CANNABIDIOL (CBD)
CBD or cannabidiol was re-discovered in 1940s as an isolated phytocannabinoid, historically derived from hemp, in formulations ranging from liquid extracts in the form of oil or tincture, to standardized capsules containing a specific mg of the active ingredient. Typically, high concentrated products will sometimes use an isolated CBD product containing only CBD as the active ingredient.
In contrast, full spectrum products will also consist of trace cannabinoids, in addition to naturally occurring terpenes and flavenoids which may contribute to an "entourage effect" which tends to increase the efficacy of the product in a more broad yet synergistic aspect which is not yet fully understood.
This compound doesn't appear to have the same psychoactivity produced by Tetrahydrocannabinol dominant formulations and instead has shown efficacy in reducing various side and desired effects produced by THC including acute intoxication and indirect 5HT2A mediated effects via mechanisms which will be explored in this text.
More importantly, the compound has shown enough evidence in relieving at least two forms of treatment-resistant seizure disorders including Lennox-Gastaut, and Dravet syndrome, especially in children with refractory forms of epilepsy, leading to an FDA-approved product called Epidiolex in 2018.
Since 2019, various clinical studies have examined its effects on anxiety disorders, pain relief and cognitive ailments including schizophrenia.
Its a highly lipophilic compound and has a significantly lower bioavailability when consumed orally of usually up to 20%, versus when inhaled although resulting in a quicker onset and shorter duration of action, can increase the bioavailability up to 45% or more, with a mean percentage of just over 30%. Alternatively, sublingual or buccal administration of the drug has shown to result in a higher absorption rate than when its taken orally, eliminating its metabolism via the CYP3A4, 2D6 and to a lesser extent (but still significant degree) CYPC19, CYP2B6 liver enzymes, as well as 3 different isoenzymes. The latter enzyme is induced by various anti-epileptic medications including Carbamazine.
This further increases the application of non-oral routes of administrations including sublingual or buccal formulations which are readily absorbed directly through mucus membranes, offering a faster onset of action, shorter half life and not as likely to produce as signficant an effect on inhibitory effects especially on the 3A4 enzyme when not having to undergo first-pass hepatic metabolism, hence potentially reducing drug/drug interactions.
Despite this however, there does appear to be at least mild inhibitory effects on 3A4 enzyme.
It should also be noted that its inhibition on the CYP2C19 enzyme appears to affect the hydroxylation of THC into 11-OH-THC, its active oral metabolite, which can affect its plasma concentrations when used in combination with CBD.
The average half life is CBD can be variable dependent on the route of administration but can be less than 11 hours, though with oral routes, its higher on average at anywhere between 24-36 +/- 6hours for acute ingestion to up to 5 days after chronic oral, 24 +/- 6 hours after IV and less than 31 +/- 4 hours after inhaled routes of administration. This information is based on more than 24 articles examining its pharmacokinetic parameters in humans.
When it comes to its various mechanisms of action, at least to the degree of which we're currently aware of at this time, a few in particular has been demonstrated. CBD appears to have a relatively low binding affinity for the CB1 receptors found primarily in the central nervous system, as well as CB2 receptors mainly found in the periphery cells in the gastrointestinal tract and immune function, in fact showing a partial antagonist effect on both receptors indirectly, unlike the partial agonism of the two sub receptors produced by THC and its metabolites.
The CB1 agonist effects of THC indirectly has an effect on the up-regulation of 5HT2A receptors, which in contrast is antagonised by CBD, potentially contributing to its anti-psychotic properties. Additionally, higher concentrations of CBD can directly act as an agonist for the 5H1A receptor, through which it may exert part of its anxiolytic and antidepressant effects.
This is especially important because the upregulation of these receptors has been associated with acute psychiatric effects including paranoia and even hallucinations, which are significantly reduced and diminished, with the addition of CBD into a formulation. Its safe to say a formulation containing a higher ratio of CBD (2:1 respectively or higher), will have a direct effect on the formulation’s psychoactivity, at least partially due to the antagonistic affects of CBDthat modulate those mediated by THC, THCV and CBN.
This weak antagonistic (through low affinity inverse agonism) effect has also shown to reduce withdrawal symptoms associated with both cannabis and tobacco dependence, via indirect modulating effects of not only the endocannabinoid system but also serotonergic systems amongst various others. Additionally, there’s partial agonism at the serotonin sub-receptor 5HT1A which may have an impact on its anxiolytic (even in acute settings) and anti-depressant effects, which are often most prominent after chronic administration, similarly to other antidepressants, both herbal and pharmaceutical.
There also appears to be a negative allosteric modulation activity by CBD at the CB receptors, and with THCV potentially being a weak inverse antagonist at the CB1 receptor at low concentrations. It should be noted that low concentrations of CBD may slightly potentiate the effects of THC and other cannabinoids, with higher doses having a more countering affect in terms of psychoactivity.
The latter cannabinoid has also shown to possess strong appetite suppressant effects, partially countering those produced by THC, in strains such as Durban Poison, a landrace sativa with a signficant level of the cannabinoid in addition to its high THC and very low CBD content.
Furthermore, CBD has shown to be an antagonist at the G protein-coupled receptor GPR55, as well as being an inverse agonist at 3 of the receptors including GPR3, GPR6 and GPR12. These molecular targets may have a role in Aβ pathology, alteration of dopamine levels, inhibition of cancer cell migration, and a regulatory effect on meiotic arrest & resumption, all of which are induced by CBD. Agonist activity at vanilloid receptor TRPV1 has also been shown to a lesser extent and potency.
It appears that CBD exerts its inhibitory effect on enzymatic hydrolysis and the re-uptake of the fatty acid neurotransmitter, anandemide through its antagonistic activity at CB1, CB2 and TRPV1 receptors, and that it has the ability to enhance anandemide signalling by inhibiting its intercelular degradation.
Various studies have shown the anti-psychotic effects of this endogenous cannabinoid in patients with psychiatric disorders like schizophrenia and psychosis associated with Parkinson’s disease. This is especially the case, when CBD is used at very high daily doses, compared to commonly used therapeutic doses used in supplements.
At least one study has also shown that CBD is a positive allosteric modulator at mu and delta receptors as well. This may allow a potentially lower opioid dose for some pain patients due to a potentially synergistic effect. The exact significance of this particular mechanism has not yet been well established in quality human trials however.
Other mechanisms of which their extent are not yet fully known but appear to be present possibly in a dose dependent manner, are an inhibition at the voltage-dependent sodium, potassium levels, intracellular calcium release, and as a relatively competitive inhibitor of adenosine re-uptake.
There also appears to be significantly less direct effect on the endocannabinoid system when compared with THC and even CBN which is formed as a metabolite of THC in the ageing process. This metabolite has a higher affinity for the partial CB2 receptors over CB1, albeit lower relative to THC itself.
It's also been found that when combining THC and CBD, despite a clear antagonistic effect in addition to a possible negative modulatory action especially on the CB1 receptors, CBD also induced an increase in THC concentrations, which despite affecting the psychoactivity of the latter compound, has shown to be superior in relieving pain to using a formulation with only CBD in a controlled human trial focusing on their effects on acute pain.
Despite this however, its shown that in chronic pain, even the use of high potency CBD products with either none or only trace THC levels has found to be beneficial for treating patients with chronic pain, who don't require immediate relief. It should be noted that the entourage effect of combining either standardized cannabinoid with other active constituents including terpenes and flavenoids have generally been found to be more effective, as opposed to using either given cannabinoid in its isolated form.
In clinical trials examining its use as both mono-therapy and adjunct therapy of schizophrenia, the first involving a randomised, double blind parallel-arm trial with 39 patients presenting with acute exacerbation of symptoms over 4 weeks, showed no difference in efficacy between the dosage regimen of 800 mg/day of oral CBD, versus 800 mg/day of the anti-psychotic medication, amisulpride.
These findings showed a lack of inferiority of CBD as an anti-psychotic, despite its lack of D2/D3 antagonism. In this study, it was a significant association was noted in the increase in the level of anandemide and a reduction in psychotic symptoms in the CBD group, likely linked to inhibition of anandemide degradation.
More importantly, in more recent studies including a 6-week randomised, double blind, parallel group trial involving 43 patients on 1000 mg CBD a day, versus 45 patients on placebo was conducted to examine the effects of CBD as an adjunct treatment as an add-on to anti-psychotic treatment. A significant effect was seen in improvements in positive symptoms from baseline (using The Positive and Negative Syndrome Scale, also known as PANSS). CBD treated patients were also more likely by their physicians to be rated as "improved" and not as "severely unwell", based on the Clinical Global Impression Scale. There were also less significant effects on general functioning and cognitive performance but no effect on negative symptoms.
It should also be highlighted that in a later study using the same methodology but a significantly lower CBD dose of 600 mg/day as an add-on therapy did not yield the same promising results. The treatment was still well tolerated and did not result in worsening of symptoms including psychosis, mood or movement disorders.
It should also be noted that therapeutic effects for various other conditions including anxiety, pain, stress, insomnia and anti-inflammatory disorders have been observed at signficantly lower doses than those required for anti-psychotic effects. Daily supplemental doses can vary greatly depending on weight, tolerance, severity of the condition and the potency of the formulation used. Even doses as small as 25-60mg daily has shown subjective benefits in many individuals.
This is especially the case, where a full spectrum formulation is used rather than one made from CBD isolate, free from other trace cannabinoids, terpenes and flavenoids.
In conclusion, although more quality studies are needed in finding specific applications for CBD as a therapeutic substance at varying doses and formulations, our gradual understanding of the endocannabinoid system, its indirect effects and contribution to psychiatric, mood, and anxiety disorders, as well as its anti-inflammatory, antioxidant and pain-relieving properties (especially when combined with other cannabinoids or opioids) and shows promising results and requires further investigation.
Its lack of significant side effects when used in titrated doses in more isolated formulations and extremely low toxicity also means that its a generally safe medicine which shouldn't be reserved for treatment-resistant cases, but rather as a safer alternative to trial before considering more invasive lines of treatment. Especially due to its lack of addiction and dependence liability.
In fact, preliminary studies have shown promising results for the use of CBD in treating opioid dependence and addiction, with signficant self-reported cravings and with a reduction on withdrawal effects and relapse.
