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cbd mechanism of action

Cannabidiol

Related terms:

  • Cannabis
  • Cannabinoids
  • Eicosanoid Receptor
  • Dementia Praecox
  • Tetrahydrocannabinol
  • Endocannabinoids
  • Cannabinoid 1 Receptor

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Cannabinoid Regulation of Intraocular Pressure: Human and Animal Studies, Cellular and Molecular Targets

Cannabidiol

Cannabidiol (CBD), a non-CB1/CB2 phytocannabinoid, has been studied for its ability to reduce IOP. Intravenous administration of CBD in normotensive rabbits was unable to reduce IOP ( Elsohly et al., 1981; Green et al., 1982 ). Additionally, a comparison of the effects of CBD and Δ 9 -THC sublingual application in humans with open angle glaucoma showed that CBD is unable to reduce IOP ( Tomida et al., 2006 ). However, in another study, CBD delivered topically to cat eye had a hypotensive effect, without ocular toxicity or neurotoxicity ( Colasanti et al., 1984a ). Thus, CBD is able to reduce IOP in cats, but not in rabbits or humans.

The Molecular Basis of Drug Addiction

13 Cannabidiol

CBD has many diverse functions in the brain and there has been much interest in it as a pharmacotherapy for numerous disorders (reviewed in Refs [8,153] ). As of 2015, over 75 studies using CBD were registered on clinicaltrials.gov. Studies in preclinical animal models and humans have provided evidence suggesting that CBD has neuroprotective, anti-inflammatory, anxiolytic, and antipsychotic properties. CBD, along with Δ 9 -THC, is found in relatively high levels in Cannabis. 154 Some strains of Cannabis are particularly rich in CBD (CBD:Δ 9 -THC content greater than 20:1).

CBD is considered a multitarget drug and interacts with a diverse array of signaling systems. Unlike Δ 9 -THC, CBD is not a direct ligand for CB1 or CB2 receptors. Depending on the interaction, CBD can have both enhance and inhibit signaling. CBD increases serotonergic activity via enhanced 5-HT1a signaling. It also has a facilitatory effect on α3 and α1 glycine receptors, transient receptor potential of ankyrin type 1 channel (TRPA1) and can both enhance and inhibit intracellular calcium flux. At higher concentrations CBD can activate TRPV1 and TRPV2 channels. CBD can inhibit multiple targets at low concentrations. It reduces signaling at the putative but poorly characterized cannabinoid receptor GPR55. It can also act as an antagonist of the transient receptor potential of melastatin type 8 channel (TRPM8) and the equilibrative nucleoside transporter (ENT). 8,32,153,155–158

One critical mechanism of CBD action that has been described is its ability to enhance intrinsic signaling of the endocannabinoid anandamide by decreasing cellular uptake and FAAH-mediated catabolism. 159 This could play a significant role in the therapeutic effects of CBD. Clinical studies have shown that endogenous anandamide levels are inversely correlated with psychotic symptoms 160,161 and administration of CBD in patients with schizophrenia enhances serum anandamide levels that correlate with significant clinical improvement. 162 These results are in contrast to findings correlating Cannabis use with the development of psychosis. 163,164

Beneficial Effects of Cannabis and Related Compounds on Sleep

Cannabidiol

CBD has previously been demonstrated to affect the sleep-wake cycle. Its effects at different doses and routes of administration are still unclear, with contradictory reports ranging from increased wakefulness to sedative and hypnotic effects ( Nicholson et al., 2004 ; Zuardi, 2008 ).

In healthy volunteers with at least 6 h of sleep, CBD (600 mg) induced sedative effects ( Zuardi, Guimaraes, & Moreira, 1993 ). In volunteers with complaints of insomnia, CBD was associated with an increased total sleep time and less frequent arousals at 160 mg/day ( Carlini & Cunha, 1981 ). This study also reported that CBD reduced dream retrieval and caused no “hangover” at 40, 80, and 160 mg/day ( Carlini & Cunha, 1981 ). However, at low doses (15 mg/day), when coadministered with delta-9-THC (15 mg/day), CBD increased wakefulness ( Nicholson et al., 2004 ).

Similar to CBD sleep clinical trials, studies in animal models are also scarce. The first investigation assessing the effects of systemic CBD administration on sleep demonstrated a decreased SWS latency at 20 mg CBD per kg and increased duration of SWS and decreased wakefulness at 40 mg CBD per kg, with no significant changes in the REM sleep phase ( Monti, 1977 ). During this study, the effects of CBD were recorded for 5 h after CBD administration. Chagas et al. (2013) evaluated the effects of acute CBD administration in rats and demonstrated that CBD appears to increase total sleep time, sleep latency and the percentage of SWS during the light period.

Recently, two studies used intraventricular administration and lateral hypothalamus infusion ( Murillo-Rodriguez, Millan-Aldaco, Palomero-Rivero, Mechoulam, & Drucker-Colin, 2006 ; Murillo-Rodriguez, Millan-Aldaco, Palomero-Rivero, Mechoulam, & Drucker-Colin, 2008 ) and observed contrasting effects compared with Monti (1977) . Intracerebroventricular CBD administration (10 μg/μL) increased wake time 1 and 4 h after CBD administration, and reduced the duration of REM sleep with no changes in SWS ( Murillo-Rodriguez et al., 2006 ). The injection of CBD or placebo in the lateral hypothalamus also increased wake time, reduced REM sleep time, and significantly decreased the SWS ( Murillo-Rodriguez et al., 2008 ). These data suggest that the effects of CBD vary according to the route and dose of administration.

Development & Modification of Bioactivity

Arno Hazekamp , . Renee L. Ruhaak , in Comprehensive Natural Products II , 2010

3.24.4.2 Cannabidiol

CBD is, together with CBG, the major nonpsychotropic cannabinoid found in Cannabis. It is the principal cannabinoid present in fiber-type Cannabis (in the form of its carboxylic acid CBDA), a plant that is easily available to researchers, in contrast to the strictly controlled drug-type Cannabis varieties. Second to THC, the pharmacological effects of CBD have been best studied of all cannabinoids. It has powerful antioxidant properties, more potent than ascorbate and α-tocopherol. Also, it has notable anti-inflammatory and immunomodulatory effects. 191 Furthermore, sedating, hypnotic, antiepileptic, and antidystonic effects have been described. Also, CBD is a modulator of some types of opioid receptors, 192 and can modulate sleep in rats. 193

CBD was found to have antianxiety effects. 194 In a clinical trial, oral administration of 400 mg of CBD resulted in decreased anxiety and increased mental sedation in test subjects. 195 It was concluded that CBD possesses anxiolytic properties, possibly mediated by an action on limbic and paralimbic brain areas, where it reduced regional cerebral blood flow. These anxiolytic properties might prove useful in psychiatry. Possibly the most significant conclusion of this study is that a dose as high as 400 mg of CBD had no adverse effects. CBD was furthermore found to have antipsychotic benefits. 196

A prominent effect of CBD was found in a variety of cancer studies. In a mouse model of metastatic breast cancer, CBD reduced the aggressiveness of breast cancer cells, by inhibiting a crucial protein for cancer development. 197 The study concluded that CBD represents the first nontoxic exogenous agent that can significantly inhibit metastatic breast cancer cells leading to the downregulation of tumor aggressiveness. Currently, there is a limited range of options in treating certain aggressive forms of cancer. CBD offers the hope of a nontoxic therapy that could achieve significant results without any of the painful side effects associated with standard therapy. Both in vitro and in vivo CBD were able to produce a significant antitumor activity on glioma cells. This antiproliferative effect of CBD was shown to be correlated to induction of apoptosis, which suggests a possible application of CBD as an antineoplastic agent. Effects were partially prevented by a (nonpsychoactive) CB2 receptor antagonist, suggesting a role for CB2 in cancer treatment. 198

In another study performed on a panel of tumor cell lines with a variety of plant-derived cannabinoids, CBD was the most potent inhibitor of cancer cell growth, with significantly lower potency in noncancer cells. A CBD-rich Cannabis extract was equipotent to CBD, whereas CBG and CBC followed in the rank of potency. 199 It was suggested that the observed effect was due to the capability of CBD to induce apoptosis through cannabinoid receptors, or cannabinoid/vanilloid receptor-independent elevation of intracellular Ca 2+ and reactive oxygen species. These data support the further testing of CBD and CBD-rich extracts for the potential treatment of cancer.

In many Cannabis varieties CBD is present in significant amounts. 200 However, only since a few years there is serious attention for THC–CBD interaction and this is mostly in studies on multiple sclerosis. Earlier studies focusing on the effect of THC alone have generally shown the use of Cannabis to be ineffective in many disease models, and such negative results unfortunately helped to shape the controversy in the discussion on the moral and ethical sides of Cannabis use in multiple sclerosis and other diseases. 201 It is known that CBD inhibits the metabolism of THC, by blocking its conversion to the more psychoactive 11-OH-THC by cytochrome P-450 (CYP) 3A11. 202 Possibly this is the reason why CBD is known to antagonize the psychotropic effects of THC. 203 Even though higher doses of THC are capable of inducing psychotic problems in some users, CBD seems to have an antipsychotic effect, its presence balancing the negative impact of THC consumption. 26 This property of CBD is exploited in the Cannabis-based medicine Sativex (discussed in Section 3.24.6.2 ).

Cannabidiol and Neuroprotection: Evidence from Preclinical Studies

N. Schröder , . J.A. de Souza Crippa , in Handbook of Cannabis and Related Pathologies , 2017

Abstract

Cannabidiol (CBD) is the main nonpsychotropic constituent of Cannabis sativa. In recent years, preclinical in vitro and in vivo studies have investigated the potential of CBD in experimental models focusing on neurodegeneration. The purpose of this chapter is to provide a comprehensive overview on the main studies reporting the effects of CBD in the context of hypoxic-ischemic injury and Alzheimer’s disease, as well as other relevant experimental models of neurodegeneration, and to discuss its putative mechanisms. Evidence indicates that CBD displays antioxidant, antiinflammatory, and antiapoptotic properties, and can also prevent excitotoxic damage, and protect mitochondria against toxins. Accordingly, CBD was shown to ameliorate damage observed in animal models of neurodegeneration associated to hypoxic-ischemic brain injury, multiple sclerosis, brain iron overload, Alzheimer’s, Parkinson’s, and Huntington’s disease. Thus, CBD may constitute a promising therapeutic agent for the prevention/treatment of neurodegenerative disorders.

Cannabidiol and 5-HT1A Receptors

Manoela V. Fogaça , . Francisco S. Guimarães , in Neuropathology of Drug Addictions and Substance Misuse , 2016

Other Relevant Mechanisms Related to Cannabidiol Effects

CBD increases intracellular calcium concentrations via mitochondrial uptake and release, associated with activation of type L voltage-gated calcium channels. CBD also inhibits oxidative and nitrosative stress, a mechanism that has been related to its action on PPARγ receptors, with promising implications for the treatment of Alzheimer, Huntington, and Parkinson diseases. CBD decreases the neuronal damage promoted by β-amyloid protein deposits and attenuates the depletion of tyrosine hydroxylase, dopamine, and γ-aminobutyric acid levels induced by neurotoxic stimuli, modulating the expression of the inducible isoform of nitric oxide synthase and reducing the production of reactive oxygen species-generating NADPH oxidases. Moreover, CBD treatment attenuated high-glucose-induced mitochondrial superoxide generation and nuclear factor-κB activation, along with expression of the adhesion molecules ICAM-1 and VCAM-1. Although the exact mechanisms involved in these CBD effects remain unclear, they might be due to CBD agonist activity at PPAR receptors. CBD could also act at the level of the mitochondria or inside the nucleus to oppose oxidative/nitrosative stress ( Fernandez-Ruiz et al., 2013 ).

Peripheral Neuropathy

Cannabinoids

Through the growing changes in the legalization of cannabis and the use of medical cannabis for chronic pain syndromes, one must start to look at the importance of cannabinoid medicine as part of an integrative medicine approach. Two primary types of cannabinoid receptors (CB1 and CB2) exist on cells throughout the body. These receptors are most abundant in the brain (CNS) and peripheral tissues, respectively. Medial cannabis contains both THC (delta-9 tetrahydrocannabinol), the part that is psychogenic, and CBD ( cannabidiols ), the part that is not. Both have numerous health benefits in diabetes and its complications. 216

Cannabinoids represent a new class of therapeutic agents for the treatment of chronic pain and other diseases that involve glycine receptor dysfunction. 217 In addition to alleviating pain, studies on the benefits of cannabinoids have included improvement of quality of life and sleep. 218

Randomized placebo-controlled trials (RCTs) involving cannabis and cannabinoids have been used in different populations of chronic neuropathic pain patients to provide effective analgesia in conditions that are refractory to other treatments. 219

Although currently not available in the US (due to its THC content), a prescription medication called Sativex, which contains THC:CBD in an approximate 1:1 ratio, has been investigated. Multicenter, randomized controlled trials, along with double-blind, randomized, placebo-controlled trials, used the THC:CBD oral spray and demonstrated a significant reduction in pain by 30%. 220-222 Current applications are pending with the FDA for the indication for treatment of peripheral neuropathy with this oral spray. However, with this combination THC:CBD formulation, tolerability of increasing doses of THC in lieu of adequate analgesia was the most common side effect and depression was also a confounding factor. 220-226

Newer sources of CBD, which are derived from industrial hemp, containing CBD and traces of THC, are currently available. Therefore, without the psychogenic component and without accessibility being an issue, as it is currently legal and available in all 50 states, these are a great alternative option for patients regardless of the federal and state restrictions that may be in place for medical cannabis. 227 With this opportunity available, CBD has now been studied on its own.

Cannabidiol (CBD) decreases inflammation and neuropathic pain in preclinical models of diabetes. CBD exposure enhances the ability of arteries to relax via enhanced production of vasodilatory COX-1/2-derived products acting at EP4 receptors. 228 CBD decreases the autoimmune inflammatory phenotype, 229 is an inhibitor of NF-kappaB and interferon-beta/STAT pro-inflammatory pathways, 230 and exhibits analgesic 231,232 and antiinflammatory actions 233,234 in chronic diseases and cancer. CBD also has been shown to lower inflammation in oxidative stress, 238 and may be used to modify the development of the neuropathic pain state by restricting the elevation of microglial density and phosphorylated p38 MAPK. 239 Furthermore, CBD has been shown to inhibit paclitaxel-induced neuropathic pain without diminishing nervous system function or chemotherapy efficacy. 240

A patient’s perception of cannabis and CBD extracts depends greatly on their age, their socioeconomic and cultural beliefs, the location and atmosphere of the dispensary, and federal and state restrictions. Many of my patients are simply afraid to try medical cannabis for one or a combination of these reasons, and, therefore, I preferentially use CBD products to provide health benefits without the other issues related to medical cannabis.

CBD is nontoxic in nontransformed cells, does not induce changes in food intake, does not induce catalepsy, does not affect physiological parameters (heart rate, blood pressure, and body temperature), does not affect gastrointestinal transit, and does not alter psychomotor or psychological functions. No toxicity or side effects have been demonstrated in subjects taking up to 600 mg in a single dose for chronic use. Even higher doses of up to 1500 mg/day of CBD have been shown to be well-tolerated in humans. 227,241-243

Dosage

CBD from industrial hemp oil (high CBD, trace THC). Legal in US without need for a medical card; 5–15 mg bid to tid, with coconut oil (to improve absorption) and stevia (optional for improved taste), held sublingually for 2–3 minutes then swallowed. Doses may be increased weekly for improved response.

CBD:THC from medical cannabis. Ratios of CBD:THC vary according to the strains and dispensary. High CBD low THC is preferred (e.g., 20:1), or similar to the prescribed drug worldwide ratio of 1:1. Administration the same as previously but start with lower doses. 1–2 mg bid to tid to start and increase dose as tolerated. Check state regulations on the legality to prescribe for peripheral neuropathy or chronic pain conditions.

Precautions

CBD and medical cannabis products should be validated by third party laboratories and checked for microbial content, pesticides, herbicides, solvents, and percentage amounts of CBD and THC per unit batch or amount acquired. Avoid cannabinoid use in pregnancy and breast-feeding.

CBD may also potentiate many prescription pain medications, NSAIDs, anticonvulsants, and antidepressants and, therefore, reduction of those medications should be monitored as necessary. Acute glucocorticoid use may be potentiated by CBD, and chronic CBD use may downregulate the glucocorticoid response. 244

Cannabidiol Related terms: Cannabis Cannabinoids Eicosanoid Receptor Dementia Praecox Tetrahydrocannabinol Endocannabinoids Cannabinoid 1 Receptor

Cannabidiol

Identification

Cannabidiol, or CBD, is one of at least 85 active cannabinoids identified within the Cannabis plant. It is a major phytocannabinoid, accounting for up to 40% of the Cannabis plant’s extract, that binds to a wide variety of physiological targets of the endocannabinoid system within the body. Although the exact medical implications are currently being investigated, CBD has shown promise as a therapeutic and pharmaceutical drug target. In particular, CBD has shown promise as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic and has shown neuroprotective, anti-inflammatory, and antioxidant activity, among other currently investigated uses 6,5 . CBD’s exact place within medical practice is still currently hotly debated, however as the body of evidence grows and legislation changes to reflect its wide-spread use, public and medical opinion have changed significantly with regards to its usefulness in a number of medical conditions ranging from anxiety to epilepsy.

From a pharmacological perspective, Cannabis’ (and CBD’s) diverse receptor profile explains its potential application for such a wide variety of medical conditions. Cannabis contains more than 400 different chemical compounds, of which 61 are considered cannabinoids, a class of compounds that act upon endogenous cannabinoid receptors of the body 11 . Cannabinoid receptors are utilized endogenously by the body through the endocannabinoid system, which includes a group of lipid proteins, enzymes, and receptors that are involved in many physiological processes. Through its modulation of neurotransmitter release, the endocannabinoid system regulates cognition, pain sensation, appetite, memory, sleep, immune function, and mood among many other bodily systems. These effects are largely mediated through two members of the G-protein coupled receptor family, cannabinoid receptors 1 and 2 (CB1 and CB2) 12,8 . CB1 receptors are found in both the central and peripheral nervous systems, with the majority of receptors localized to the hippocampus and amygdala of the brain. Physiological effects of using cannabis make sense in the context of its receptor activity as the hippocampus and amygdala are primarily involved with regulation of memory, fear, and emotion. In contrast, CB2 receptors are mainly found peripherally in immune cells, lymphoid tissue, and peripheral nerve terminals 9 .

Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two types of cannabinoids found naturally in the resin of the marijuana plant, both of which interact with the cannabinoid receptors that are found throughout the body. Although THC and CBD have been the most studied cannabinoids, there are many others identified to date including cannabinol (CBN), cannabigerol (CBG), Cannabidivarin (CBDV), and Tetrahydrocannabivarin (THCV) that can be found within the medical cannabis 10 . While both CBD and THC are used for medicinal purposes, they have different receptor activity, function, and physiological effects. If not provided in their activated form (such as through synthetic forms of THC like Dronabinol or Nabilone), THC and CBD are obtained through conversion from their precursors, tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA), through decarboxylation reactions. This can be achieved through heating, smoking, vaporization, or baking of dried unfertilized female cannabis flowers.

The primary psychoactive component of Cannabis, delta 9-tetrahydrocannabinol (Δ9-THC), demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors. This activity results in the well-known effects of smoking cannabis such as increased appetite, reduced pain, and changes in emotional and cognitive processes. In contrast to THC’s weak agonist activity, CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body 5 . Allosteric regulation is achieved through the modulation of receptor activity on a functionally distinct site from the agonist or antagonist binding site which is clinically significant as direct agonists (such as THC) are limited by their psychomimetic effects such as changes to mood, memory, and anxiety 5 .

In addition to the well-known activity on CB1 and CB2 receptors, there is further evidence that CBD also activates 5-HT1A/2A/3A serotonergic and TRPV1–2 vanilloid receptors, antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin and gamma-aminobutyric acid (GABA), and cellular uptake of anandamide, acts on mitochondria Ca2+ stores, blocks low-voltage-activated (T-type) Ca2+ channels, stimulates activity of the inhibitory glycine-receptor, and inhibits activity of fatty amide hydrolase (FAAH) 1,2 .

CBD is currently available in Canada within a 1:1 formulation with tetrahydrocannbinol (THC) (as the formulation known as “nabiximols”) as the brand name product Sativex. It is approved for use as adjunctive treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis (MS). Sativex was also given a conditional Notice of Compliance (NOC/c) for use as adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis and as adjunctive analgesic treatment for moderate to severe pain in adult patients with advanced cancer 17 .

In April 2018, a Food and Drug Administration advisory panel unanimously recommended approval of Epidiolex (cannabidiol oral solution) for the treatment of two rare forms of epilepsy – Lennox-Gastaut syndrome and Dravet syndrome, which are among the two most difficult types of epilepsy to treat 20,18 . Epidiolex was granted Orphan Drug designation as well as Fast Track Approval from the FDA for further study in these hard to treat conditions. Notably, phase 3 clinical trials of Epidiolex have demonstrated clinically significant improvement in Lennox-Gastaut syndrome and Dravet syndrome 19 . On June 25th, 2018, Epidiolex was approved by the FDA to be the first CBD-based product available on the US market.

Type Small Molecule Groups Approved, Investigational Structure

An active cannabinoid used as an adjunctive treatment for the management of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome and symptomatic relief of moderate to severe neuropathic pain or other painful conditions, like cancer.