Neurological benefits of phytocannabinoids

Review of the neurological benefits of phytocannabinoids – free full-text /PMC5938896/ – 2018 Apr

INTRODUCTION

Numerous physical, psychological, and emotional benefits have been attributed to marijuana since it was first reported in 2,600 BC (e.g., Chinese pharmacopoeia). The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC), the most studied extracts from the cannabis sativa subspecies, include hemp and marijuana.

Recently, it has been successfully utilized as an adjunctive treatment for  

  • malignant brain tumors,
  • Parkinson’s disease (PD),
  • Alzheimer’s disease (AD),
  • multiple sclerosis (MS),
  • neuropathic pain, and
  • the childhood seizure disorders, Lennox-Gastaut and Dravet syndromes

In this review, we provide animal/human research data on the current clinical/neurological uses for CBD alone or with Δ9-THC, emphasizing its

  • neuroprotective,
  • antiinflammatory, and
  • immunomodulatory

benefits when applied to various clinical situations.

The discovery in the early 1990s of specific membrane receptors for Δ9-THC led to the identification of endogenous signaling system, now known as the endocannabinoid system (ECS). Shortly thereafter, the endogenous cannabinoids, N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), were identified.

The ECS consists of two major types of endogenous G protein-coupled cannabinoid receptors (CB1 and CB2) located in the mammalian brain and throughout the central and peripheral nervous systems, including tissues associated with the immune system. CB1 and CB2 receptors can also co-exist in a variety of concentrations in the same locations.

Both phytocannabinoids and endogenous cannabinoids function as retrograde messengers that provide feedback inhibition of both excitatory and inhibitory transmission in brain through the activation of presynaptic CB1 receptors.

Manipulations of endocannabinoid degradative enzymes, CB1 and CB2 receptors, and their endogenous ligands have shown promise in modulating numerous processes associated with neurodegenerative diseases, cancer, epilepsy, and traumatic brain injury [Table 1].

In addition, the ECS is known to influence neuroplasticity, apoptosis, excitotoxicity, neuroinflammation, and cerebrovascular breakdown associated with stroke and trauma.

Phytocannabinoids CBD and Δ9-THC

In addition to the phytocannabinoid Δ9-THC, it is estimated that the cannabis plant consists of over 400 chemical entities, of which more than 60 of them are phytocannabinoid compounds.

Some of these compounds have been identified as acting uniquely on both CB1 and CB2 receptors separately and simultaneously, and/or to inhibit or activate receptor functions.

CBD, like Δ9-THC, is a major phytocannabinoid accounting for up to 40% of the plant’s extract. CBD was first discovered in 1940 more than 20 years before Δ9-THC.

Until recently, Δ9-THC dominated cannabis research. All classes of phytocannabinoid compounds found in marijuana and hemp, including Δ9-THC and CBD, are derived from various changes to base molecular structure of cannabigerol-type compounds [Figure 1].

Cannabinoid receptors

Phytocannabinoid compounds and extracts can come from both hemp and marijuana subspecies, including CBD.

CBD does not elicit the same psychoactive effects as seen with Δ9-THC (i.e., users of CBD do not feel euphoric). The various psychoactive effects generally associated with Δ9-THC are attributed to activation of the CB1 cannabinoid receptor found abundantly in the brain.

CB1 receptors have the highest densities on the outflow nuclei of the basal ganglia, substantia nigra pars reticulata (SNr), and the internal and external segments of the globus pallidus (a portion of the brain that regulates voluntary movement).

The hippocampus, particularly within the dentate gyrus, and cerebellum also have higher CB1 receptor densities. Very few CB1 receptors are found in the brainstem

These locations suggest CB1 receptor involvement in the modulation of memory, emotion, pain, and movement.

Δ9-THC, which targets CB1 receptors, has been shown to reduce nociception in animal models of acute, visceral, inflammatory, and chronic pain. In patient studies with chronic pain and neuropathic pain, the use of marijuana or cannabinoid extracts produced positive and improved symptoms

Activation of neuronal CB1 receptors

Activation of neuronal CB1 receptors results in inhibition of adenylyl cyclase and decreased neurotransmitter release through blockade of voltage-operated calcium channels.

The activation of these signaling pathways by CB1 receptors and the high levels of these receptors on presynaptic terminals indicates that endocannabinoid stimulation of CB1 receptors suppresses neuronal excitability and inhibits neurotransmission. These effects have led to the study of phytocannabinoids for the treatment of epilepsy.

Several pharmaceutical companies are attempting to develop synthetic high-affinity CB1 antagonists and inverse agonists as therapeutic drugs for diabetes, metabolic syndrome, and drug dependence.

The CB2 receptor

The CB2 receptor, unlike CB1, is not highly expressed in the central nervous system (CNS). Effects of Δ9-THC on immune function have been attributed to the CB2 cannabinoid receptor interaction found predominantly in immune cells.

CB2 receptors are distributed widely in the major tissues of immune cell production and regulation, including the spleen, tonsils, and thymus.These cell lines include B and T lymphocytes, natural killer cells, monocytes, macrophages, microglial cells, and mast cells.

Like CB1 receptors, endocannabinoid stimulation inhibits neurotransmission of CB2 receptors.

Cultured microglial dells

A study of cultured microglial cells showed c-interferon and granulocyte macrophage-colony stimulating factor (GM-CSF), known as inflammatory response activators of microglial cell, were accompanied by significant CB2 receptor upregulation.

This suggested that the CB2 receptors play an important role in microglial cell function in the CNS inflammatory response. Activation of CB2 has been implicated in several neurodegenerative diseases such as Huntington’s (HD) and AD

Increased expression of CB2 in the brain was confirmed with CB2-selective positron emission tomography (PET) tracers in Alzheimer’s mice models. This increased expression was concomitant with the formation of amyloid-beta plaques, suggesting a potential utility for CB2 PET tracers as a diagnostic modality for detecting the onset of neuroinflammation.

Unique mechanisms of CBD

The interaction of CBD with CB2 receptors is more complex, but like Δ9-THC, CBD is believed to reduce the inflammatory response. CBD’s action with the CB2 receptor is just one of several pathways by which CBD can affect neuroinflammation [Table 2].

Because both CBD and Δ9-THC modulate the activity of G protein-coupled receptors associated with the endocannabinoid system, and CBD can function as a partial agonist and antagonizes Δ9-THC, CBD at higher doses may counter to some extent the psychoactive effects of Δ9-THC.

Anecdotally, this effect is noted by many cannabis users who co-ingest CBD.

Ongoing research indicates a wide range of cellular mechanisms associated with CBD and the ECS. Specific cellular targets include neurons, endothelial cells, oligodendrocytes and microglial cells

Molecular targets of CBD

Molecular targets of CBD, including cannabinoid and noncannabinoid receptors, enzymes, transporters, and cellular uptake proteins, help to explain CBD’s low-binding affinity to both CB1 and CB2 cannabinoid receptors.

In animal models, CBD has demonstrated an ability to attenuate brain damage associated with neurodegenerative and/or ischemic conditions outside the ECS.

CBD appears to stimulate synaptic plasticity and facilitates neurogenesis that may explain its positive effects on attenuating psychotic, anxiety, and depressive behaviors. The mechanisms underlying these effects involve multiple cellular targets to elevate brain-derived neurotropic factor (BDNF) levels, reduce microglia activation, and decrease levels of proinflammatory mediators.

Very low toxicity of CBD in humans

Unlike the psychoactive properties associated with Δ9-THC, CBD has been shown to have very low toxicity in humans and in other species (see Safety section). Ingested and absorbed CBD is rapidly distributed, and due to its lipophilic nature can easily pass the blood–brain barrier.

The terminal half-life of CBD is about 9 h and is preferentially excreted in the urine as its free and glucuronide form

Research on the endocannabinoid system

Research on the ECS is fervently ongoing with wide-ranging discoveries. The roles of endogenous cannabinoid, phytocannabinoids, and synthetic pharmacological agents acting on the various elements of the ECS have a potential to affect a wide range of pathologies, including food intake disorders, chronic pain, emesis, insomnia, glaucoma, gliomas, involuntary motor disorders, stroke, and psychiatric conditions such as depression, autism, and schizophrenia

Research into ECS’s role in the stress response has revealed a significant influence on the hypothalamic–pituitary–adrenal axis, the control of reproduction by modifying gonadotropin release, fertility, and sexual behavior.

The remaining sections will focus on the ECS and the effects of the phytocannabinoids, CBD and Δ9-THC, on neuroinflammation, neuroprotection, and their potential use in the treatment of specific neurological disorders including trauma involving the CNS

Neuroprotective benefits of phytocannabinoids

CBD research in animal models and humans has shown numerous therapeutic properties for brain function and protection, both by its effect on the ECS directly and by influencing endogenous cannabinoids.

Broadly, CBD has demonstrated anxiolytic, antidepressant, neuroprotective antiinflammatory, and immunomodulatory benefits.

CBD decreases the production of inflammatory cytokines, influences microglial cells to return to a ramified state, preserves cerebral circulation during ischemic events, and reduces vascular changes and neuroinflammation.

Other effects of CBD

Other effects of CBD include the inhibition of calcium transport across membranes, the inhibition of anandamide uptake and enzymatic hydrolysis, and inhibition of inducible NO synthase protein expression and nuclear factor (NF)-κB activation.

CBD increases brain adenosine levels by reducing adenosine reuptake. Increased adenosine is associated with neuroprotection and decreased inflammation after brain trauma.

CBD is also known to exert vascular effects, producing vasodilation as well as hypotension that may hold promise as protectant against cerebrovascular damage associated with stroke.

CBD has several features that may be exploited for the treatment of AD, including the prevention of glutamate-induced excitotoxicity, reduction of proinflammatory mediators, and the ability to scavenge reactive oxygen species (ROS) and reduce lipid peroxidation

Experimental in vitro cannabinoid receptor interactions

Experimentally, in vitro, cannabinoid receptor interactions with CBD and Δ9-THC, together and separately, have demonstrated neuronal protection from excitotoxicity, hypoxia, and glucose deprivation; in vivo, cannabinoids decrease hippocampal neuronal loss and infarct volume after cerebral ischemia, acute brain trauma, and induced excitotoxicity.

These effects have been ascribed to inhibition of glutamate transmission, reduction of calcium influx, reduced microglial activation, and subsequent inhibition of noxious cascades, such as tumor necrosis factor-alpha generation and oxidative stress

Delta-9-THC

Δ9-THC can mediate the effects of the neurotransmitter serotonin by decreasing 5-HT3 receptor neurotransmission. This can contribute to the pharmacological action to reduce nausea. This effect can be reversed at higher doses or with chronic use of Δ9-THC.

Synthetic analogs of Δ9-THC, nabilone (Cesamet, Valeant Pharmaceuticals North America) and dronabinol (Marinol-Solvay Pharmaceuticals), are prescribed for the suppression of the nausea and vomiting produced by chemotherapy.

There is limited use for synthetic Δ9-THC due to multiple side effects mediated through activation of CB1 on the CNS in this population.

Brain neuroprotective effects of delta-9-THC

Δ9-THC has also been shown to protect the brain from various neuronal insults and improve the symptoms of neurodegeneration in animal models of MS, PD, HD, amyotrophic lateral sclerosis (ALS), and AD.

Like CBD, Δ9-THC can offer non-ECS protection by direct effect on neuronal cells, and nonneuronal elements within the brain.

Mechanisms include modulation of excitatory glutamatergic transmissions and synaptic plasticity, modulation of immune responses, the release of antiinflammatory mediators, modulation of excitability of N-methyl-D-aspartate receptors and its effect on gap junctions, calcium, and antioxidants

Neurodegenerative diseases

Neurodegenerative diseases include a large group of conditions associated with progressive neuronal loss leading to a variety of clinical manifestations. Histomorphological changes can include gliosis and proliferation of microglia along with aggregates of misfolded or aberrant proteins. The most common neurodegenerative conditions include AD, ALS, HD, Lewy body disease, and PD.

Overview

Numerous applications of CBD and delta-9-THC for neurodegenerative diseases.

Both CBD and Δ9-THC can function as agonist and antagonistic on various receptors in the ECS. In addition, a wide range of non-ECS receptors can be influenced by both endogenous and phytocannabinoids.

Neuroprotection for AD

AD is characterized by enhanced beta-amyloid peptide deposition along with glial activation in senile plaques, selective neuronal loss, and cognitive deficits.

Cannabinoids are neuroprotective against excitotoxicity in vitro and in patients with acute brain damage. In human AD patients, cellular studies of senile plaques have shown expression of cannabinoid receptors CB1 and CB2, together with markers of microglial activation. Control CB1-positive neurons, however, are in greater numbers compared to AD areas of microglial activation.

AD brains also have markedly decreased G-protein receptor coupling and CB1 receptor protein expression. Activated microglia cluster at senile plaques is generally believed to be responsible for the ongoing inflammatory process in the disease.

Research with administered cannabinoids for AD

Research with administered cannabinoids for AD in animals has demonstrated CB1 agonism is able to prevent tau hyperphosphorylation in cultured neurons and antagonize cellular changes and behavioral consequences in β-amyloid-induced rodents.

CB2 antagonists were protective in in vivo experiments by downregulating reactive gliosis occurring in β-amyloid-injected animals. In addition, AD-induced microglial activation and loss of neurons was inhibited.

AD-induced activation of cultured microglial cells, as judged by mitochondrial activity, cell morphology, and tumor necrosis factor release, is blunted by cannabinoid compounds.

Additionally, Δ9-THC has been shown to reduce the agitation that is common in patients with severe AD.

Cannabidiol

CBD is effective in an experimental model of Parkinsonism (6-hydroxydopamine-lesioned rats) by acting through antioxidant mechanisms independently of cannabinoid receptors.

It attenuates PD-related dystonia, but not tremor, in agreement with a positive correlation between CBD levels measured in the putamen/globus pallidus of recreational users of cannabis

CBD, and to a lesser degree Δ9-THC, can have both direct and indirect effects on isoforms of peroxisome proliferator-activated receptors (PPARs α, β, and γ). Activation of PPAR, along with CB1 and CB2, mediates numerous analgesic, neuroprotective, neuronal function modulation, antiinflammatory, metabolic, antitumor, gastrointestinal, and cardiovascular effects, both in and outside the ECS.

In addition, PPAR-γ (gamma) agonists have been used in the treatment of hyperlipidemia and hyperglycemia. PPAR-γ decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells, thereby reducing atherosclerosis. Phytocannabinoids can increase the transcriptional activity of and exert effects that are inhibited by selective antagonists of PPAR-γ, thus increasing production.

CBD is further involved in the modulation of different receptors outside the ECS. The serotonin receptors have been implicated in the therapeutic effects of CBD. In a rat model, CBD was observed to stimulate hippocampal neurogenesis. Neuroprotective effects of CBD in hypoxic–ischemic brain damage model involve adenosine A2 receptors. CBD activation of adenosine receptors can enhance adenosine signaling to mediate antiinflammatory and immunosuppressive effects. In a rat model of AD, CBD blunted the effects of reactive gliosis and subsequent β-amyloid-induced neurotoxicity

Delta-9-THC

n an animal model of AD, treatment with Δ9-THC (3 mg/kg) once daily for 4 weeks with addition of a COX-2 inhibitor reduced the number of beta-amyloid plaques and degenerated neurons. Δ9-THC has been used for AD symptom control. Treatment with 2.5 mg dronabinol (a synthetic analog of Δ9-THC) daily for 2 weeks significantly improved the neuropsychiatric inventory total score for agitation and aberrant motor and nighttime behaviors

Multiple sclerosis

MS is an autoimmune disease that promotes demyelination of neurons and subsequent aberrant neuronal firing that contributes to spasticity and neuropathic pain.

The pathologic changes of MS include neuroinflammation, excitotoxicity, demyelination, and neurodegeneration. These pathological features share similarities with other neurodegenerative conditions, including AD and cerebral ischemia. The combination of antiinflammatory, oligoprotective, and neuroprotective compounds that target the ECS may offer symptomatic and therapeutic treatment of MS.

CBD and delta-9-THC

The use of cannabis-based medicine for neurodegenerative conditions

The use of cannabis-based medicine for the treatment of MS has a long history and its interaction with the ECS shares many of the same pathways of other neurodegenerative conditions.

In models of experimental MS, stimulation of CB1 and CB2 receptors has been shown to be beneficial against the inflammatory process, lending support to early findings showing that individuals with MS experience a reduction in the frequency of relapses when smoking marijuana

Neuropsychiatric and brain trauma

CBD is recognized as a nonpsychoactive phytocannabinoid. Both human observational and animal studies, however, have demonstrated a broad range of therapeutic effects for several neuropsychiatric disorders. CBD has positive effects on attenuating psychotic, anxiety, and depressive-like behaviors. The mechanisms appear to be related to the CBD’s benefit to provide enhanced neuroprotection and inhibition of excessive neuroinflammatory responses in neurodegenerative diseases and conditions. Common features involving neuroprotective mechanisms influenced by CBD—oxidative stress, immune mediators, and neurotrophic factors—are also important in conditions such as posttraumatic stress disorder (PTSD), postconcussion syndrome, depression, and anxiety.

Cannabidiol

Many studies confirm that the function of the ECS is markedly increased in response to pathogenic events like trauma. This fact, as well as numerous studies on experimental models of brain trauma, supports the role of cannabinoids and their interactions with CB1 and CB2 as part of the brain’s compensatory and repair mechanisms following injury. Animal studies indicate that posthead injury administration of exogenous CBD reduces short-term brain damage by improving brain metabolic activity, reducing cerebral hemodynamic impairment, and decreasing brain edema and seizures. These benefits are believed to be due to CBD’s ability to increase anandamide.

Link to post about anandamide

Treatment with CBD

Treatment with CBD may also decrease the intensity and impact of symptoms commonly associated with PTSD, including chronic anxiety in stressful environments

By reducing induced anxiety, CBD may help to regulate the negative effects associated with PTSD. In rodent models, CBD effectively blocked the formation of fearful memories

Perhaps because it inhibits the formation of memories?

CBD may be an effective strategy to combat PTSD fear memory acquisition because of its direct effects diminishing the severity of traumatic memory. Rat trials also show CBD’s potential in fear memory extinction, demonstrated through a significant decrease in freezing time when re-exposed to an anxiety-inducing situation. Treatment with CBD has also been shown to attenuate contextual memories associated with past experience in murine experiments, showing CBD’s ability to disrupt harmful memories.

Antidepressant and neuroprotective properties

Antidepressants, used for the treatment of depression and some anxiety disorders, also possess numerous neuroprotective properties, such as preventing the formation of amyloid plaques, elevation of BDNF levels, reduction of microglia activation, and decreased levels of proinflammatory mediators. 

Similarly, CBD decreases the production of inflammatory cytokines, the activation of microglial cells, and brain leucocytes infiltration.

Rat models; efficacy of CBD in neurobehavioral disorders

In rat models of neurobehavioral disorders, CBD demonstrated attenuation of acute autonomic responses evoked by stress, inducing anxiolytic and antidepressive effects by activating 5HT1A receptors in a similar manner as the pharmaceutical buspirone that is approved for relieving anxiety and depression in humans. 

CBD experimentally attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation in a pharmacological model of schizophrenia. A double-blind, randomized clinical trial with CBD reported a significant clinical improvement similar to the antipsychotic amisulpride, but with less side effects. 

Modulation of autophagy and enhanced neuronal survival have been reported using CBD in neurodegenerative experimental models, suggesting benefits of CBD for psychiatric/cognitive symptoms associated with neurodegeneration

Human imaging studies correlated with CBD

Human imaging studies have demonstrated CBD affects brain areas involved in the neurobiology of psychiatric disorders. A study has showed that a single dose of CBD, administered orally in healthy volunteers, alters the resting activity in limbic and paralimbic brain areas while decreasing subjective anxiety associated with the scanning procedure.

CBD reduced the activity of the left amygdala–hippocampal complex, hypothalamus, and posterior cingulated cortex while increasing the activity of the left parahippocampal gyrus compared with placebo. In healthy volunteers treated with CBD and submitted to a presentation of fearful faces, there was a decrease of the amygdala and anterior and posterior cingulate cortex activities and a disruption in the amygdala–anterior cingulated cortex connectivity.

In healthy humans, CBD reversed the anxiogenic effects of Δ9-THC and reduced anxiety in a simulated public-speaking task

Tetrahydrocannabinol

Interestingly, THC, administered prior to a traumatic insult in human case studies and animal models has had measurable neuroprotective effects.

In a 3-year retrospective study of patients who had sustained a traumatic brain injury (TBI), decreased mortality was reported in individuals with a positive Δ9-THC screen. In mouse models of CNS injury, prior administration of Δ9-THC provided impairment protection.

Anxiety relief in humans

For anxiety relief in humans, variability in the responses to cannabis depends on multiple factors, such as the relative concentrations of Δ9-THC and other phytocannabinoids. Studies have found Δ9-THC facilitates fear extinction. The 9-THC disrupts the reconsolidation of a fear memory in a manner dependent on activation of CB1.

In humans, oral dronabinol (synthetic 9-THC) prevents the recovery of fear. In general, conditions associated with chronic stress appear to be positively responsive to phytocannabinoids.

Studies in rat models reported that cannabinoids prevented the effects of acute stress on learning and memory and improved neuroplasticity, behavioral, and neuroendocrine measures of anxiety and depression.

Cancer

Cancer is a disease characterized by uncontrolled division of cells and their ability to spread. Novel anticancer agents are often tested for their ability to induce apoptosis and maintain steady-state cell population.

In the early 1970s, phytocannabinoids were shown to inhibit tumor growth and prolong the life of mice with lung adenocarcinoma.

Later studies have demonstrated cannabinoids inhibited tumor cell growth and induced apoptosis by modulating different cell signaling pathways in gliomas, lymphoma, prostate, breast, skin, and pancreatic cancer cells as well.[

CBD and THC

Utility for glioblastoma multiforme

Glioblastoma multiforme (GBM) is the most frequent class of malignant primary brain tumors. Both animal and human studies have demonstrated both Δ9-THC and CBD, combined and separately, have significant antitumor actions on GBM cancer cell growth. The mechanism of Δ9-THC antitumoral action is through ER stress-related signaling and upregulation of the transcriptional coactivators that promote autophagy

CBD reduces growth different tumor xenografts

CBD has also been shown to reduce the growth of different types of tumor xenografts including gliomas. The mechanism of action of CBD is thought to be increased production of ROS in glioma cells, thereby inducing cytotoxicity or apoptosis and autophagy.

CBD is able to inhibit cancer cell invasion and metastasis mediated by inhibition of epidermal growth factor, NF-κB, and mTOR pathways. mTOR signaling pathway acts as the central regulator of cell metabolism, growth, proliferation, and survival, and is critical for tumor suppression. CBD also reduces angiogenesis through actions on both tumor and endothelial cells

In Feb 2017, GW Pharmaceuticals announced positive results from a phase 2 placebo-controlled clinical study of their proprietary drug combining of Δ9-THC and CBD in 21 patients with recurrent GBM. The results showed 83% one-year treatment group survival rate compared with 53% for patients in the placebo cohort (P = 0.042).

Intractable epilepsy

Reports of cannabis use in the treatment of epilepsy appear as far back as 1800 BC. Scientific reports appear in 1881 from neurologists using Indian hemp to treat epilepsy with dramatic success. 

The use of cannabis therapy for the treatment of epilepsy diminished with the introduction of phenobarbital and phenytoin and the passage of laws prohibiting marijuana use in the U.S.

Cannabidiol

Experiments with Δ9-THC have demonstrated a rebound hyperexcitability in the CNS in mice, with enhanced neuronal excitability and increased sensitivity to convulsions and has not been used on most trials of intractable epilepsy. CBD, however, produces antiepileptiform and anticonvulsant effects in both in vitro and in vivo models

As with most cannabinoid research to date, conducting studies can be difficult due to limited legal access to medical grade marijuana and phytocannabinoid extracts. Hemp-derived CBD, however, has recently experienced less regulation and as a result research using CBD for refractory epilepsy has experienced a resurgence.

CBDs reduce neuronal hyperactivity in epilepsy. CBD’s overall effect appears to result in reduction of neuronal hyperactivity in epilepsy. 

As discussed earlier, the CB1 receptor is a presynaptic, G-protein-coupled receptor that activates voltage-gated calcium channels and enhances potassium-channel conduction in presynaptic terminals.

While Δ9-THC binds directly to CB1 receptors, CBD has indirect effects by increasing endogenous anandamide expression. Anandamide affects excitability in neuronal networks by activating the transient receptor potential (TRP) cation channel. CBD regulation of Ca2+ homeostasis via several mechanisms may contribute to these actions, particularly for partial or generalized seizures

Endogenous cannabinoids

Endogenous cannabinoids appear to affect the initiation, propagation, and spread of seizures. Studies have identified defects in the ECS in some patients with refractory seizure disorders, specifically having low levels of anandamide and reduced numbers of CB1 receptors in CSF and tissue biopsy. Additionally, the ECS is strongly activated by seizures, and the upregulation of CB1 receptor activity has antiseizure effects

The pharmaceutical company, GW Pharmaceuticals, is currently developing the CBD drug, Epidiolex® that is a purified, 99% oil-based CBD extract from the cannabis plant. Results of a recent 2015 open-label study (without a placebo control) in 137 people with treatment-resistant epilepsy indicated that 12 weeks of Epidiolex® reduced the median number of seizures by 54%.

Despite the preclinical data by GW Pharmaceutical and anecdotal reports on the efficacy of cannabis in the treatment of epilepsy, a 2014 Cochrane review concluded that “no reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy.” This report noted this conclusion was mostly due to the lack of adequate data from randomized, controlled trials of Δ9-THC, CBD, or any other cannabinoid in combination

Safety

A comprehensive safety and side effect review of CBD in 2016 on both animal and human studies described an excellent safety profile of CBD in humans at a wide variety of doses. The most commonly reported side effects were tiredness, diarrhea, and changes of appetite/weight. 

In studies comparing other medicinal drugs used for the treatment of these medical conditions, CBD also had a very favorable side effect profile. CBD does have interactions with common hepatic (drug)-metabolizing enzymes, belonging to the cytochrome P450 family. Therefore, interactions with drug transporters and interactions with drugs must be considered.

CBD – better safety profile vs. other cannabinoids

CBD also has a better safety profile compared to other cannabinoids, such as THC. For instance, high doses of CBD (up to 1500 mg/day) are well tolerated in animals and humans. In contrast to THC, CBD does not alter heart rate, blood pressure, or body temperature, does not induce catalepsy, nor alter psychomotor or psychological functions.

Adverse effects

The 2014 AAN review of 34 articles on MS using cannabinoids of various forms noted several adverse effects. Reported symptoms included nausea, increased weakness, behavioral or mood changes (or both), suicidal ideation or hallucinations, dizziness or vasovagal symptoms (or both), fatigue, and feelings of intoxication. Psychosis, dysphoria, and anxiety were associated with higher concentrations of THC. However, no direct fatalities or overdoses have been attributed to marijuana, even in recreational users of increasingly potent marijuana possibly due to lack of endocannabinoid receptors in the brainstem

In a recent rule change by the World Anti-Doping Agency or WADA, CBD will no longer be listed as a banned substance for international sport competition for 2018.

Dosing

It is beyond the scope of this review to provide any meaningful dosing recommendations for CBD or Δ9-THC. Like other cannabinoids, CBD produces bell-shaped dose–response curves and can act by different mechanisms according to its concentration or the simultaneous presence of other cannabinoid-ligands.[11,70] In general, due to significant psychoactive properties of Δ9-THC, the therapeutic dose range is limited by side effects

FDA approvals

The FDA has approved the synthetic drugs Cesamet®, Marinol®, and Syndros® for therapeutic uses in the U.S. FDA-posted indications include nausea and the treatment of anorexia associated with weight loss in AIDS patients. Marinol® and Syndros® include the active ingredient dronabinol, a synthetic delta-9-THC. Cesamet® contains the active ingredient nabilone that has a chemical structure similar to THC and is also synthetically derived. Although these medications are often cited in human clinical research, their general use is limited based both on side effects and indication constraints.

CONCLUSION

Although federal and state laws are inconsistent about the legality of cannabis production, its increasingly documented health benefits make it once again relevant in medicine.

Current research indicates the phytocannabinoids have a powerful therapeutic potential in a variety of ailments primarily through their interaction with the ECS.

CBD is of particular interest due to its wide-ranging capabilities and lack of side effects in a variety of neurological conditions and diseases.

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2 thoughts on “Neurological benefits of phytocannabinoids

  1. leejcaroll

    just nmade legal in Pa and was so excited cause my pain is neuropathic. have tried a few different formats with no success so far (well minimal it does seem to stop it from ‘jumping the shark” get to a point where if I continue the pain will put me down for 2 – 3 hours and instead seems not to get to that final I cant take it level. which is a benefit I g uess just a lot less then what I had hoped for but then hope springs eternal

    Liked by 1 person

    Reply
    1. Zyp Czyk Post author

      What a wonderful development for you! How much it helps is very individual; I know some for whom it works as well as opioids and others whom it doesn’t help at all. I’m pretty far down on the scale myself and don’t get much serious relief from it.

      But it does wonders for the frustration and anger that sometimes arises when pain has made me cranky. It allows me to “unhook” myself from whatever is irritating me, just let it go… and that helps a little with pain too.

      Like

      Reply

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