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Cannabidiol (CBD). Pharmacology and capabilities

Paracelsus

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In recent years, the trend towards legalization and institutionalization, industrial cultivation, breeding and the eternal desire of people to get more, have made a psychosogenic monster out of more or less safe cannabis, It can create mental problems for both predisposed and healthy people.

The active component of cannabis - THC, for the sake of high concentrations of which the best minds of growers are fighting, has become predominant in most varieties. And if 50 years ago its percentage was around 5%, today on average it can reach 15% or even 20%. What to say about concentrated derivatives - hashish, oils, cannafood. High concentrations of cannabis pose a risk to mental health. Primarily associated with psychotic reactions and impaired thinking, memory, emotions, motivation with prolonged and regular intake.

However, nature likes to keep everything in balance. And cannabis research and breeding also has positive aspects. One of the active components of the plant loved by many is Cannabidiol (CBD). A substance having the opposite THC vector and, with your permission, a charge. SBD has protective properties in terms of mental and physical health. It can be said that SBD is a guarantee that cannabis can be used not only as a recreational substance, but also as a medicine, modulator, bioactive additive. Moreover, the potential of SIBIDI can become the key to long-term research on cannabis and its decriminalization and legalization in those countries where this has not yet happened.

Let's try to figure out how the SBD works and what it can give people.

Cannabis contains more than 400 different chemical compounds, 61 of which are considered cannabinoids - a class of compounds that act on endogenous cannabinoid receptors. In addition to THC and CBD, many other potes have been identified today, including cannabinol (CBN), cannabigerol (CBG), cannabidivarin (CBDV) and tetrahydrocannabivarin (THCV), which can be found in medical cannabis

CBD, like THC, is obtained by converting from their precursors, tetrahydrocannabinolic acid-A (THCA-A) and cannabidiolic acid (CBDA), through decarboxylation reactions. This can be achieved by heating, smoking, steaming or baking dried unfertilized female cannabis flowers.

Pharmacology 👨‍⚕️
The exact mechanism of action of CBD looks so layered that so far we know only individual application points, but we do not see the whole picture. CBD is known to act on cannabinoid (CB) receptors.

Cannabinoid receptors are used by the body through the endocannabinoid system, which includes a group of lipid proteins, enzymes and receptors that are involved in many physiological processes. By modulating the release of neurotransmitters, the endocannabinoid system regulates cognitive abilities, pain, appetite, memory, sleep, immune function and mood among many other body systems.

These effects are largely mediated by two members of the G-protein-coupled receptor family, cannabinoid receptors 1 and 2 (CB1 and CB2). CB1 receptors are found in both the central and peripheral nervous systems, with most receptors localized in the hippocampus and amygdala of the brain. The physiological effects of cannabis use make sense in the context of its receptor activity, since the hippocampus and amygdala are primarily involved in the regulation of memory, fear and emotions. On the contrary, CB2 receptors are mainly found peripherally in immune cells, lymphoid tissue and peripheral nerve endings.

The issues of functioning of the endocannabinoid system are covered in detail in this topic.

A systematic review concluded that CBD effects at CB1 receptors are primarily due to indirect effects (i.e., no direct interaction with the orthosteric CB1 receptor-binding site). One proposed mechanism of indirect CBD action at CB1 receptors is negative allosteric modulation, which has been reported in several in vitro studies. Allosteric modulators differ from receptor agonists in that they alter the activity of the receptor by binding to a functionally distinct binding site rather than directly to the receptor. This is an important point because direct agonists (such as THC) are limited by their psychomimetic effects, such as changes in mood, memory and anxiety

CBD inhibition of fatty acid amide hydrolase (FAAH) with increased anandamide has also been reported - this is another proposed indirect mechanism of action. However, another study reported CBD activation of FAAH, and these cross-study inconsistencies have been attributed to differences in in vitro physiological test environments. With regard to CB2 receptors, CBD was reported to act as a low-affinity agonist in receptor-binding preparations. In vivo studies support a potential role for CB2 as both CBD-induced reductions in cocaine self-administration and CBD’s anti-seizure effects were blocked by CB2 antagonist pretreatment.

Although direct effects of CBD on cannabinoid receptors appear limited, over 65 molecular targets for CBD have been identified, including transient receptor potential vanilloid (TRPV) channels and serotonin (5-HT1A) receptors, which have the most supporting evidence and are at least partially responsible for CBD’s pharmacodynamic effects. Multiple studies have demonstrated that CBD acts as a low-potency, full agonist at TRPV1 and causes rapid desensitization of TRPV1. In vivo studies have reported blockade of CBD effects by TRPV1 antagonists, including reductions in cocaine selfadministration, antiseizure effects, decreases in heart rate (in anesthetized rodents), and antiinflammatory effects. CBD has also been shown to activate other TRPV receptors, including TRPV2, TRPV3, and TRPV4. Together, these findings suggest a role for TRPV receptors, particularly TRPV1, in mediating several potential therapeutic effects of CBD, such as neuroprotection and anti-convulsant effects, antipsychotic effects, and immunomodulatory effects.

CBD is an agonist at 5-HT1A receptors both in vitro and in vivo. In vivo, the 5-HT1A antagonist WAY100635 blocked CBD-induced panicolytic effects, antidepressant–like effects, reversal of haloperidol induced catalepsy, anti-aggression, reductions in cocaine selfadministration, and reductions in autonomic stress responses. WAY100635 also blocked CBD-induced anxiolytic effects, stress-associated cardiovascular effects, fear-associated freezing behavior, and changes in baroreflex activity when CBD was microinjected into the bed nucleus of the striaterminalis. These rodent studies suggest that many of CBD’s behavioral effects are due to actions at 5HT1A and that CBD may potentially be therapeutic for certain psychiatric disorders. While these preclinical findings are exciting, rigorous clinical trials of CBD for psychiatric disorders are really needed.

While there is more evidence supporting a role for TRPV channels and 5-HT receptors in CBD’s mechanism of action, there is an emerging literature suggesting a multitude of other potential targets, including, but not limited to, adenosine, G-coupled protein receptor (GPR)55, GPR18, GPR119) proliferator-activated receptor alpha, and glycine receptors. Due, in part, to the multiplicity of CBD molecular targets, the speculation regarding its therapeutic potential has been broad and includes applications for pain, inflammation, and psychiatric disorders, among others. However, evidence in support of its efficacy for these conditions is quite limited and only the efficacy of Epidiolex for the treatment of epilepsy has been rigorously tested in humans resulting in FDA approval.

In addition there is evidence that CBD also antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of norepinephrine, dopamine, serotonin and gamma-aminobutyric acid (GABA) and anandamide uptake by cells affect Ca2+ stores in mitochondria, block Ca2+ channels activated by low voltage (T-type), stimulate the activity of the glycine inhibitory receptor and inhibit the activity of fatty amidhydrolase (FAAH).

About the isometric form of CBD. Briefly
I have an unhealthy interest in isomers, sorry:alien:
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Abnormal cannabidiol (Abn-CBD) is a synthetic regioisomer of CBD , which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive effects.

It has been shown that the actions of Abn-CBD are mediated through a site separate from the CB1 and CB2 receptors, which responds to abnormal cannabidiol, O-1602, and the endogenous ligands. Multiple lines of evidence support the proposed identification of this novel target in microglia as the previously "orphan" receptor GPR18.

Another possible target of abnormal cannabidiol is GPR55, which has also received much attention as a putative cannabinoid receptor, although a growing body of evidence points to lysophosphatidylinositol (LPI) as the endogenous ligand for GPR55. Further research suggests there are yet more additional cannabinoid receptors.

Research of the effects on abnormal cannabidiol in mice has indicated that atypical cannabinoids have therapeutic potential in a variety of inflammatory conditions, including those of the gastrointestinal tract. After inducing colitis by means of trinitrobenzene sulfonic acid, wound healing of both human umbilical vein endothelial and epithelial cells was enhanced by the Abn-CBD.

I think this list is already incomplete and the latest research will add new centers of CBD application. That is why so far we can only isolate point mechanisms and apply them in a limited number of cases. otherwise, focus on effects and research with good design.


Bioavailability 🍟
The most effective form of CBD delivery to the action points is obviously the inhalation route. Studies that studied the delivery of CBD by aerosolization or evaporation using specialized devices showed rapid peak plasma concentrations (<10 min) and bioavailability of ~31%,5.

In some human trials, CBD was delivered orally in an oil-based capsule. Due to the low solubility in water, absorption from the gastrointestinal tract is unstable and leads to a change in pharmacokinetics. Bioavailability with oral administration is estimated at 6% due to significant metabolism during the first passage in the liver.

Bioavailability with oral mucosal / sublingual administration via sprays / lozenges is similar to bioavailability with oral administration, but with less variability.

Transdermal methods of CBD delivery have also been investigated, but due to the effect of CBD on the body and high lipophilicity, special ethosomal delivery systems are needed for this pathway so that the substance does not accumulate in the skin - currently impractical and expensive.


Distribution 🌀
The distribution of CBD is governed by its high lipophilicity, and a high volume of distribution(~32 L/kg) has been estimated, with rapid distribution inthe brain, adipose tissue, and other organs. CBD is alsohighly protein bound, and~10% is bound to circulating redblood cells. Preferential distribution to fat raises the possi-bility of accumulation of depot in chronic administration, especially in patients with high adiposity.


Elimination 👇
Like most cannabinoids, CBD is metabolized exten-sively by the liver, where it is hydroxylated to 7-OH-CBD by cytochrome P450 (CYP) enzymes, predominantly by the CYP3A (2/4) and CYP2C (8/9/19) families of isozymes. This metabolite then undergoes significantfurther metabolism in the liver, and the resulting metabolites are excreted in the feces and to a much lesserextent in the urine. The terminal half-life of CBD inhumans is estimated at 18–32 h, and following singledose administration in chronic cannabis users, the clearance was 960–1,560 ml/min.


Half-life 3️⃣
It was found that the CBD component of sublingual Sativex has a half-life (HL) of 1.44 hours, whereas buccal Sativex has a HL of 1.81 hours.

Few studies have determined the HL of CBD after acute dosing, it has been reported that Epidiolex has a HL of 14.39–16.61 h.

One study in adult men with a history of cannabis reported a HL of 24 and 31 h, respectively, for intravenous CBD (20 mg) and smoked CBD (19 mg).

It has been shown that the presence of food (i.e., a high-fat meal) can significantly increase CBD exposure, with a 4-fold increase in exposure compared to fasting in healthy normal volunteers.


Drug–drug interactions 🤯
Few data exist regarding drug interactions with CBD inhumans, although there are some theoretical concerns thatcould have implications for its use in people with epilepsy (PWE). CBD is a potent inhibitor of CYP isozymes, primar-ily CYP2C and CYP3A classes of isozymes, in vitro and inanimal models. This is particularly important becausemany medications are substrates for CYP3A4. However, inhibition has typically not been observed at concentrationsused in human studies. Repeated administration of CBD may induce CYP2B iso-zymes (CYP2B1/6) in animal models, which may haveimplications for PWE, because antiepileptic drugs (AEDs)such as valproate and clobazam are metabolized via theseisozymes. Finally, because CBD is metabolized in a largepart by CYP3A4, it is likely that common enzyme-inducingAEDs such as carbamazepine and phenytoin could reduceserum CBD levels.

Last in vitro findings suggest that CYP2C19 is the main enzyme responsible for the formation of 7-hydroxy-CBD, but in the drug interaction study the CYP2C19 inhibitor omeprazole had no significant influence on CBD exposure. Stiripentol, another CYP2C19 inhibitor, was also found not to affect the AUC of CBD after oral administration at steady state, and it actually reduced by about 30% the concentration of 7-hydroxy-CBD. Asstiripentol also has CYP3A4 inhibiting activity, its lack of influence on CBD exposure in the latter study is surprising and possibly explained by the relatively low stiripentol dose tested (1500 mg/day, equal to about 20 mg/kg/day).

CBD acts as an inhibitor or inducer of several cytochrome P450 isoforms including 3A4, 2C19, 2C8, 2C9, 2D6, 1A2, and 2B6, and has minor activity at several others. As CYP450 enzymes are involved in metabolism of the majority of pharmacotherapies, CBD has the potential to interact with many over the-counter and prescription medications.


Active use in medicine⚕️
CBD has shown promise as a target for therapeutic and pharmaceutical drugs. In particular, CBD has demonstrated promising properties as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic, and also showed neuroprotective, anti-inflammatory and antioxidant activity among other currently investigated applications.

CBD is currently available in Canada as a 1:1 compound with THC (in the form of a drug known as "nabiximols") as a product of the Sativex trademark. It`s approved for use as an adjunct to relieve the symptoms of spasticity in adult patients with multiple sclerosis. Sativex has also received a Conditional Compliance Notice for use as an adjunct to relieve symptoms of neuropathic pain in adult patients with multiple sclerosis and as an adjunct pain reliever for the treatment of moderate to severe pain in adult patients with advanced cancer.

In April 2018, the advisory commission of the Food and Drug Administration unanimously recommended the approval of Epidiolex (an oral solution with cannabidiol) for the treatment of two rare forms of epilepsy - Lennox-Gastaut syndrome and Dravet syndrome, which belong to the two most difficult types of epilepsy to treat. Epidiolex received the status of an orphan drug, as well as accelerated FDA approval for further study in these intractable conditions. On June 25, 2018, Epidiolex was approved by the FDA as the first CBD-based product available on the U.S. market.

Safety and abuse 💉
Multiple small studies of CBD safety in humans in bothplacebo-controlled and open trials have demonstrated that itis well tolerated across a wide dosage range. No significantcentral nervous system side effects, or effects on vital signsor mood, have been seen at doses of up to 1,500 mg/day(per os) or 30 mg (iv) in both acute and chronic administra-tion. Limited safety data exist for long-term use inhumans, although there have been many patient-years ofexposure to nabiximols following approval in many European countries and Canada. There is some theoretical risk ofimmunosuppression, as CBD has been shown to suppress interleukin 8 and 10 production and to induce lymphocyteapoptosis in vitro. It should be noted that the above studies were performedin adults. The pharmacokinetics and toxicity of CBD in chil-dren is not well understood.

The World Health Organization’s report on CBD concluded that it has a good safety profile with limited side effects. Several controlled human laboratory studies of oral (200–800 mg) and sublingual (20 mg) CBD reported limited effects on physiological outcomes, including heart rate and blood pressure. In contrast, two recent randomized, double-blind, placebo-controlled studies found a modest decrease in arterial pressure and systolic blood pressure after acute CBD administration, but this effect dissipated when CBD was administered daily for 7 days.

The registration studies for Epidiolex reported the most common side effects as diarrhea, headache, decreased appetite, and somnolence. Interestingly, a recent meta-analysis reported, in children with epilepsy, that CBD was associated with higher rates of pneumonia compared to placebo and that high doses of CBD (≥ 20 mg/kg) were associated with abnormal liver function tests.

With regard to abuse liability, the vast majority of studies evaluating acute dosing concluded that there is no signal for abuse potential with CBD. This is consistent with the re-scheduling of Epidiolex as a non-scheduled drug in the USA. The exceptions to this body of evidence include two randomized, double-blind, placebo-controlled studies: one examined vaporized CBD (100 mg) and reported increased ratings of “pleasant drug effect” and “like drug effect” while another reported that vaporized CBD (400 mg) increased subjective ratings of intoxication on a Visual Analog Scale.

Analysis of 48 products in 2017 purchased online found that only 31% were accurately labeled in regard to CBD concentration and 21% contained THC. Similarly, a 2020 study in the UK reported only 38% of over-the-counter products contained ± 10% of the advertised quantity and 55% contained THC. Contamination with 5-fluoro MDMB-PINACA and dextromethorphan has also been reported. CBD product contamination could lead to unanticipated psychoactive effects and positive urine drug screens in the case of THC.

There has been concern that oral CBD could transform into THC in the human gut, but this hypothesis has recently been refuted by empirical studies confirming that CBD does not transform to THC in humans, even at high doses (4500 mg acute oral dose). Thus, intoxication or THC-positive drug screens associated with CBD products are thought to be due to contamination.



Possible implications
Get ready. Many identical words 😵

In addition to the already well-trodden directions, such as the treatment of neurological disorders, pain suppression, stabilization of inflammation and stimulation of immunity, СBD has other points of application. In particular, psychiatric disorders and substance use.

Numerous studies of varying rigor have examined CBD for its anxiolytic effects. This body of work is difficult to interpret because studies test different doses, several limit

A small (n = 10), randomized, double-blind, placebo-controlled, crossover study in men with generalized anxiety reported that CBD (400 mg, p.o.) reduced subjective anxiety on a Visual Analog Mood Scale. A double-blind study of healthy adults (n = 40) reported that CBD (300 mg, p.o.) decreased anxiety after a simulated public speaking test compared to placebo (and similar to other anxiolytics). CBD 300 mg, p.o., but not 100 or 900 mg, also reduced subjective ratings of anxiety during a test of experimentally induced public speaking in a randomized, double-blind, placebo-controlled study (n = 60). Similarly, a randomized, double-blind, placebo-controlled study (n = 57) in men reported that 300 mg oral CBD, but not 150 or 600 mg, decreased anxiety during a simulated public speaking test. However, one study found that 600 mg oral CBD was anxiolytic in a randomized, double-blind, placebo-controlled study of 36 undergraduate students with social phobia.

In regard to repeated CBD administration, in one randomized, double-blind study, patients (n = 58) with a clinically high risk for psychosis received 600 mg CBD (p.o.) daily for 1 week. There was no significant difference between participants who received CBD versus placebo on the Trier Social Stress Test. Overall, these mixed results suggest that controlled studies to identify an effective dose range and dosing regimen (acute, repeated dosing) are needed, particularly in individuals with anxiety disorders. Despite this lack of controlled data, over-the counter CBD products are being advertised as beneficial for such conditions.

In regard to other psychiatric disorders, a randomized, double-blind study in 33 patients reported that CBD (200–800 mg/daily) improved clinical symptoms of schizophrenia compared to baseline and similar to the anti-psychotic amisulpride. Another randomized, double-blind, placebo-controlled clinical trial in 88 patients with schizophrenia found oral CBD solution (1000 mg/day for 6 weeks) decreased positive psychotic symptoms. Yet, CBD (600 mg/day, p.o.) did not improve psychotic symptoms in a randomized, double-blind, placebo-controlled study of 36 patients with schizophrenia.

Although it is unclear if CBD can reduce psychiatric illness, it may reduce psychotic symptoms associated with THC usage. In a double-blind, placebo-controlled, crossover study, CBD prevented the acute psychotic symptoms of THC (1.25 mg, I.V.) in three out of three men that experienced THC-induced psychosis, oral CBD (600 mg) prevented THC (1.5 mg, I.V.)-induced paranoia in a randomized, double-blind, placebo-controlled study). Vaporized CBD (16 mg) inhibited THC (8 mg, vaporized)-induced increases on the Psychomimetic State Inventoryin a randomized, double-blind, placebo-controlled study of light cannabis users (n = 24). CBD may also alter THC intoxication, although results from these studies are inconsistent, possibly due to differences in CBD formulation and/or route of administration. In a randomized, double-blind study (n = 36), vaporized CBD-THC combinations with relatively high CBD (400 mg) were less intoxicating than THC alone (8 mg); however, when the CBD dose was reduced to 4 mg, it increased THC-induced intoxication.

In a randomized, double-blind, placebo-controlled, within-subject study, participants (n = 14) reported no subjective difference in drug effect between vaporized CBD + THC (11% CBD, 11% THC) and THC only (< 1%CBD, 11% THC).

Despite popular belief, few human studies examining CBD treatment of substance use have been conducted and whilesome of these results are intriguing, not enough evidence exists to indicate CBD as a viable treatment option for substance use disorders. Inhaled CBD decreased tobacco smoking by 40% in a randomized, double-blind, placebo-controlled study of 24 participants who wanted to quit smoking. In a randomized, double-blind, placebo-controlled, crossover study of 33 non-treatment-seeking smokers undergoing short-term tobacco abstinence, CBD (800 mg, p.o.) decreased attention bias toward cigarette cues, but did not alter craving or withdrawal ratings. In a randomized, double-blind, place-bo-controlled, crossover study (n = 10), CBD (200 mg, p.o.) decreased blood alcohol levels, but did not alter the behavioral effects of alcohol.

Regarding opioids, one double-blind, placebo-controlled, crossover study (n = 17) reported that CBD (400 or 800 mg, p.o.) did not alter pharmacokinetics or adverse effects of I.V. fentanyl. Another random-
ized, double-blind, placebo-controlled study of participants (n= 42) with heroin use disorder who were abstinent reported that Epidiolex® (400 or 800 mg) inhibited drug cue–induced craving and anxiety, but not heroin craving. While these studies are intriguing, they do not provide substantive data to draw clinically meaningful conclusions unfortunatly.


Adoption and market 💸
Of critical importance, the majority of CBD products being sold have not been approved by the regulators. Unregulated CBD is available in numerous formulations, including oral capsules or tinctures; sublingual oils; topical creams, balms, and salves; e-liquids or crystalized formations (wax) for vaporization; and dietary supplement forms. These products are sold online and inretail shops with advertising suggesting a vast array of unsubstantiated medical and psychiatric benefits, and to improve beauty, hygiene, and nutrition.

Estimated sales of these products were between 600 million and 2 billion USD in 2018, and investment companies predict sales will reach 16 billion USD by 2025.


As always, thank you for your time.
I invite those interested in the topic to the discussion.
 
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