what receptors control the amygdala?

[trainman04]

So whats the purpose of anandamide besides activating CB1? also what about 2-AG does FAAH inhibitors increase that? (edit) oh nevermind MAGL inhibitor? increase 2-ag right? do u know of any MAGL inhibitors? otc or drugs? also are there any other important endocannabinoid receptor or stuff im forgetting?
so THC can make New CB 1 receptors? but long term THC usage decreases cb1?.... I saw a comment on reddit "Less CB1 receptors = less places for THC to attach to = a weaker high." Me already having less cb1 receptors accordin to the snp but they also dont get disentized... I need more cb1 receptors tho.
what antidepressant drugs create/activate cb1?

wats the diff between 2-ag and 2-age ? 2-ag turns into 2-age?? both are agonist on cb1 also what is N-Arachidonoyl dopamine ? Is dopamine itself an agonist on cb1?

so all these (2ag/2age/anandimide/NADA etc) produce anti anxiety effect by increasing cb1?


is
2- ag degraded by FAAH or MAGL OR Both?




maca - https://www.ncbi.nlm.nih.gov/pubmed/23853040

pterostilbene http://www.fasebj.org/doi/abs/10.1096/fasebj.28.1_supplement.1144.10

pterostilbene is better absorbed by the body than reservatol

black pepper im a little confused dont know what it does think it activates cb1
https://www.ncbi.nlm.nih.gov/pubmed/28942644



what is the CRHR1-IT1 (CRHR1 intronic transcript 1) & MGC57346-CRHR1 gene ? I have risk alles with these but theres no description about them anywhere.
I already eat healthy and excercise 5 days a week its not working

random study

These rats exhibit a mutation in a gene called Crhr1 that increases CRF (type 1) receptor signaling.
​

increased CRF signaling led to elevated activity of the anandamide clearance enzyme fatty acid amide hydrolase (FAAH). Increased CRF was also associated with drops in anandamide levels in the central nucleus of the amygdala. Together, increased FAAH activity and decreased anandamide with low cb1 the signaling reduce inhibitory control of excitatory neurotransmission in this critical region, and lower the brain’s ability to regulate stress and anxiety.

[1] CB1 stimulation helps hold anxiety in check.

CB1 Receptors control stress-mediating circuits by inhibiting neurotransmitter release — a sort of gating mechanism to keep anxiety in check.
​

[2] CRF increases our stress response

corticotropin-releasing factor (CRF) activates the stress response and promotes increased sensitivity to stress and anxiety when activated over and over again.
​

[3] Too much CRF in the Amygdala and probably the Nucleus Accumbens can shut down this stress releaving system and leave you in a state of constant anxiety.

overactive CRF signaling in this region produces a wide range of effects that override the stress-reducing capabilities of a major eCB called N-arachidonoylethanolamine (anandamide), turning chronic stress into unchecked, or pathological, anxiety.
​

 

[trainman04]

here is a list of supposed CB1 agonst I wanna try first
Butyric Acid
KAVA
Agmatine
Galantamine
Oleamide
Palmitoylethanolamide


Inositol best thing that worked so far for me saw a very big anxiety reduction. also why does THC cause a person to get high? It activates CB1 but why does that cause a high?
weirdly EGCG didnt work for me its an agonist on CB1 with an affinity of 33.6 μM. how much is that compared to Anandamide with an affinity of 78 nM?

 

[sekio]

Me already having less cb1 receptors accordin to the snp

That SNP does not decrease the number of receptors, it changes how likely the existing receptors are to activate or become desesnitized.

wats the diff between 2-ag and 2-age

They are two different endocannabinoids with similar structures, 2-AG is naturally present but 2-AGE has not been reliably detected in humans.

is 2- ag degraded by FAAH or MAGL OR Both?

Both.

here is a list of supposed CB1 agonst I wanna try first
Butyric Acid
KAVA
Agmatine
Galantamine
Oleamide
Palmitoylethanolamide

Of those, only kava is an orally active cannabinoid, and even then it's not exclusively a cannabninoid, it has many other effects. The other compoounds either do not bind CB₁ or they are too rapidly destroyed in the body to be a drug.

weirdly EGCG didnt work for me its an agonist on CB1 with an affinity of 33.6 μM. how much is that compared to Anandamide with an affinity of 78 nM?

1 uM = 1000 nM. EGCG is not a psychoactive cannabinoid because it doesn't cross BBB very well and is too water soluble. Also it's about 500x weaker.

what antidepressant drugs create/activate cb1?

Fluoxetine, desipiramine, tranylcypromine, etc.

Inositol best thing that worked so far for me saw a very big anxiety reduction

Inositol doesn't effect cannabinoid levels or NMDA or anything like that...

I already eat healthy and excercise 5 days a week its not working

What sort of exercise? What's a typical day's worth of food to you?

 

[trainman04]

Yeah You are probably right ...I tried Inositol for a second time this time nothing happend.. But I swear it worked the first dosage .. I defintely felt a difference.
I eat fish/chicken , veggies, only drink water , rice, daily. I dont count the calories. for exercise I run on the treadmil for 30 minutes. Do some workouts on the machines they have in the gym. its not that complicated tbh very basic.
So My problem is just little CB1 activation. Since my SNP also said the CB1 receptors dont become desesnitized. So the only fix would be THC ? Dont know where to get that yet but I do know where to get CBD oil. Should I try cbd oil first? if I do start this thc/cbd how am I supposed to take it? since you said long term usage decreases cb receptors.

1. Is dopamine an agonist on cb1 ?
2. What do you think about the studies for the FAAH inhibitor supplements? Im very bad at understanding studies do they say they are potent or weak?
3. Should I combine CBD oil with thc oil so they even each other out?

 

[Weltmeister]

The best source for THC is (obviously) Cannabis. Cannabis and THC are probably illegal in your country so the only source are black market dealers. In some countries possession of even the smallest quantities is punishable by execution so definitely read up on your local laws.

 

[Limpet_Chicken]

CBD (not sure about this but hypothetically, mainly due to its difference as a CB1 antagonist to the likes of rimonabant etc) might induce a compensatory upregulation of CB1 after use for a period. I'm thinking here, rather like how for example, memantine acts not only as an NMDA receptor uncompetitive antagonist, but also as an antagonist of the neuronal alpha7-type nicotinic acetylcholine receptor, activation of this type of NAChR can confer nootropic effects, such as by the (mainly cholinesterase inhibitor) galantamine, but with memantine, there is at first, due to the antagonism at this site, a sort of anti-nootropic effect, temporarily, can cause some temporary short term brain fog etc. but after this; due to the antagonism, the brain responds with a homeostatic adjustment, causing upregulation of alpha7-type NAChRs leading to clearing of any brain fog and an improvement in cognitive functioning.

 

[trainman04]

The best source for THC is (obviously) Cannabis. Cannabis and THC are probably illegal in your country so the only source are black market dealers. In some countries possession of even the smallest quantities is punishable by execution so definitely read up on your local laws.

yeah but marijuana has lots of other cannabinoids in there and who knows what they do.

 

[sekio]

Most marijuana has been bred to contain primarily THC, CBD, (usually primarily as their carboxylate forms - need to be heated to decarboxylate them) and maybe a little CBN from oxidisation of the THC on storage. The other cannabinoids are present usually only in trace levels (less than 1 percent in the extractable oil).

Certainly the other cannabinoids don't do anything bad - they are all fat-soluble antioxidants at the very least and people have been using marijuana for thousands and thousands of years to either induce visionary states or as medicine. Even today, plant based marijuana is generally reccomended over purified THC because it is easier to dose, cheaper, and easier to acquire.

The major reason to use marijuana over isolated THC is that in countries where cannabis is illegal, purified THC will also be illegal and will be even harder to source/more expensive (as it must be made by extracting & processing plant based cannabis products). It's easier to dose too high and get into an uncomfortable state.

I eat fish/chicken , veggies, only drink water , rice, daily.

You may want to start taking a multivitamin plus iron supplement or eating more red meat, sticking to exclusively vegetables and chicken/fish can lead to deficiencies... I know people who have had the same problem in that they reported a severe lack of energy and problems concentrating/emotional issues and it turned out to be anemia from a genetic factor plus a diet that lacked any meat. (tofu/veggies only).

Switching to brown rice/wild rice and increasing the diversity of grains you intake could also provide more carbohydrate energy for you to have throughout your day. Also, adding sugars as snacks can increase cannabinoid receptor production. If you can tolerate it, drinking milk or eating yoghurt are also good sources of fats and protien.

Also you should increase the amount of polyunsaturated fats to increase natural cannabinoid production... try taking fish oil supplements for that. That would be the first thing I would try if you don't do that already.

It can be amazing how simple dietary changes can improve things... I would suspect your diet is just too lean, rather than any sort of problem with cannabinoids. Although, ingesting THC will probably change all that quickly It's known for increasing appetite.

1. Is dopamine an agonist on cb1 ?
2. What do you think about the studies for the FAAH inhibitor supplements? Im very bad at understanding studies do they say they are potent or weak?
3. Should I combine CBD oil with thc oil so they even each other out?

1. No
2. Most natural supplements are not effective FAAH compounds in the human body, only in petri dish cell cultures.
3. It's best to find a strain of marijuana that contains both rather than taking the two seperately. But, if you can find purified THC and CBD for sale, there's no reason you couldn't try that. I would take them at a 1:10 ratio, so 1 mg of THC per 10mg of CBD. And probably no more than 10mg of THC on your first dose.

 

[Limpet_Chicken]

A question, folks, if I may.

Assuming someone were to say, start out with THC (probably as a mixture of mostly delta-9-THC and lesser but significant quantities of delta-8-THC.) and separately, CBD. What would be ideal ratios, if one were to attempt to prepare a blend corresponding to either a trippy, lively sativa skunk, or a lazy, red-eyed munchies-inducing couch-locker hash? Assuming that one wasn't starting from plants, and had to blend the cannabinoids themselves, in order to dissolve them either in something like diethyl ether to dip a cigarette, or prepare an E-liquid as a solution in propylene glycol, for a stealthy, publicly usable intake mechanism?

(since it would lack the scent produced by the terpenoids in weed itself, it'd thus serve as a nicely sneaky little preparation for such crafty portable toking without the odor of weed giving the game away)

 

[trainman04]

@sekio Im looking at these drugs that are supposed CB1 agonist but they all seem dangerous whats up with that? Like I found a source for a cb1 agonist called MMB-CHMINACA then when I went to Wikipedia to read about it it says its causes a lot of deaths... And when I go read about other CB1 agonists same thing. Its like its common with these CB1 agonist drugs.

 

[Limpet_Chicken]

A lot of the later-released synthetic cannabinoids seem to be a lot more dangerous than the first wave or two of such RC products. Repressive crackdowns one after another, with the filthy government witch-hunting for such things proceeding as such evils usually do, caused the distributors and chemists making them for the vendors supplying to end users, to start having to scrape ever further into the bottom of the barrel, until they were literally digging into the dirt underneath, having scraped right through the bottom of said barrel.

The indole and indazole cannabinoids with an isovaline, valine or 3-methylvaline appear to be particularly toxic, and it seems that those cannabinoids containing these branched-chain aminoacid tails on the upper sidechain are those which have produced a large number of fatalities. Perhaps it is a noncannabinoid-mediated toxicological pathway. Even 5F-cumyl-PINACA didn't seem dangerous in THAT kind of way. (and this stuff, released as C-liquid for a while, is possessed of, reportedly, as little as low picomolar affinity for CB1) Not to say it is safe though, it is potent enough to downregulate cannabinoid receptors very rapidly with continued use, and with cannabinoid receptor agonism having antiemetic effects this can result in SEVERE hyperemesis. And its also so short lived that tapering would be near impossible (20-30min or so), and active at low double digit micrograms to hundreds of nanogram estimated range (a 1mg/ml solution in propylene glycol was sufficient to stone me so damn hard I near enough passed out, or a least fell straight to sleep after just a couple of drags on a vape pen loaded with it. Probably the most potent cannabinoid I've ever encountered, making HU-210 look like baby formula, although ultrashort-duration. I kind of think of that one as the remifentanil of cannabinoids. Incredibly potent, duration so short that it feels almost as if it were of similar duration to nitrous oxide or ether, only on steroids)

But it didn't otherwise seem intrinsically toxic-feeling. The likes of MMB-CHMINACA are really nasty seeming things though, never taken any of them, but these branched-chain aminoacid-tailed indole and indazoles do seem extremely dangerous, and have indeed caused waves of deaths.

Also some of the synthetic cannabinoids, the ones utilizing a terminal fluoroalkyl N-sidechain, in particular those in which the sidechain contains an even number of carbon atoms get metabolized to produce fluoroacetate in-vivo, fluoroacetate is a truly deadly, more or less untreatable (theoretically this is not the case, but no hospital will have a chemical antidote to it, and supportive measures are all they are going to be able to offer) metabolic poison that disrupts the Krebs cycle (citrate cycle) by being metabolized to fluorocitrate which unlike the citrate which is meant to be processed through the Krebs cycle, jams up one of the enzymatic steps, blocking aconitase, and starving cells of ATP.

If it is administered in a dose which does not kill outright, then the effects of the poisoning by fluoroacetate will be cumulative, and being a mitochondrial poison, it targets those bodily organs which have the highest requirement for energy most of all, although it is not selective, organs such as the brain, the heart, the lungs and reproductive system. Like I said, scraping the bottom of the barrel, and so far that one gets past the dirt, through the bedrock and ends up tunneling into the bowels of hell itself.

Also, a lot of the synthetics are full agonists at CB1, CB2 or both. THC from weed is a partial agonist, which means that there is a limit to the amount of stimulation it can produce of these receptors, a ceiling effect if you will, kind of like with buprenorphine, where after a certain quantity, additional bupe would not produce a greater degree of opioid effects, only an extension of the duration of effect.

So with a partial agonist at cannabinoid receptors there is a correspondingly lesser degree of E.g receptor downregulation, overactivation and what have you that can take place, depending in its degree on the intrinsic efficacy of the drug. With a full agonist, especially a highly potent one, there is no such intrinsic, built-in hardwired safety margin.

Certainly, though these branch chain amino-acid compounds, they seem more toxic than the other cannabinoids.

Reports of lactic acidosis are common, in particular, with seizure etc.

Would anybody with the software and knowledge in using it to overlay some of these, such as MMB-CHMINACA and other branch-chain AA-featuring synthetic cannabinoids with this:

[(1R,4aS,10aR)-1,4a-Dimethyl-7-propan-2-yl-2,3,4,9,10,10a-hexahydrophenanthren-1-yl]methanamine

Its known as leelamine, and is a CB1/CB2 agonist, but also an inhibitor of pyruvate dehydrogenase kinase. Which seems to me like at least a possible pointer to a route to look down, in respect that it is, as a result of the existence of leelamine, de facto proves that it is possible for the effects of a pyruvate dehydrogenase kinase inhibitor and of a cannabinoid CB1/CB2 agonist to cross paths in a common molecule. Perhaps others share such effects.

 

[trainman04]

I have a theory why THC makes you high. Becuase its so potent at increasing CB1 receptors even more so than 2-AG And Anandamide and its long half life. It Causes CB1 Downregulation and this somehow causes an increase in serotonin neurontransmission and increases serotonin receptor activity and serotonin receptor 5ht3 I think is known for making you dizzy/nauseas and I think this is were the "high" feeling comes from.

 

[sekio]

I think your issue may be as simple as diet changes, trainman. See my above post.

THC is a partial agonist of CB₁, whereas anandamide is a full agonist, because THC it activates CB₁ receptors only about 60% as strongly as anandamide. It is still enough activation to produce druglike effects because there is far more THC binding to receptors when it is dosed than there is natural anandamide, and is part of the reason why THC does not produce a strong physical dependence or serious psychological side effects like synthetic cannabinoid drugs like JWH-018.

CB₁ receptor activation is much more complex than altering the levels of serotonin, not every drug effect boils down to simple monoamine level changes. CB₁ is actually a G-protein coupled receptor, and its activation actually changes the activity of other ion channels present on the cell that has the receptors.

Research suggests that the majority of CB1 receptors are coupled through Gi/o proteins. Upon activation, CB1 receptor exhibits its effects mainly through activation of Gi, which decreases intracellular cAMP concentration by inhibiting its production enzyme, adenylate cyclase, and increases mitogen-activated protein kinase (MAP kinase) concentration. Alternatively, in some rare cases CB1 receptor activation may be coupled to Gs proteins, which stimulate adenylate cyclase. cAMP is known to serve as a second messenger coupled to a variety of ion channels, including the positively influenced inwardly rectifying potassium channels (=Kir or IRK), and calcium channels, which are activated by cAMP-dependent interaction with such molecules as protein kinase A (PKA), protein kinase C (PKC), Raf-1, ERK, JNK, p38, c-fos, c-jun, and others.

In terms of function, the inhibition of intracellular cAMP expression shortens the duration of pre-synaptic action potentials by prolonging the rectifying potassium A-type currents, which is normally inactivated upon phosphorylation by PKA. This inhibition grows more pronounced when considered with the effect of activated CB1 receptors to limit calcium entry into the cell, which does not occur through cAMP but by a direct G-protein-mediated inhibition. As presynaptic calcium entry is a requirement for vesicle release, this function will decrease the transmitter that enters the synapse upon release. The relative contribution of each of these two inhibitory mechanisms depends on the variance of ion channel expression by cell type.

[...]

In summary, CB1 receptor activity has been found to be coupled to certain ion channels, in the following manner:

Positively to inwardly rectifying and A-type outward potassium channels.
Negatively to D-type outward potassium channels
Negatively to N-type and P/Q-type calcium channels.

THC binding to receptors causes a decrease in the intercellular level of cyclic adenosine monophosphate (cAMP), which alters the activity of potassium and calcium channels (causing some types to become more likely to fire and some less likely to fire). However in areas of the brain that have high anandamide signalling levels normally, THC causes a slight relative increase in intercellular cAMP because it displaces the anandamide and reduces the amount of receptor activation (but still activates the receptor).

It is impossible to point to any one thing that causes the "high", but the best way to put it simply is THC changes the electrical activity of cells in the brain that have cannabinoid receptors on them.

It is the activation of CB₁ receptors resulting in downstream effects that causes your body to produce more receptors (and in the long term eventually desensitize/downregulate the receptors), not the direct effect of THC binding. THC actually is used to treat nausea in medical usage and only causes nausea at very high doses. THC also does not directly produce more CB₁ receptors right away, it will take several days at least.

Receptor downregulation does not happen instantly either, it usually takes several weeks or even months for your body to deactivate the receptors permanently. Changes in the level of neurotransmitters happens over a similarly long timescale, days to weeks. This is part of why SSRI antidepressants usually need to take around two weeks to become fully effective in some individuals, they need to keep taking the drug for ~14 days before the brain begins to start adjusting the number of receptors and how rapidly serotonin is manufactured.

Also, THC does have other effects like positive allosteric modulation of the mu- and delta- opioid receptors (increases the effects of natural endorphins) and it produces an active metaboite, 11-OH-THC, which also may have other effects.

What would be ideal ratios

Anywhere from 100% THC and 0% CBD to 10% THC/90% CBD is fine, adjust the dosage to match your personal preference. I haven't actually found a correlation between THC/CBD ratios and indica/sativa phenotype though.

 

[trainman04]

no offence but thats ridicilous. my issue is not as simple as diet. Changing my diet wont increase my CB1 receptors Enough to so I feel good, It wont decrease my Overactive CRFR1 gene which deplets my CB1 further more. This brings up my previous example. Go tell cancer patients to just change their diet and their cancer will be gone. Anyway I think I know enough now... I will test the CB1 agonists and faah inhibitor supplements, and if they dont work, I will try CBD oil, and if that doesent work I will try THC somehow, and if that doesent work, I will try Research chemicals cb1 agonists..... You said omega 3 can increase cb1??? is that true? how much epa/dha do I need daily

also what do you think about Astressin-B? it blocks CRF . You can find it on amazon but its topical and supposedly U put it in ur hair. Might give it a shot .

 

[Moxious]

What would be ideal ratios, if one were to attempt to prepare a blend corresponding to either a trippy, lively sativa skunk, or a lazy, red-eyed munchies-inducing couch-locker hash? Assuming that one wasn't starting from plants, and had to blend the cannabinoids themselves, in order to dissolve them either in something like diethyl ether to dip a cigarette, or prepare an E-liquid as a solution in propylene glycol, for a stealthy, publicly usable intake mechanism?

(since it would lack the scent produced by the terpenoids in weed itself, it'd thus serve as a nicely sneaky little preparation for such crafty portable toking without the odor of weed giving the game away)

Terpenes are the main factor contributing to indica/sativa effects, without them your high is never going to feel like weed, only like THC/CBD. You'd want to add something like myrcene or beta-carotene to contribute some indica-like effects. Currently there's a lot of work being put into trying to figure out exactly what you're referring to, because from an industrial standpoint it's easier and far more consistent to start from something like pure/isolated thc and add other ingredients. There has been some progress but the samples I've tried were less than impressive. Tends to be people try to combine thc isolate with 'naturally-sourced' terpenes like from blueberry plants. I don't know what the chemical difference is but there is a very noticeable difference in effects between naturally derived terpenes from other plants and hemp-derived terpenes. The best I've tried were just that, isolate + hemp terpenes. I can't imagine it would be much cheaper to produce than extracting straight from cannabis though.

Sorry to derail your thread, trainman

 

[sekio]

Go tell cancer patients to just change their diet and their cancer will be gone.

A cancer patient who eats an unbalanced diet is going to have a far worse prognosis than one that eats a well-balanced meal. It certainly won't make you feel any worse, eating a more diverse set of foods. At the least, start taking a multivitamin with iron if you don't already, it's a cheap and effective way to help ensure your body can produce enough energy, and if you are deficient in say iron or B vitamins, you will start feeling better quite rapidly.

I'm only trying to help here. The notion that diet effects mood is not so far fetched, have you ever heard the idiom "you are what you eat"? And it does tie back in to the functioning of your cannabinoid system - if your body does not have the raw materials to produce anandamide then how do you think your cannabinoid system will function? Not well of course.

also what do you think about Astressin-B? it blocks CRF . You can find it on amazon but its topical and supposedly U put it in ur hair. Might give it a shot .

The reason it's being used topically is supposedly because it increases hair growth by that mechanism. Topically applied drugs are generally not absorbed into the blood, the studies that show an effect on stress and cortisol levels use injected forms of it in rhesus monkeys and not the topical form. So I don't think rubbing anything on your head will help you.

You said omega 3 can increase cb1??? is that true? how much epa/dha do I need daily

The main acid you are interested in is arachidonic acid, which is also found in peanut oil and many other foodstuffs, and as much of it as possible, because that's the precursor to anandamide in the body. EPA/DHA are another thing entirely but studies seem to show that at least 2-4 grams of each a day (more EPA than DHA if possible) can lower blood triglycerides and lead to better heart health.

 

[Limpet_Chicken]

No harm in eating a healthy diet, obviously there is nothing to be lost, only to be gained by eating healthily.

And moxious-the idea I have is based on starting with CBD (99.5-99.8%) and treatment with boron trifluoride in order to cyclize it to a mixture of delta-9-THC and delta-8-THC, primarily the former. Then blending the result, after quenching any unreacted BF3 and extraction, distillation, with a portion of CBD to achieve something functionally equivalent, or at least close enough, to weed. Whilst not smelling like weed and therefore being able to be used in public. Plus of course, of very high potency, or potentially so, depending on the dilution chosen, the end result being essentially a super-strength, stealthy 'hash oil'

 

[trainman04]

any thoughts on Jiaogulan as a FAAH inhibitor?

 

[Cotcha Yankinov]

Idk about that substance but I don't think FAAH inhibitors have proven safe quite yet.

 

[trainman04]

Idk about that substance but I don't think FAAH inhibitors have proven safe quite yet.

its a supplement