. However, it is not clear whether this improvement is due to improved sleep itself or the improvement in pain. Cannabinoids are increasingly used to treat sleep disorders, but the mechanism is unclear.

3.6. Stroke

Stroke is divided into two types: ischemic and hemorrhagic stroke. The excitotoxicity and inflammatory were considered key factors to ischemic neuron damage. Glutamate release is due to brain ischemic, which would cause NMDA receptors over-activation and Ca2+ influx, leading to excitotoxicity-induced cell death. The activated microglia clear dead cells, which causes the production of anti-inflammatory and pro-inflammatory factors and ROS/RNS (reactive oxygen species/reactive nitrogen species). The activated microglia have M1 and M2 two phenotypes, the M1 microglia are pro-inflammatory and could induce neurons cells death, whereas the M2 microglia are associated with the recovery of brain damage. Microglia could synthesize 2-AG and AEA, this could be a source of endocannabinoids under inflammatory conditions. Mecha et al. reported that more synthesis of 2-AG and AEA significantly activated the M2 microglia than resting microglia. The increasing endocannabinoid synthesis has positive feedback on CB1/2 receptors activation and enhances the anti-inflammatory effect and the M2 microglia protection. This will promote the M2 microglia producing neuroprotective factors and reduce pro-inflammatory factors. Studies have shown that the M1 microglia and the M2 microglia were interconvertible under certain circumstances. Microglia is an important modulator of immune response in ischemic stroke. However, the modulation mechanism of microglia activation and proliferation remains unclear. Thus, understanding M1/2 is up- or down-regulation, exploring the mechanism of M1-M2 microglia transformation, and controlling the transformation of M1-M2 microglia might be important directions for treating ischemic stroke (Fig. 4).

Fig. 4

The effect of activated microglia in several CNS diseases. Microglia has two phenotypes: M1 was activated by LPS which produces IL-1β, TNF, IL-6, and iNOS. M2 was activated by IL-4 and expressed IL-10, IL-4, and TGFβ, which contributes to brain injury recovery. M1 and M2 were interconvertible under certain circumstances.

3.7. Multiple sclerosis

The onset of multiple sclerosis (MS) was associated with genetic, environmental, and other infectious factors. But the onset mechanism and the specific sequelae responsible for the development of MS were still unclear. Experimental autoimmune encephalomyelitis (EAE) is a common animal model used in MS research and may help in the development of new treatments for MS, but it still has limitations. M1 and M2 microglia have been proved to show different predominate during the EAE model established. M1 microglia might be related to aggravating EAE, whereas increased M2 microglia levels were related to inflammation and disease improvement. It was reported that the inhibition of M1 microglia accumulation in CNS could relieve disease. Also, the activation of M2 microglia could inhibit CD4+ T cells in EAE mice and relieve disease. The CB1 receptor was detected to express in neurons and injured axons, whereas CB2 was absent. Previous studies have shown that the endocannabinoid system is involved in the development of MS, and cannabinoids were used to treat MS. A combination of 27 mg/mL △9-THC and 25 mg/mL CBD (Sativex®) was proven to relieve spastic and pain in MS patients. Sativex® (△9-THC + CBD) might be a potentially effective medicine for treating MS. Exploring the role of cannabinoids in the development of MS will contribute to understanding the mechanism of this disease and developing new therapeutic methods (Fig. 4).

4. Conclusion

The predominant natural component of cannabis-derived drugs is Δ9-THC followed by CBD and CBN. AEA and 2-AG are the main endocannabinoids. Although cannabinoids have many health benefits, a long-term consumption of cannabinoids can also put patients at risk for mental illnesses such as depression. Exposure to cannabis during development may be particularly harmful to the brain and central nervous system. It is shown that the negative effects of cannabinoids include dependence, delayed response, anxiety, and others, which depend on the administration method and dosage. Cannabis-derived drugs are widely used in the world. However, legalizing and rationalizing these drugs are rapidly changing the research and use of cannabis. Cannabis derivatives are popularly developed for pharmaceutical use, despite the lack of safety and efficacy evidence. Pieces of evidence showed that cannabinoids had beneficial effects on CNS diseases, which tend to encourage further exploration of their biological activities. Cannabinoids have diverse chemical structures and pharmacology activities, which have been used in many fields of modern medicine over the past decades. Table 1 summarizes the effects and recommended doses of cannabinoids on CNS diseases. Even though the use of C. sativa L. is prohibited in many countries, its beneficial effect should not be ignored.

Table 1

The pharmacological effects of prominent cannabinoids on CNS diseases.

Diseases Compounds Effects Reference
Alzheimer’s disease

 THC (0.75 mg/kg·bw, i.p.) reduce cognitive impairment in AD model mice
CBD (0.75 mg/kg·bw, i.p.)
a mix of △9-THC and CBD (0.75 mg/kg·bw each botanical extract, i.p.) decrease microgliosis and the expression of several cytokines; reduce the pro-inflammatory response of ERK 1/2 (extra-cellular signal-regulated kinase)
△9-THC (1.5 mg twice daily)

 reduce the aggregation of Aβ; side effects: euphoria, drowsiness, or fatigue

Parkinson’s disease

 △9-THC (3 mg/kg·bw, i.p.);
CBD (3 mg/kg·bw, i.p.)		 relieve LPS-induced neuroinflammation in mice, have a neuroprotective effect via PPARγ activation
THC

 activate PPARγ; relieve l-dopa dyskinesia

Huntington’s disease

 CBG neuroprotective effect in R6/2 and 3 – nitropropionate-lesioned mice
△9-THC (10 mg/kg·bw);
CBD (10 mg/kg·bw)

 bind to CB1/2 receptors to alleviate neurotoxicity

Pain

 Cesamet® (nabilone), Marinol® (△9-THC + dronabinol), Sativex® (△9-THC + CBD) analgesic treatment of cancer, neuropathic and spasticity associated with multiple sclerosis

endocannabinoids (AEA and 2-AG)

 regulation of pain and inflammation
Epilepsy

 △9-THC (1–100 mg/kg·bw, i.p.);
CBD (5–400 mg/kg·bw, i.p.)

 CBD had a significant effect on reducing seizures

 ,
Depression

 CBC used in combination with CBD (0.2 ng/nL, intracranial infusions) or THC (0.2 ng/nL, intracranial infusions) improve insomnia and antidepressants ,
CBD

 anti-depression and anxiolytic

Sleep disorders

 CBD inhibit FAAH to increase the level of AEA to promote sleep

AEA sleep-promoting effect
△9-THC

 activate CB1 receptor to promote sleep
Stroke

 AEA and 2-AG

 activate the M2 microglia, anti-inflammatory effect, improve ischemic neuron damage

Multiple sclerosis Sativex® (△9-THC + CBD) activate M2 microglia, inhibit CD4+ T cells in EAE mice, treat multiple sclerosis ,

This review focused on natural cannabinoids reporting 112 phyto-cannabinoids (divided into eight types) and five endocannabinoids. The diversities of the cannabinoids’ chemical structures lead to a variety of pharmacological effects. By activating cannabinoid receptors 1 or 2, cannabinoids exhibit various pharmacological activities. Sometimes cannabinoids can also act on other targets such as GPR55, TRPV1, and others. Currently, cannabinoids are beneficial to the medical and scientific communities. A large amount of scientific literature has shown the therapeutic potential of cannabinoids in pathological conditions. These compounds can be used as potential therapies for CNS diseases. The endocannabinoid system and microglia played an important role in CNS diseases. Microglia as immune cells are involved in the pathological reactions of various diseases of the central nervous system, while the regulating mechanism was not fully clarified. The specific mechanism of the endocannabinoid system and microglia remains to be explored. Up to now, the role and pharmacological mechanism of more cannabinoids besides THC and CBD in CNS diseases remain to be investigated. It is believed that cannabinoids can be efficient and reasonably used in the future.

Declaration of competing interest

The authors declare no conflict of interest.

Footnotes

Peer review under responsibility of The Center for Food and Biomolecules, National Taiwan University.

 

Appendix ASupplementary data to this article can be found online at https://doi.org/10.1016/j.jtcme.2022.10.004.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1:

Click here to view.(364K, docx)Multimedia component 1

 

References

1. Ahmed S.A., Ross S.A., Slade D., Radwan M.M., Zulfiqar F., ElSohly M.A. Cannabinoid ester constituents from high-potency Cannabis sativa. J Nat Prod. 2008;71(4):536–542. doi: 10.1021/np800261x. [PMC free article] [PubMed] [CrossRef] []
2. Husni A.S., McCurdy C.R., Radwan M.M., et al. Evaluation of phytocannabinoids from high-potency Cannabis sativa using in vitro bioassays to determine structure-activity relationships for cannabinoid receptor 1 and cannabinoid receptor 2. Med Chem Res. 2014;23(9):4295–4300. doi: 10.1007/s00044-014-0972-6. [PMC free article] [PubMed] [CrossRef] []
3. Rodziewicz P., Loroch S., Ł Marczak, Sickmann A., Kayser O. Cannabinoid synthases and osmoprotective metabolites accumulate in the exudates of Cannabis sativa L. glandular trichomes. Plant Sci. 2019;284:108–116. doi: 10.1016/j.plantsci.2019.04.008. [PubMed] [CrossRef] []
4. Javid F.A., Phillips R.M., Afshinjavid S., Verde R., Ligresti A. Cannabinoid pharmacology in cancer research: a new hope for cancer patients? Eur J Pharmacol. 2016;775:1–14. doi: 10.1016/j.ejphar.2016.02.010. [PubMed] [CrossRef] []
5. Bauer R., Woelkart K., Salo-Ahen O. CB receptor ligands from plants. Curr Top Med Chem. 2008;8(3):173–186. doi: 10.2174/156802608783498023. [PubMed] [CrossRef] []
6. Jacobs J.A., Sehgal A. Anandamide metabolites protect against seizures through the TRP channel water witch in Drosophila melanogaster. Cell Rep. 2020;31(9) doi: 10.1016/j.celrep.2020.107710. [PMC free article] [PubMed] [CrossRef] []
7. Shahbazi F., Grandi V., Banerjee A., Trant J.F. Cannabinoids and cannabinoid receptors: the story so far. iScience. 2020;23(7) doi: 10.1016/j.isci.2020.101301. [PMC free article] [PubMed] [CrossRef] []
8. Nogueiras R., Veyrat-Durebex C., Suchanek P.M., et al. Peripheral, but Not Central, CB1 antagonism provides food intake-independent metabolic benefits in diet-induced obese rats. Diabetes. 2008;57(11):2977–2991. doi: 10.2337/db08-0161. [PMC free article] [PubMed] [CrossRef] []
9. Garofano F., Schmidt-Wolf I.G.H. High expression of cannabinoid receptor 2 on cytokine-induced killer cells and multiple myeloma cells. Int J Mol Sci. 2020;21(11):3800. doi: 10.3390/ijms21113800. [PMC free article] [PubMed] [CrossRef] []
10. Da Rovare V.P., Magalhães G.P.A., Jardini G.D.A., et al. Cannabinoids for spasticity due to multiple sclerosis or paraplegia: a systematic review and meta-analysis of randomized clinical trials. Compl Ther Med. 2017;34:170–185. doi: 10.1016/j.ctim.2017.08.010. [PubMed] [CrossRef] []
11. Fezza F., Marrone M.C., Avvisati R., et al. Distinct modulation of the endocannabinoid system upon kainic acid-induced in vivo seizures and in vitro epileptiform bursting. Mol Cell Neurosci. 2014;62:1–9. doi: 10.1016/j.mcn.2014.07.003. [PubMed] [CrossRef] []
12. Gates P.J., Albertella L., Copeland J. The effects of cannabinoid administration on sleep: a systematic review of human studies. Sleep Med Rev. 2014;18(6):477–487. doi: 10.1016/j.smrv.2014.02.005. [PubMed] [CrossRef] []
13. Holgado M.A., Martín-Banderas L., Álvarez-Fuentes J., Fernández-Arévalo M. Neuroprotective effect of cannabinoids nanoplatforms in neurodegenerative diseases. J Drug Deliv Sci Technol. 2017;42:84–93. doi: 10.1016/j.jddst.2017.04.023. [CrossRef] []
14. Welcome M.O. Neuroinflammation in CNS diseases: molecular mechanisms and the therapeutic potential of plant derived bioactive molecules. PharmaNutrition. 2020;11 doi: 10.1016/j.phanu.2020.100176. [CrossRef] []
15. Hanuš L.O., Meyer S.M., Muñoz E., Taglialatela-Scafati O., Appendino G. Vol. 33. 2016. (Phytocannabinoids: A Unified Critical Inventory). [PubMed] [CrossRef] []
16. Gaoni Y., Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of Hashish. J Am Chem Soc. 1964;86(8):1646–1647. doi: 10.1021/ja01062a046. [CrossRef] []
17. Bobrich M., Schwarz R., Ramer R., Borchert P., Hinz B. A simple LC-MS/MS method for the simultaneous quantification of endocannabinoids in biological samples. J Chromatogr B. 2020;1161 doi: 10.1016/j.jchromb.2020.122371. [PubMed] [CrossRef] []
18. Ibarra-Lecue I., Pilar-Cuéllar F., Muguruza C., et al. The endocannabinoid system in mental disorders: evidence from human brain studies. Biochem Pharmacol. 2018;157:97–107. doi: 10.1016/j.bcp.2018.07.009. [PubMed] [CrossRef] []
19. Gowran A., Noonan J., Campbell V.A. The multiplicity of action of cannabinoids: implications for treating neurodegeneration. CNS Neurosci Ther. 2011;17(6):637–644. doi: 10.1111/j.1755-5949.2010.00195.x. [PMC free article] [PubMed] [CrossRef] []
20. Maurya N., Velmurugan B.K. Therapeutic applications of cannabinoids. Chem Biol Interact. 2018;293:77–88. doi: 10.1016/j.cbi.2018.07.018. [PubMed] [CrossRef] []
21. Palazuelos J., Aguado T., Pazos M.R., et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington’s disease excitotoxicity. Brain. 2009;132(11):3152–3164. doi: 10.1093/brain/awp239. [PubMed] [CrossRef] []
22. Köfalvi A., Rodrigues R.J., Ledent C., et al. Involvement of cannabinoid receptors in the regulation of neurotransmitter release in the rodent striatum: a combined immunochemical and pharmacological analysis. J Neurosci. 2005;25(11):2874–2884. doi: 10.1523/JNEUROSCI.4232-04.2005. [PMC free article] [PubMed] [CrossRef] []
23. Di Marzo V., Bifulco M., De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nat Rev Drug Discov. 2004;3(9):771–784. doi: 10.1038/nrd1495. [PubMed] [CrossRef] []
24. Rosenberg E.C., Patra P.H., Whalley B.J. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. Epilepsy Behav. 2017;70:319–327. doi: 10.1016/j.yebeh.2016.11.006. [PMC free article] [PubMed] [CrossRef] []
25. Aso E., Sánchez-Pla A., Vegas-Lozano E., Maldonado R., Ferrer I. Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice. J Alzheim Dis. 2015;43(3):977–991. doi: 10.3233/JAD-141014. [PubMed] [CrossRef] []
26. Aymerich M.S., Aso E., Abellanas M.A., et al. Cannabinoid pharmacology/therapeutics in chronic degenerative disorders affecting the central nervous system. Biochem Pharmacol. 2018;157:67–84. doi: 10.1016/j.bcp.2018.08.016. [PubMed] [CrossRef] []
27. Van Den Elsen G.A.H., Tobben L., Ahmed A.I.A., et al. Effects of tetrahydrocannabinol on balance and gait in patients with dementia: a randomised controlled crossover trial. J Psychopharmacol. 2017;31(2):184–191. doi: 10.1177/0269881116665357. [PubMed] [CrossRef] []
28. Solas M., Francis P.T., Franco R., Ramirez M.J. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging. 2013;34(3):805–808. doi: 10.1016/j.neurobiolaging.2012.06.005. [PubMed] [CrossRef] []
29. Sveinbjornsdottir S. The clinical symptoms of Parkinson’s disease. J Neurochem. 2016;139:318–324. doi: 10.1111/jnc.13691. [PubMed] [CrossRef] []
30. Duffy S.S., Hayes J.P., Fiore N.T., Moalem-Taylor G. The cannabinoid system and microglia in health and disease. Neuropharmacology. 2021;190 doi: 10.1016/j.neuropharm.2021.108555. [PubMed] [CrossRef] []
31. Sieradzan K.A., Fox S.H., Hill M., Dick J.P.R., Crossman A.R., Brotchie J.M. Cannabinoids reduce levodopa-induced dyskinesia in Parkinson’s disease: a pilot study. Neurology. 2001;57(11):2108–2111. doi: 10.1212/WNL.57.11.2108. [PubMed] [CrossRef] []
32. Baul H.S., Manikandan C., Sen D. Cannabinoid receptor as a potential therapeutic target for Parkinson’s Disease. Brain Res Bull. 2019;146:244–252. doi: 10.1016/j.brainresbull.2019.01.016. [PubMed] [CrossRef] []
33. Gómez-Gálvez Y., Palomo-Garo C., Fernández-Ruiz J., García C. Potential of the cannabinoid CB2 receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog Neuro Psychopharmacol Biol Psychiatr. 2016;64:200–208. doi: 10.1016/j.pnpbp.2015.03.017. [PubMed] [CrossRef] []
34. Lastres-Becker I., Molina-Holgado F., Ramos J.A., Mechoulam R., Fernández-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis. 2005;19(1-2):96–107. doi: 10.1016/j.nbd.2004.11.009. [PubMed] [CrossRef] []
35. Navarro G., Borroto-Escuela D., Angelats E., et al. Receptor-heteromer mediated regulation of endocannabinoid signaling in activated microglia. Role of CB1 and CB2 receptors and relevance for Alzheimer’s disease and levodopa-induced dyskinesia. Brain Behav Immun. 2018;67:139–151. doi: 10.1016/j.bbi.2017.08.015. [PubMed] [CrossRef] []
36. Crotti A., Glass C.K. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 2015;36(6):364–373. doi: 10.1016/j.it.2015.04.007. [PMC free article] [PubMed] [CrossRef] []
37. Fernández-Ruiz J. The endocannabinoid system as a target for the treatment of motor dysfunction. Br J Pharmacol. 2009;156(7):1029–1040. doi: 10.1111/j.1476-5381.2008.00088.x. [PMC free article] [PubMed] [CrossRef] []
38. Dowie M.J., Howard M.L., Nicholson L.F.B., Faull R.L.M., Hannan A.J., Glass M. Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington’s disease transgenic mice. Neuroscience. 2010;170(1):324–336. doi: 10.1016/j.neuroscience.2010.06.056. [PubMed] [CrossRef] []
39. Pascual D., García M.M., Goicoechea C. Chronic pain and cannabinoids . Great expectations or a christmas carol. Biochem Pharmacol. 2018;157:33–42. doi: 10.1016/j.bcp.2018.07.033. [PubMed] [CrossRef] []
40. Semple D.M., McIntosh A.M., Lawrie S.M. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol. 2005;19(2):187–194. doi: 10.1177/0269881105049040. [PubMed] [CrossRef] []
41. Mathers D.C., Ghodse A.H. Cannabis and psychotic illness. Br J Psychiatry. 1992;161:648–653. doi: 10.1192/bjp.161.5.648. [PubMed] [CrossRef] []
42. Long J.Z., Li W., Booker L., et al. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects. Nat Chem Biol. 2009;5(1):37–44. doi: 10.1038/nchembio.129. [PMC free article] [PubMed] [CrossRef] []
43. Gaston T.E., Friedman D. Pharmacology of cannabinoids in the treatment of epilepsy. Epilepsy Behav. 2017;70:313–318. doi: 10.1016/j.yebeh.2016.11.016. [PubMed] [CrossRef] []
44. Yao I., Stein E.S., Maggio N. Cannabinoids, hippocampal excitability and efficacy for the treatment of epilepsy. Pharmacol Ther. 2019;202:32–39. doi: 10.1016/j.pharmthera.2019.06.002. [PubMed] [CrossRef] []
45. Ashton C.H., Moore P.B. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand. 2011;124(4):250–261. doi: 10.1111/j.1600-0447.2011.01687.x. [PubMed] [CrossRef] []
46. Hill M.N., Miller G.E., Ho W.S.V., Gorzalka B.B., Hillard C.J. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry. 2008;41(2):48–53. doi: 10.1055/s-2007-993211. [PMC free article] [PubMed] [CrossRef] []
47. Hill M.N., Miller G.E., Carrier E.J., Gorzalka B.B., Hillard C.J. Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress. Psychoneuroendocrinology. 2009;34(8):1257–1262. doi: 10.1016/j.psyneuen.2009.03.013. [PMC free article] [PubMed] [CrossRef] []
48. Hill M.N., Gorzalka B.B. Is there a role for the endocannabinoid system in the etiology and treatment of melancholic depression? Behav Pharmacol. 2005;16(5-6):333–352. doi: 10.1097/00008877-200509000-00006. [PubMed] [CrossRef] []
49. Choi S., Huang B.C., Gamaldo C.E. Therapeutic uses of cannabis on sleep disorders and related conditions. J Clin Neurophysiol. 2020;37(1):39–49. doi: 10.1097/WNP.0000000000000617. [PubMed] [CrossRef] []
50. Szkudlarek H.J., Rodríguez-Ruiz M., Hudson R., et al. THC and CBD produce divergent effects on perception and panic behaviours via distinct cortical molecular pathways. Prog Neuro Psychopharmacol Biol Psychiatr. 2021;104 doi: 10.1016/j.pnpbp.2020.110029. [PubMed] [CrossRef] []
51. Mechoulam R., Parker L.A. The endocannabinoid system and the brain. Annu Rev Psychol. 2013;64:21–47. doi: 10.1146/annurev-psych-113011-143739. [PubMed] [CrossRef] []
52. Zhu B., Dong Y., Xu Z., et al. Sleep disturbance induces neuroinflammation and impairment of learning and memory. Neurobiol Dis. 2012;48(3):348–355. doi: 10.1016/j.nbd.2012.06.022. [PMC free article] [PubMed] [CrossRef] []
53. Mullington J.M., Simpson N.S., Meier-Ewert H.K., Haack M. Sleep loss and inflammation. Best Pract Res Clin Endocrinol Metabol. 2010;24(5):775–784. doi: 10.1016/j.beem.2010.08.014. [PMC free article] [PubMed] [CrossRef] []
54. Manchanda S., Singh H., Kaur T., Kaur G. Low-grade neuroinflammation due to chronic sleep deprivation results in anxiety and learning and memory impairments. Mol Cell Biochem. 2018;449(1-2):63–72. doi: 10.1007/s11010-018-3343-7. [PubMed] [CrossRef] []
55. Bellesi M., Vivo L De, Chini M., Gilli F., Tononi G., Cirelli C. Sleep loss promotes astrocytic phagocytosis and microglial activation in mouse cerebral cortex. J Neurosci. 2017;37(21):5263–5273. doi: 10.1523/JNEUROSCI.3981-16.2017. [PMC free article] [PubMed] [CrossRef] []
56. Shokri-Kojori E., Wang G.J., Wiers C.E., et al. β-Amyloid accumulation in the human brain after one night of sleep deprivation. Proc Natl Acad Sci U S A. 2018;115(17):4483–4488. doi: 10.1073/pnas.1721694115. [PMC free article] [PubMed] [CrossRef] []
57. Suraev A.S., Marshall N.S., Vandrey R., et al. Cannabinoid therapies in the management of sleep disorders: a systematic review of preclinical and clinical studies. Sleep Med Rev. 2020;53 doi: 10.1016/j.smrv.2020.101339. [PubMed] [CrossRef] []
58. McPartland J.M., Duncan M., Di Marzo V., Pertwee R.G. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol. 2015;172(3):737–753. doi: 10.1111/bph.12944. [PMC free article] [PubMed] [CrossRef] []
59. Babson K.A., Sottile J., Morabito D. Cannabis, cannabinoids, and sleep: a review of the literature. Curr Psychiatr Rep. 2017;19(4):23. doi: 10.1007/s11920-017-0775-9. [PubMed] [CrossRef] []
60. Liu R., Pan M.-X., Tang J.-C., et al. Role of neuroinflammation in ischemic stroke. Neuroimmunol Neuroinflammation. 2017;4(8):158–166. doi: 10.20517/2347-8659.2017.09. [CrossRef] []
61. Slevin M., Matou S., Zeinolabediny Y., et al. Monomeric C-reactive protein – a key molecule driving development of Alzheimer’s disease associated with brain ischaemia? Sci Rep. 2015;5:1–21. doi: 10.1038/srep13281. [PMC free article] [PubMed] [CrossRef] []
62. Mecha M., Feliú A., Carrillo-Salinas F.J., et al. Endocannabinoids drive the acquisition of an alternative phenotype in microglia. Brain Behav Immun. 2015;49:233–245. doi: 10.1016/j.bbi.2015.06.002. [PubMed] [CrossRef] []
63. Mikita J., Dubourdieu-Cassagno Nadège, Deloire M.S., et al. Altered M1/M2 activation patterns of monocytes in severe relapsing experimental rat model of multiple sclerosis. Amelioration of clinical status by M2 activated monocyte administration. Mult Scler J. 2011;17(1):2–15. doi: 10.1177/1352458510379243. [PubMed] [CrossRef] []
64. Moreno M., Bannerman P., Ma J., et al. Conditional ablation of astroglial CCL2 suppresses CNS accumulation of M1 macrophages and preserves axons in Mice with MOG peptide EAE. J Neurosci. 2014;34(24):8175–8185. doi: 10.1523/JNEUROSCI.1137-14.2014. [PMC free article] [PubMed] [CrossRef] []
65. Benito C., Romero J.P., Tolón R.M., et al. Cannabinoid CB1 and CB2 receptors and fatty acid amide hydrolase are specific markers of plaque cell subtypes in human multiple sclerosis. J Neurosci. 2007;27(9):2396–2402. doi: 10.1523/JNEUROSCI.4814-06.2007. [PMC free article] [PubMed] [CrossRef] []
66. Yiangou Y., Facer P., Durrenberger P., et al. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol. 2006;6:1–14. doi: 10.1186/1471-2377-6-12. [PMC free article] [PubMed] [CrossRef] []
67. Morales P., Jagerovic N. Advances towards the discovery of GPR55 ligands. Curr Med Chem. 2016;23(20):2087–2100. doi: 10.2174/0929867323666160425113836. [PubMed] [CrossRef] []
68. Zalesky A., Solowij N., Yücel M., et al. Effect of long-term cannabis use on axonal fibre connectivity. Brain. 2012;135(7):2245–2255. doi: 10.1093/brain/aws136. [PubMed] [CrossRef] []
69. Augustin S.M., Lovinger D.M. Synaptic changes induced by cannabinoid drugs and cannabis use disorder. Neurobiol Dis. 2022;167 doi: 10.1016/j.nbd.2022.105670. [PubMed] [CrossRef] []
70. Lustenberger S., Boczkaj G., Castro-Muñoz R. Cannabinoids: challenges, opportunities and current techniques towards its extraction and purification for edibles. Food Biosci. 2022;49 doi: 10.1016/j.fbio.2022.101835. [CrossRef] []
Articles from Journal of Traditional and Complementary Medicine are provided here courtesy of Elsevier

Leave a Reply