The Cannabinoids, CBDA and THCA, Rescue Memory Deficits and Reduce Amyloid-Beta and Tau Pathology in an Alzheimer’s Disease-like Mouse Model
The cannabinoic Acids as marketable compounds will someday out perform the “neutrals”
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CBN & CBN analogues anyone?
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Yep and those that didn’t t see that coming are not up to par with development
Very happy to say the least that my hunch that mechlaums statement on shelflife was wrong
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Isn’t it odd that the linked study seems to purposefully omit comparison of THCA/CBDA to plain THC/CBD? I’d hazard a guess that there’s no difference at all.
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Between having the A or not ?
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yes, that’s what i was trying to say
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Down in the middle of the first link is says:
THCA has anti-inflammatory, neuroprotective, anti-convulsant, and anti-seizure effects. CBDA and THCA inhibit T-type calcium channels. In a pharmacokinetics study, CBDA and THCA exhibited a higher Cmax in serum compared with CBD and THC. CBDA and THCA function directly in the brain because of their ability to cross the blood–brain barrier. Although no clinical trials have been reported thus far, CBDA and THCA may have increased efficacy and bioavailability compared with CBD and THC.
I’m all doped-up on seizure meds (Keppra and lamotrigine) and and am always looking for better alternatives. Didn’t know till now that there was even CBDA available.
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2023 review of Wnt signal pathway and role in Alzheimer’s.
ibrain. 2023;9:316–325
This is a very complicated pathway that functions in 3 separate pathways.
@roiplek …yes there is evidence published back in 2006 concering CBD and this pathway.
J Mol Med (Berl). 2006 Mar;84(3):253-8. doi: 10.1007/s00109-005-0025-1. Epub 2005 Dec 31.
PMID: 16389547
2021 review;
Int J Mol Sci. 2021 Apr 6;22(7):3798. doi: 10.3390/ijms22073798.
The most recent paper (above and main. Topic) ….concerns the effects of the Cannabinoid Acids. Here they imply a BDNF - TrPk pathway , but it should be pointed out that the canonical Wnt-b-catenin pathway is upstream of BDNF….(for example)
There seems to be a great future in cannabinoids and these rather complex regulatory modules…especially the wnt.
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That may be true but it in fact says nothing about the respective efficacy or strength of each compound. THC might just distribute into (fatty) tissue much faster than THCA (which might also have stronger protein binding due to its higher polarity), attenuating the observed Cmax. Knowing the AUC along with Cmax would be much more relevant here, which i suspect would show higher total bioavailability in favor of THC/CBD.
The researchers apparently not knowing or even misrepresenting this kinda disqualifies the entire paper.
Unless there’s a specific active transport mechanism across the BBB for THCA/CBDA, it’s unlikely that those compounds accumulate in the CNS at a greater rate than THC/CBD, which are lipophilic enough to cross the BBB rather easily. They’re also not substrates of p-GP afaik.
Thus, in theory to me it seems highly implausible for ANY therapeutic advantage to exist, especially since THCA/CBDA are much less stable and less practical to use.
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I have not seen the “decarboxylation studies”, please advise and your points are well taken.
But I should point out what is truly unknown: is the transport method of THC in blood/plasma. Considering its solubility in saline…it would seem unlikely un-complexed. At least at physiological pH the Cannabinoics are anions. If you smoke/vape…you have virtual proof of THC transport to brain.! there is no such rapid bioassay for THCA/CBDA with regards to crossing BBB: both being considered non psychoactive.
Have you looked at Mechoulan’s 2019 (?) patent. I think there are many peripheral effects….but you have a point about CNS access. It needs looking into.
I can only remember one pharmacokinetic study of smoked marijuana components in blood.
I think there is an 11 COOH-THC metabolite and in the metabolism-literature this is often referred to as thc-acid….is it this form you are thinking of that is decarbed? Or do some radio- labeled THCA studies that show Phytogenic THCA(a) is decarbed to THC in human tissues…liver or otherwise?
(Or a similar study with CBDA to CBD)??? there is such a torrent of research literature one can certainly be unaware.
Clearly there is a need to separate Cannabinoic Acid action on peripheral tissues from any possible CNS effects. And studies done in vitro do not necessarily translate effective drug action when ingested: for example the subject of this post.
There is a pharmacokinetic study of Cannabinoic acids in Plasma and Brain tissue ….worth looking at. Specifically state that they did not see any decarboxylation…I need to study it a bit…worth looking at.
https://doi.org/10.1021/acs.jnatprod.9b00600
Cut and paste
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Yep, thanks. Says right there that there was little to no CBDA/THCA detectable in brain tissue after i. p. administration, which obviously bypasses 1st pass metabolism.
So the OP study directly contradicts this. Either study could be wrong, but i’m putting my money on Cannabinoic acids largely not being able to cross the BBB or even them being a substrate of p-GP, or both.
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I have to look a p-GP …thanks…and lets keep an close eye on similar studies…
You might find the article on CBDA and neuropathic pain.
If you look at the charts in that Cannabinoic acid uptake study…you see the numbers and quantity on right are in micromolar amounts…which is quite high…and a clear discrepancy between THCA uptake and CBDA acid uptake.
Everything I’ve looked at has been CBDA…so my ideas are a little biased. When I think about the pharmacodynamics of CBDA I am not thinking about CB1 or CB2 receptors at all. I am thinking a hydrophobic version of salicylic acid.
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If there’s anything 50 years of Alzheimer’s research should teach us it’s that “Alzheimer’s Disease-like Mouse Model” means nothing. There have been like 100 drugs that worked on mouse models. Not a single one worked when brought to human trials. So call me when they get to the human trials.
Anecdotally, neither THC nor CBD appeared to do squat to slow or reverse progression of Alzheimers in any of my friends who died from it, with daily use at various doses…
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CBD and THC do not work: certainly a valued observation. It is always nice to get preliminary data with humans not having to spend 10M for study. I think a great example was the anti-seizure effects of CBD. The etiology of “Dementia” is varied,.You can get everything from galloping prion, to classic Alzheimer’s to vascular aberrations and classic domoic acid poisoning from clams. Of course “bad genes” can usher in nice conditions such as ALS, FTD and MSA…might make you wish a fatal heart attack would save you from these journeys.
I think there is more money in CBDA as an anti-pain med for the aged population, than there is in get high cannabinoids for younger generations.
Saving people from Alzheimer’s decrepitude is a “big order.”
I don’t see any reason not to dose your family-Alzheimer’s case with 100 mgs a day of CBDA for a week, and ask him /her whether the patient knows who you are? Keep an eye on Wnt signaling …just for fun. Cheers!
One additional thought here: We are not looking for some classic GCPR CB1 receptor agonism causing a temporary decrease in presynaptic Ca++ entry …But more likely some nuclear reprogramming …Wnt signaling for example…frizzled etc…action???
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Might want to look at this paper
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Yes, CB1 allosteric modulation is in play, PAM,neutral,and NAM. This subject is a small slice of a very complicated pie. I am rather surprised you bring it up.perhaps some sorcerer’s apprentice lurking about.
- Overview (Translational potential of allosteric modulators targeting the cannabinoid CB1 receptor | Acta Pharmacologica Sinica) ;
- https://www.jstage.jst.go.jp/article/jts/45/4/45_227/_pdf
OK (1) discusses the classic CB1 receptor and its allosteric binding site. Most here know that THC binds to the orthosteric site and that CBD binds to an allosteric site and acts as a negative allosteric modulator. That neutral cannabinoid like THC can act on this receptor and suppress pain sensation is known. As pointed out in the article you posted Positive Allosteric modulators advance this action.
2. Addresses non-canonical actions of CBDA. these are mediated to some extent (in my understanding) by nuclear reprogramming . This is what I am referring to when I say we are not (necessarily) looking at classical CB1 receptor activation as in “get high” mode.
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You start to know me well
It s indeed jiberisch to me but I have a great team around
And my question was
Can we find something to enhance the high ?
As a result we fiddled with 211 Wich
Seems to do yust that
At least in a blind essay with 8 testers
Still very preliminary and basic but looking into it a bit deeper since it does seem to make a difference
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Very amazing. The thought that such action and experiments might be going on crossed my mind.
Compared to pharma companies and university academics…their hands are tied concerning such investigations.
High usage of cannabinoids may result in the b-arrestin modulated CB1-receptor removal from neuronal surfaces.i.e., so experienced bioassay personnel may have a different receptor display than inexperienced.
Anyone who has experience with “rosin” tokers knows what I am talking about. But to give someone experienced like that a hit of something special and have them recognize it a “different”…you know your are on to some thing.
I have to say you are on the “edge of cannabis receptor science.” I do not think a lot of people appreciate the complexities of GPCR signaling. It is so complex when bioassayed from the CB1 receptor/ human consciousness point of view….it seems to be one continuum with subtle pattern variation. It might well be the search for a usable PAM of CB1 creates a new fad in Cannabis industy. Seems like it may be “different”.
Whether you can get such a PAM to co-vaporize and form an effective aerosol for vaping…is another.
One would have to think deeply about how to add that goodies to pile. …get it into theCNS and loaded on the allosteric site. You would think that the PAM alone might give a “high” additive effect to endogenous agonist of waking consciousness…keep us posted…exciting work.
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My friends dad was dying and in the end he was pretty much completely senile for the last bit of his life . My buddy always smoked with his dad so he figured why not let him rip the dab pen it might relax him or calm him down . It made him way more coherent and able to remember stuff and relax more . It literally brought him back to an extent . So for as long as it could last they just smoked the pen and it gave him bonding time and something he would of never had if it wasn’t for him hitting the pen. This lasted for a week or two until he passed .
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My dad passed in the same manner
Sadly never thought about this option 
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