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Inhibiting the memory impairing effects of cannabis with cox-2 inhibitors?

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nintey

Bluelighter
Joined
Jul 7, 2006
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Does anyone have any anecdotal experience with using cox-2 inhibitors to inhibit the memory impairing effects caused by cannabis?

I ask because because an article was released this year that stated the cognitive impairing effects of cannabis was due to an induction in cox-2 in the brain.

Here is a short summary of the article

Marijuana has been used for thousands of years as a treatment for medical conditions. However, untoward side effects limit its medical value. Here, we show that synaptic and cognitive impairments following repeated exposure to Δ(9)-tetrahydrocannabinol (Δ(9)-THC) are associated with the induction of cyclooxygenase-2 (COX-2), an inducible enzyme that converts arachidonic acid to prostanoids in the brain. COX-2 induction by Δ(9)-THC is mediated via CB1 receptor-coupled G protein βγ subunits. Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of glutamate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated Δ(9)-THC exposures. Ablation of COX-2 also eliminates Δ(9)-THC-impaired hippocampal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing β-amyloid plaques and neurodegeneration by Δ(9)-THC in Alzheimer's disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical marijuana would be broadened by concurrent inhibition of COX-2.

Theoretically cox-2 inhibitors would be useful to stop some of the unwanted effects of cannabis, although the study was done using pure thc and mice, which is obviously not the same as a human smoking cannabis flowers.
 
I doubt it'd work the same in humans... I've taken maximum recommended daily doses (4g) of paracetamol (=acetaminophen) when ill and gotten high in the evening waking up a with a rather cloudy recollection of the night before. Paracetamol is a pretty weak inhibitor of this enzyme though, maybe it would work with more potent COX inhibitors... I'm interested in reading this paper have you got the first author's name and title?
 
theres the article and here is the title Δ9-THC-Caused Synaptic and Memory Impairments Are Mediated through COX-2 Signaling
 
Does anyone have any anecdotal experience with using cox-2 inhibitors to inhibit the memory impairing effects caused by cannabis?
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Tweex ran himself through a single-blind procedure, using I believe ibuprofen and an n-back inventory to measure short-term memory. He found it to increase his digit span from 6 to 9 with concurrent heavy use of cannabis. It should be noted that his 'impaired' short-term memory performance is similar to an average individual's.

steve said:
Paracetamol is a pretty weak inhibitor of this enzyme though, maybe it would work with more potent COX inhibitors...
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Yeah, to the point that this isn't even its primary mechanism.

ebola
 
Cox-2 inhibitors have some pretty nasty side effects as I'm sure you know. It is worth asking the question if it is worth doing. Or, stopping the cause may be the best idea as opposed to treating one effect with another.
 
Another pharmaceutical that has shown to somewhat attenuate the memory impairment from cannabis in man is propanolol. I've combined them before, but without paying any attention to it's effects. Can't remember I felt any difference than from the weed alone, but I guess it could be worth doing some experiments.
 
4 grams of paracetamol sounds like quite a lot despite being the dayly recommended dose. You might be better trying ibuprophen, selacoxib, or even high dose asperin, next time just before you smoke. Also your right, paracetamol has little to know affect on cox2, its not even classed as ananti imflamitory. Paracetamol is thought to work by inhibiting the enzyme fatti acid amide hydrolase due to a minor metabolite, causing a buildup of endocanabinoids. As paracetamol can be difficult for the liver to handle, it may be best to avoid it if using cannabis and use other cox inhibitors instead.
 
I know their are some scary long term side affects to cox2 inhibitors, e.g. high blood pressure induced heart problems, but they may be ideal for the occational cannabis user. They may also enhance the pleasureable aspects of the high and eliminate the negative ones. also, THC, being an antioxidant and lowing blood pressure may reduce some of the side affects of cox2 inhibitors.
Another interesting compound to try with cannabis is the oraly active 5lypoxygenase inhibitor zileuton. It is generaly neuroprotective and may be a good add on to or replacement for cox2 inhibitors. However I have know idea of the side affects.
 
Pharmacological or genetic inhibition of COX-2 blocks downregulation and internalization of gluta- mate receptor subunits and alterations of the dendritic spine density of hippocampal neurons induced by repeated D9-THC exposures. Ablation of COX-2 also eliminates D9-THC-impaired hippo- campal long-term synaptic plasticity, working, and fear memories. Importantly, the beneficial effects of decreasing b-amyloid plaques and neurodegenera- tion by D9-THC in Alzheimer’s disease animals are retained in the presence of COX-2 inhibition. These results suggest that the applicability of medical mari- juana would be broadened by concurrent inhibition of COX-2.
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Wow, just wow. This linked paper is so fucking amazing stuff. Thanks! :)

Is there the possibility for genetically (or due to whatever else non-drug related cause) upregulated COX-2, leading to inflammation response, glutamate imbalance -> mood disorders, cognitive impairments, etc. that would respond to NMDA antagonists...!?? What would be the cause of this and how could it be solved, seeing that the COX-2 inhibitors have been withdrawn from the market cause of their unbearable side effects?

I've stumbled over some anecdotal reports before of Ibuprofen use improving some weird cognitive disturbances also related to ADHD / depression / mood swings, but found no serious research or evidence to this topic so I've quickly lost interest in that... but it would all make so real sense..

Also I've never used any NSAIDs for more than an occasional dosage due to a cold, because they did not help me with headaches (I also have some doubts in why an anti-inflammatory agent should help with tension headaches when they are not inflammation-related) and so I can not say if dosing chronically on something like Ibuprofen would give rise to neurogenesis. All that I can say is that I have chronic weird 'tension' headaches that get worse with stress / sensory / emotional overload and NMDA antagonists alleviate them whilst when coming off dissociatives or memantine, the headaches are more pronounced for a while associated with inner tension and mood swings.

It is also very remarkable that the selective COX-2 inhibitor celecoxib has been shown to improve major depression as well as other psychiatric symptoms. It also seems to have less severe side effects than the withdrawn COX-2 inhibitors ... that cancer link is somewhat concerning (in that celecoxib gets used in cancer treatment and so COX-2 & its neurological problems & cancer could be interconnected..) but I don't want to see connections where there aren't any of course.

Pretreatment with ibuprofen to prevent electroconvulsive therapy-induced headache.
Could aspirin and ibuprofen help fight depression? Scientists discover inflammation may cause mental illness - and say these drugs could treat it <---very interesting

Scientists at the university analysed blood samples from 4,500 volunteers at the age of nine and followed up at 18 to see if they had experienced episodes of depression or psychosis.
The samples were examined for signs of previous infection.
When the immune system is mobilised, the bloodstream is flooded with proteins such as interleukin-6 (IL-6), a tell-tale marker of infection, which help fight and remove it.
Even after recovery the blood carries trace levels of these proteins – known as ‘inflammatory markers’.
The team found that children with high everyday levels of IL-6 were nearly two times more likely to have experienced depression or psychosis than those with low levels.
The study – which was published in the journal JAMA Psychiatry – says anti-inflammatory drugs should be investigated to see if they could treat illnesses such as depression. Treatment with such agents leads to levels of inflammatory markers falling to normal.
Previous research has suggested that anti-inflammatory drugs such as aspirin used at the same time as anti-psychotic treatments may be more effective than anti-psychotics alone.
Professor Peter Jones, head of the department of psychiatry at Cambridge, said: ‘Inflammation may be a common mechanism that influences both our physical and mental health.
‘It is possible that early life adversity and stress lead to a persistent increase in levels of IL-6 and other inflammatory markers in our body, which in turn increase the risk of a number of chronic physical and mental illnesses.’
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Does anyone have access to the full text of this study?

And so on ...
 
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I registered here just to post this as its very relevant to the discussion. Ive always noticed that when i combine harmalas (smoked syrian rue) with weed i dont have any of the mindfuck / memory impairment. Reading this thread i got curious and after a quick google search i found this : " ... Moreover, harmine decreased production of other factors by tumor cells, which play a significant role in angiogenesis like cyclooxygenase (COX-2), ... " (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841998/). So this combination seems to be extremely beneficial especially because syrian rue is dirt cheap and it also tremedously increases weed euphoria while decreasing the unwanted sideeffects.
 
Hi, Weltmeister (do you speak German? ;)), welcome to bluelight & thanks for sharing your experiences!

Again, just wow. Would fit so well.

In an in vitro study desoxypeganine, one of the P. harmala alkaloids, dose-dependently decreased ethanol consumption in female Alko alcohol rats with no effect on food and fluid consumption.[39] This may represent a safe way to decrease the consumption of alcohol in alcoholics. Harmane, another alkaloid isolated from P. harmala induced amnesia with a suggested mechanism of interaction with dopaminic (D1 and D2) receptors.[24] Harmaline and harmane have been shown to modulate voltage-activated calcium- ICa (V)-channels in vitro and in a reversible and use independent manner.
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Beta-carboline alkaloids of P. harmala are shown to have immune-modulatory effects in several studies.[26,75] Extracts of this plant have significant anti-inflammatory effect via the inhibition of some inflammatory mediators including prostaglandin E2 (PGE2) (100 μg/mg) and tumor necrosis factor alpha (TNF-α) (10 μg/mg).[46]
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And they are antioxidant, neuroprotective, reversible MAO-inhibitors etc ... harmala alkaloids could be a fucking miracle! (How much does one need to avoid tyrosine-rich food when dosing on syrian rue? Is this the same like with moclobemide that it isn't such an issue because of the reversibility?)
 
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Ja ich bin Vertreter der deutschen Herrenrasse (joke)

Theres a few things you always have to keep in mind when using syrian rue tho. At normal doses it inhibits MAO-A but in high doses it inhibits MAO-B to a significant extend. It also inhibits acetylcholinesterase and interacts with various other neurotransmitters so there has to be more research done.

The most significant downside is definitely that you cant combine Syrian rue with many other drugs (especially stims including caffeine) without getting some serious sideffects. On the other hand you dont have to worry about dietry restrictions (even if you use it oraly) and i never felt any negative effects no matter what i ate. Theres rumours that it damages your DNA but i dont know if thats true.

Overall weed and syrian rue is one of my favorite combinations.
 
I'm from Switzerland ;) so it's always nice to meet someone speaking German in the endless world of the WWW ... you seem to speak English very well too! (I'm unsure about my skills but they don't seem too bad.. but that's finally OT now)

Yeah, the MAO inhibition is definitely something to keep in mind. There is conflicting evidence afaik about the MAOIs, with moclobemide for example you don't have to do any diet, as well as with the irreversible selegiline & rasagiline as long as they are dosed below the MAOA-inhibiting threshold... then again, there are the Emsam patches used for depression at levels where MAO-A is affected too, and they seem to be much less serious on the side effects because not used orally (?)

So it seems to be more of a matter when the MAO enzymes in the digestive tract are disabled directly, but I guess any MAOI in the bloodstream will eventually reach the digestive tract independently of the ROI, but it would be very nice of course if e.g. nasally administered harmala alkaloids in a saline solution would have less severe side effects!

The interesting thing is that some irreversible, non-selective MAOIs like tranylcypromine are in fact NDRAs and in the dosages they are used sometimes (tranylcypromine being 1/10 the strength of amphetamine & gets used at up to 70-80mg/d) this effect must be quite strong. There is the thing that with chronic MAOI use the NE stored in the vesicles might get replaced with the less strong octopamine:

One study noted that octopamine might be an important amine that influences the therapeutic effects of inhibitors such as monoamine oxidase inhibitors, especially because a large increase in octopamine levels was observed when animals were treated with this inhibitor. Octopamine was positively identified in the urine samples of mammals such as humans, rats, and rabbits treated with monoamine oxidase inhibitors.
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If Syrian Rue would work, I would love to not having to do any more drugs. Otherwise maybe even very, very low doses of e.g. methylphenidate might being tolerated cause of the tranylcypromine thing. I've had moclobemide + 2.5mg of d-amphetamine before w/o serious side effects, but then again the moclobemide was utterly useless.
And of course, as you describe it, maybe the combo of Syrian Rue & pot might be very interesting if they show such a synergy with abolished negatives of the THC & CBD leading to an anxiolytic, mood-elevating experience ... maybe even CBD alone could work, who knows... maybe I'll figure it out soon ;) as unfortunately medical marijuana isn't available yet here to the general public to my knowledge, and for these few individuals actually having a prescription it's prohibitively expensive..

I've never been seriously interested in pot before because of said negatives, but we'll see ...

And the NMDA antagonists like memantine don't seem to be particularly dangerous when combined with a MAOI, so as I get already strong benefits from NMDA antagonism alone, maybe low dose Syrian Rue + low dose memantine might be that miracle I've been desperately looking & searching for, knowing that it has to be possible but it wasn't yet. The best results I have got from the unfortunately now prohibited methoxetamine in the very right, very low dosage & this one is not available any more..

I will further look into Syrian Rue & the possible mutagenic side effects you mentioned, although in the paper you linked above it's said to be possibly anti-carcinogenic too, so I'll have to research more.

Many thanks & take care!
(Sorry for getting off topic, feel free to move or delete my post if it's too lengthy.)
-dopamimetic
 
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regardless of the research that has been presented on this subject, selective cox-2 inhibitor celebrex did not produce any notable decrease in the fog-effect of cannabis. I think there is a missing link between this research and reality.
 
Could well be true of course.

OR the COX-2 thing is just more difficult than currently thought & there are some subtypes or it is dependent on certain brain regions etc... if the evidence for beneficial effects of COX-2 inhibition is real, but some specific agents do not work, this does not mean at all that the theory is flawed in my eyes! I strongly feel / believe that sometimes final conclusions are drawn too quickly in many areas. People usually get further by thinking out-of-the-box (they can make more mistakes too, but this is the nature of the matter & doesn't mean that the same mistake has to been done over and over. No advantage without risks).
 
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Hey boys https://www.ncbi.nlm.nih.gov/m/pubmed/20047157/ Thought you'd be interested Dopa :)

Concerning cannabis, I will just say this: There are CB1 receptors everywhere. I was under the impression some of the short term memory effects were from CB1 agonism and are therefore unavoidable unless you don't care about getting stoned. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2141681/figure/F1/
 
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Inflammation in schizophrenia.
Kynurenine pathway in schizophrenia: pathophysiological and therapeutic aspects.
Inflammatory biomarkers and depression.
COX-2 inhibition in schizophrenia and major depression.
The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression.

Cytokines and major depression.
Cytokines: abnormalities in major depression and implications for pharmacological treatment.

The immune system, depression and the action of antidepressants.
The stress system in the human brain in depression and neurodegeneration.

And so on ... wow, just wow again! :) This is enough stuff to keep my brain busy for quite some time.
Doctors really should work only 50% or so and have the other half time available to study all the new science... this could make so much advantages.
 
nintey said:
regardless of the research that has been presented on this subject, selective cox-2 inhibitor celebrex did not produce any notable decrease in the fog-effect of cannabis. I think there is a missing link between this research and reality.
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That may be the case, but before coming to such a conclusion we should consider several factors.1 COX2 inhibitors, can themselves, produced temporary mild memory imparement, given the role of prostaglandins in glutamatergic signalling and memory consolidation. however, COX2 inhibitors are neuroprotective through suppression of prostaglandin synthesis, and the short term memary impairment produced while these compounds remain in the animal test subjects system certainly doesn't mean neurotoxicity.2 COX2 inhibitors might not prevent the THC/cannabis induced memory impairment seen during the intoxication phase, as such symptoms are likely due to cannabinoid (cb1 agonist) induced inhibition of acetyl choline and norepinephrine transmition in certain brain regions such as the hippocampus. Rather in my opinion, COX2 inhibitors may protect against the perminant/long lasting memory defforsits caused by heavy cannabis use in the long term. In a similar way, powerful memory impairing drugs such as barbiturates, and ketamine, or a mixture of both, can be used to treat or prevent brain damage following an axident, or stroke.Also did you come to the conclusion that COX2 inhibitors don't work, based on scientific research or from self experimentation, that would be interesting. If you have tried the combo please post your experience.
 
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