I added some links to my post earlier. One is an article from Scientific American that, in my opinion, does a pretty good job of summarizing the current situation. The second is a study done by biorxiv, entitled "Absence of entourage: Terpenoids commonly found in
Cannabis sativa do not modulate the functional activity of Δ9-THC at human CB1and CB2 receptors".
I suppose I should clarify some semantics as well. I am coming from a purely skeptical position in reference to the "Entourage Effect". I am completely open to the idea and possibility that that is an interaction between certain compounds in cannabis, however, far too many unsubstantiated claims are made based on this
possibility. If you want to make a claim in favor, please provide evidence not speculation. And be specific about your claims. I know this might seem pedantic, but it seems necessary with the abundance of anecdotal claims. I have my own, which contradict others, so clearly we need a better standard of evidence.
I'd rather stick to debating the facts rather than each other, and if we do get to a point where we have established all the known facts while still being unable to determine exactly what/why is possible, then I'd gladly conclude to agree we don't know and more research is needed. I'm not against anecdotal or even speculation, but I'm looking to unblur the lines first.
Impairment of inhibitory control processing related to acute psychotomimetic effects of cannabis
"Severity of psychotic symptoms was directly correlated with inhibition error frequency and inversely with inhibition efficiency under the influence of delta-9-THC. Delta-9-THC attenuated left inferior frontal activation which was inversely correlated with the frequency of inhibition errors and severity of psychotic symptoms and positively with inhibition efficiency under its influence. These results provide experimental evidence that impairments in cognitive processes involved in the inhibitory control of thoughts and actions and inferior frontal function under the influence of cannabis may have a role in the emergence of transient psychotic symptoms under its influence"
So, based on this study, it appears that D9THC and psychosis are related to the level of impairment it causes to the inhibitory control process.
Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders
"In addition to its low and variable oral bioavailability in humans [
135], it causes bell-shaped dose-response curves and, judging from the studies with laboratory animals, possesses a narrow therapeutic dose range."
This quote highlights the importance of considering dose when talking about the efficacy of a drug, CBD in this case. Really, all claims would be dependent upon dose as even water and oxygen become toxic at high enough levels. Below threshold dose, the major effect will be the placebo.
There does seem to be quite a bit of evidence for the "entourage/synergistic effect" of CBD and THC:
Cannabis with high cannabidiol content is associated with fewer psychotic experiences.
"We found a significant inverse relationship (F(1,1877) : 14.577, p<0.001) between cannabidiol content and self-reported positive symptoms, but not with negative symptoms or depression. The estimated effect size of cannabidiol content was small." "Although the observed effects are subtle, using high cannabidiol content cannabis was associated with significantly lower degrees of psychotic symptoms providing further support for the antipsychotic potential of cannabidiol"
CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy
"This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. " "The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64% ). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71% ) than patients treated with purified CBD (81/223, 36% ), with statistical significance (
p < 0.0001)" "...when the standard clinical threshold of a "50% reduction or more in the frequency of seizures" was applied, only 39% of the individuals were considered "responders,"..." "Patients treated with CBD-rich extracts reported lower average dose (6.1 mg/kg/day) than those using purified CBD (27.1 mg/kg/day). The reports of mild (109/285 vs. 291/346,
p < 0.0001) and severe (23/285 vs. 77/346,
p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. "
This study has provided the first evidence that cannabidiol can display CB2 receptor inverse agonism, an action that appears to be responsible for its antagonism of CP55940 at the human CB2 receptor
"We have shown previously that cannabidiol can enhance electrically evoked contractions of the mouse vas deferens, suggestive of inverse agonism. We have also shown that cannabidiol can antagonize cannabinoid receptor agonists in this tissue with a greater potency than we would expect from its poor affinity for cannabinoid receptors." "The ability of cannabidiol to behave as a CB2 receptor inverse agonist may contribute to its documented anti-inflammatory properties."
Overcoming the Bell-Shaped Dose-Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol
" In the present study, we have studied in mice the anti-inflammatory and anti-nociceptive activities of standardized plant extracts derived from the
Cannabis sativa L., clone 202, which is highly enriched in CBD and hardly contains any psychoactive ingredients. In stark contrast to purified CBD, the clone 202 extract, when given either intraperitoneally or orally, provided a clear correlation between the anti-inflammatory and anti-nociceptive responses and the dose, with increasing responses upon increasing doses, which makes this plant medicine ideal for clinical uses." "It is
likely that other components in the extract synergize with CBD to achieve the desired anti-inflammatory action that may contribute to overcoming the bell-shaped dose-response of purified CBD. We therefore
propose that
Cannabis clone 202 (Avidekel) extract is superior over CBD for the treatment of
inflammatory conditions."
Cannabis-based medicines--GW pharmaceuticals: high CBD, high THC, medicinal cannabis--GW pharmaceuticals, THC:CBD.
"includes investigations in the relief of pain of neurological origin and defects of neurological function in the following indications: multiple sclerosis (MS), spinal cord injury, peripheral nerve injury, central nervous system damage, neuroinvasive cancer, dystonias, cerebral vascular accident and spina bifida, as well as for the relief of pain and inflammation in rheumatoid arthritis and also pain relief in brachial plexus injury." " GW stated in its 2002 Annual Report that it was currently conducting five phase III trials of its cannabis derivatives, including a double-blind, placebo-controlled trial with a sublingual spray containing High THC in more than 100 patients with cancer pain in the UK. Also included is a phase III trial of THC:CBD (narrow ratio) being conducted in patients with severe pain due to brachial plexus injury, as are two more phase III trials of THC:CBD (narrow ratio) targeting spasticity and bladder dysfunction in multiple sclerosis patients."
The fact that GW Pharm was already studying this in the UK back in 2002 leads me to believe it isn't as mysterious as some might propose, as it has been studied for decades despite its illicit status. Also, being that they were already focused in on THC and CBD in combo to treat pain seems to suggest that it is mostly CBD and THC responsible for pain relief. It doesn't rule out the potential of others, as their focus could be for logistic reasons as THC and CBD are the most prevalent.
More evidence suggesting it is still too early to make claims about cannabinoids beyond THC and CBD:
Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures
"the exact mode of action of major phytocannabinoids has to be elucidated, but both, receptor and non-receptor mediated effects are discussed.
Focusing on the often presumed structure–affinity-relationship, Ki values of phytocannabinoids cannabidiol (CBD), cannabidivarin (CBDV), cannabichromene (CBC), cannabigerol (CBG), cannabinol (CBN), THC acid (THCA) and THC to human CB1 and CB2 receptors were detected by using competitive inhibition between radioligand [3H]CP-55,940 and the phytocannabinoids." "Most of the phytocannabinoids did not affect the number of dopaminergic neurons in primary cultures, whereas propidium iodide and resazurin formation assays revealed cytotoxic properties of CBN, CBDV and CBG." "THC showed positive effects on N18TG2 cell viability at a concentration of 10 μM, whereas CBC and THCA also displayed slightly positive activities.
These findings are neither linked to structural characteristics nor to the receptor binding affinity therewith pointing to another mechanism than a receptor mediated one."
OK, that's enough for today. I will continue tomorrow.