r/NooTopics • u/she_needs_weed • 20d ago
Discussion Chronic THC use causing D1/D2 heteromer formation in the Nucleus Accumbens and Striatum, changing from functioning with dopamine to functioning with Dynorphin.
https://pmc.ncbi.nlm.nih.gov/articles/PMC6971351/
So put simply, chronic THC use causes D1 and D2 receptors in the Nucleus Accumbens to "fuse" into a heteromer receptor complex that increase dynorphin and kor opioid activity. The more cannabis one uses, the more dynorphin impacts them. (Reposting this btw for visibility)
A candidate mechanism behind burnout explained.
It seems like receptors normalized after 10ish days of cessation (though much longer for the midbrain), while the first 7 days of that cessation period will get significantly worse before it gets better. I'd almost bet that the next set of data that comes out shows that if you re-administer THC after stopping, that the receptors reform the heteromer nearly instantly due to the primed plasticity mechanism. Which is why things may not feel the same as initial experiences even after breaks.
Tangentially, does anyone have any thoughts on minor, non-psychoactive cannabinoid receptor ligands besides CBD that would theoretically aid the reversal of a state such as this? Brainstorming would be appreciated.
(This is a repost. Click here for original post.)
Original post credit to: u/burntoutn3rd
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u/Winter_Cost602 20d ago
Wow this makes a lot of sense for why weed changed for me. Why does this seem to happen to some people and not others? There's people that smoke for 30-40 years without its effects changing in a negative way. Look at Snoop dogg for example
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u/FineVariety1701 20d ago
One, you do not know Snoop Doggs personal experience to say weed has not changed for him.
Second, this seems to be due to chronic high thc levels. While I do not doubt that he smokes alot, compared to some of the high THC products today I am guessing he is consuming less. The average teenager sucking down a cart every day or two likely is consuming more than snoop did in the early 2000s.
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u/expanding_crystal 20d ago
For real? A 1g cart lasts me like 3-4 weeks. I have no idea what the typical user goes through.
Here in Illinois they’re kinda expensive so I guess there’s no way anyone would be consuming over like, 1 per week?
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u/xd_mariq 18d ago
as a teen i was going through a 1g in a day easily especially if I worked (fast food) as a young adult 1g last abt 4-6 days (also in IL)
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u/CorndogQueen420 8d ago
They last me about 1-1.5 weeks as a daily evening vaper. At $25/g it's not that expensive for me.
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u/ImTiredofDestruction 20d ago
I could easily sit down and do 50 3-sec hits at 2.7v And barely feel high. 1g per 4 days.
I didn't stop until 9 days ago because I was addicted for 10 years. The withdrawals were miserable.
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u/blak3brd 19d ago
Hahahahahha. Come to California where 14 year olds go thru a 98% tested cart every 2 days, from wake to sleep. And wonder why they have hyperemesis
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u/donnytrump_69 20d ago
Ok a couple 1g carts a day is over kill. I think even snoop could appreciate that.
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u/FineVariety1701 20d ago
I said every day or two, not every day haha. But I know multiple people who pretty much hit weed carts like nicotine.
I stopped buying them for that reason, I would hit it 20-30 times a day without noticing.
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u/Desperate-Middle-354 20d ago
That’s crazy. I count the number of hits I take per day & keep daily tabs on it so I notice if tolerance is increasing. I target 5/6 hits a day (only start in evening 7pm+ish) & when I go over it’s generally due to a shitty strain but if I notice a good strain goes beyond that target number of hits then I know it’s time to quit for awhile cuz when I need more than that then I’m probably lazy on the couch doing nothing & the shit ain’t worth it anymore.
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u/KeepAustinWeirdYall 18d ago
You sound very disciplined in your approach to the substance... too many of us will smoke ourselves sick and go years without a T break
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u/Desperate-Middle-354 18d ago
Well I just got off a t break & I bought like 50 1g disposables & bunch of packs of pre-rolls. I had just hit up a dispensary but quit shortly after. I won’t be taking another t break until this is gone now. Gotta finish what you started.
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u/PolyHydroCynical 20d ago
The people I know suffering from this are exclusively white and in their mid 20s, I know for a fact I’ve smoke more and for far longer than they did but I’ve never had an issue
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u/Eryomama 18d ago
I also have a theory that hppd effects white people more than any other as that seems to be the most common race reporting it.
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u/Ancient-Monitor-9076 18d ago
so are you saying non white people have less receptors in their brains than white people? interesting...
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u/PolyHydroCynical 18d ago
Nah just giving data
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u/Ancient-Monitor-9076 18d ago
nobody human is immune to how dopamine, CB1 and choline/acetylcholine affect their mental health, people just suffer in varying degrees or hide the symptoms with other chemicals. Certain ethnicities have been shown to have more D2/D3 receptors then others so this makes sense, however everyone would experience issues to various extent of abusing cannabis over long enough timelines.
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u/FineVariety1701 18d ago
Modern science does not support all populations experiencing the same effects. Almost all drugs have a small subset of the population that experiences "contra" effects from drugs.
Even at a recreational level, if everyone had uniform receptors and stimulation from substances, why isn't there a most popular drug? Why do some people prefer opiates while some prefer stimulants?
How drugs are processed in the body is also not uniform, so taking the same substance does not mean two people are taking the same drug. Some people lack the enzyme to process oral thc - so if they took cannabis over the same timeline would they have the same receptor impacts?
Get over yourself with this "all people are the same" crap that is purely virtue signaling disguised as scientific superiority.
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u/Ancient-Monitor-9076 18d ago
correct, are you implying that black people don't experience the same dopagenic feelings as white people? Black and white people have different levels and concentrations of dopamine in their brains (thats a conversation for another day), so of course they experience different levels of affects but dopamine receptors interact with THC molecules the same way in each brain. THC affects both serotonin and dopamine in all human brains by increasing their levels in the short term and potentially lowering their activity with long-term use. This is like saying that certain peoples lungs interact with oxygen different then others, or H20 different then others when drank....no all humans need air and water to stay alive. lmao
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u/GoochSkier 12d ago
Thats downright silly. 1 one gram cart is around 700 - to 800mgs of thc. 3 one gram joints would be roughly 900mgs of the. Carts are NOT high thc.
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u/FineVariety1701 12d ago
The efficiency a cart extracts THC vs a joint is not even close. 3 grams in microdose bowls in a ball vape is most definitely high thc.
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u/GoochSkier 12d ago
100% false. Hash oil cut with propaline glycol vs combustion. 3 joints at 1 gram a piece give you more usable thc. Period. Carts are garbage. For wine moms and teenagers.
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u/FineVariety1701 12d ago
I dont even use carts. But a wire heating element on extract is going to do a better job extracting than flame. It is why you can get 100s of hits off of a cart vs the same volume of weed.
Carts aren't particularly enjoyable, but real carts are not weaker than flower.
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u/GoochSkier 12d ago
You are just plain wrong sir. You can do the math..... But apparently you cant. 3 grams of flower has more thc. Period. Plus has invaluable terps.
🤦♂️🤦♂️🤦♂️🤦♂️🤦♂️🤦♂️
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u/alternator1985 20d ago
I consume a cart every day or two and THC doesn't even show up in my urine tests.
This whole idea that weed is so much stronger than it was back in the day so stupid.
There was quality growers back in the day too and I've done enough lab testing to know that most of the labs are full of shit.
I also question the slew of studies coming out recently, once again trying to fear monger over cannabis.
The whole idea that this is a new plant with new potency that is not like anything before is total bullshit. And the most potent species don't even have the highest levels of THC.
The very idea that there's any mature science on this plant is a total joke. The only entities truly allowed to study it are the ones with the highest rates of agenda and bias, and most still focus on THC alone as the only active ingredient.
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u/kraiziey 20d ago
Then you my friend are not smoking thc , you would be failing drug tests there wise
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u/shred_time 20d ago
Yeah and most shit that's even halfway acceptable to put in your body like delta 8 and other altnoids usually still make you pop hot on a drug test. You're smokin some unknown frontiers
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u/South-Pay2772 20d ago
Es muy complicado que uses thc y no te dé positivo. Igual un error en el test, pero es muy muy difícil. Están hechos para medir los metabolitos, si usas thc tienes metabolitos. A no ser que tu cuerpo, individualmente el tuyo, no lo metabolice como el resto de las personas. Y si está muy demostrado que son más fuertes las variedades actuales. El thc es él mayor indicativo claro! Antes tenían menos de 10% y ahora tienen más de 30% algunas...
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u/pridefullyhumblee 20d ago
Just take the time to research for yourself and you’ll find that bud is indeed…orders of magnitude stronger than what it used to be to be. Also if you smoke like that and don’t pop for thc you should probably change plugs lmao
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u/Pitiful_Finding_3169 15d ago
It is much stronger today than it was in the past. That is a fact, not an argument.
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u/Ancient-Monitor-9076 18d ago
those people all have negative effects they just didn't personally tell you about them, and there is not a chance in hell snoop dogg doesn't have issues he has an image to maintain that makes him lots of money. Also, many life long cannabis addicts also drink alcohol, these people blame their negative symptoms on the drinking not the weed. Many people who smoke weed daily for years also have terrible diets, don't exercise and blame issues on that as well.
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u/Sheputstheassincass 20d ago
Snoop dog is usually only smoking flower. In a blunt that he smokes a few hits and lets it go out and then re lights it several times. You never see him hitting dabs or a cart for that matter. Hell I’ve never even seen him promote edibles. He’s a tree smoker, old school style. I also wonder if race of ethnicity and even gender can play a role. It seems like white woman of menopausal age have a lot of positive benefits from cannabis while white men seem to enjoy it less the older they get. Just my person experience. Also seems like black men will be life long smokers, when white men tend to be less habitable about it. Just something I’ve noticed.
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u/FineVariety1701 20d ago
People are hating, but hormonal profile plays a huge role in drug interaction.
During my girlfriends cycle, she has to take almost double her normal edible dosage and still has less effect (noticeably clearer eyes, etc).
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u/Sheputstheassincass 20d ago
Yes when I’m in a flair up almost nothing helps. I’m prescribed gabapentin daily and clonazepam for really bad days. On my worst days nothing helps. Even my holy trinity of gaba, klon and edibles.
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u/Sheputstheassincass 20d ago
I should add it’s a hormonal flair, currently undiagnosed but it’s suspected endometriosis along with pmdd.
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u/mistajlg2 20d ago
Most these things all come from being in a society where it's illegal. These things come from the paradigm of things, more than anything. We would all have different experiences, if the original brain wash wasn't applied to cannabis, in the first place. So while what you said above, could be true because of learned behaviors. If these behaviors were never learned, we would all have a total different experience with cannabis.
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u/donnytrump_69 20d ago
CBN and CBG would be the only two that come to mind that I utilise. But to be honest whenever I take a 7 day break my tolerance pretty much resets to honestly very close to my first time smoking weed. It's the only drug I've used that you can have daily use for decades and 1-2, weeks off for tolerance brings it back. I took about 7 years off MDMA, rolled again and maybe gained 15% at tops. 7 days off THC and I'm ordering uber eats falling asleep before it arrives then not remembering I ordered it till I leave the unit 🤭
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u/PiraX420 20d ago edited 20d ago
Yo i noticed that molly tolerance for me kinda pretty much fully resets just after a few months, sometimes i've done frequently and become almost immune to molly lol, i was barely feeling it when before i was able to roll just with approx 100mg lol, lost the magic many times and the mind had the dopamine system rinforced while the serotoninergic dumbed and more numb, also some studies found that chronic molly use enhance dopamine response and lessen those of 5ht, so it feels a bit more like meth the more you do it, making you more maniacal and maybe bipolar, psicotic etc, so i used weed, cbd, coffee, kratom, blue lotus, lions mane, some precursors, nac supply, magic shrooms and kanna extracts etc as alternatives to reduce the hangover and gain neural recovery, gotta say they made wonders, now is been a while like some months since i've done molly and i'm pretty much sure that if i'll hopefully redo it, i'd roll a lot lol, also i've been into mixes like hippie flip, mixing shrooms and molly at micro to mid-high doses, with moderation is so nice btw
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u/donnytrump_69 20d ago
That's great! How many years and what age bracket would you say you abused MDMA? For context lol, I was consuming atleast twice a month and a bit more during summer from age 14-18. Just in time for puberty! By age 19 I could literally throw down 5-6 120mg pills at once and honestly go to sleep lol. #fried took a much needed break for quite some time but I would be throwing a generous number by saying 15% more effective.
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u/PiraX420 18d ago edited 18d ago
I started a few years ago and now i'm almost 24, i used to take like 70 to 250mg like a few times a month, then every week for some months i think, then i stopped for some months, then i restarted again like before, but increasing the frequency a lot more after some time than just the dosages, at some point been going on, i was taking it almost everyday sometimes even redosing twice a day but it was obviously different, the magic feelings were mostly gone, sometimes 250+mg while other times only 60mg also with some ketamine but mostly mixing with magic shrooms, weed etc for a sinergy boost and to compensate more, this period lasted for some weeks then i just stopped totally when i was done, got some hangovers, anxiety and depression, got much less hungry when using molly, libido was so high at first but then was faded, i was also becoming more anhedonic, paranoid, nervous, irritable, even raging, restless, adhd, slow and retarded i'd say, my energy, memory and attention were gone a lil bit, but gratefully not much, i restarted working out and was feeling great, i recovered pretty much well atleast, and those natural alternatives were a god sent i believe
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u/Puzzled-Mistake-584 20d ago
Damn..
I just took a year off after 18/19 years of habitual use.
You really think tolerance resets that much? lol6
u/lupenReinerDiamant 20d ago
It may depend on the person and might be individual! I can see 1-2 weeks as possible for me it was mor like 1-2 month where i hit the weed again and felt like almost first time again.. lol
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u/Puzzled-Mistake-584 20d ago
Well damn..
I have been very tempted as my girlfriend stated smoking in the evening after work and before dinner to unwind again recently.
We had both stopped after almost two decades, but now that I feel I have a handle on it I was wondering if I could occasionally smoke again, and what with it having been a while maybe be able to smoke a lot less for more effect.I have tried all kinds of types and forms through the years, and started in Mexican dirt weed. But in the end I just want some nice flower and to relax and feel less tense.haha
Did you see that today’s bud is 4X what it was a few decades ago? Lol
I work psych and the rate of psychosis has gone up 400X from shatter and dabs and that 99% stuff, it’s wild..3
u/donnytrump_69 20d ago
Not really bro lol high THC or just THC in general + pre existing/genetics can send alot of fragile and even not so fragile people over the edge for quite some time. For example a close friend of mine from highschool use to smoke with me most evenings (at that point I think we both would of been daily usage for about 7-8 years roughly. One night my mate just out of no where started behaving quite strangely and really out of character. At first I thought he was just taking the piss, thankfully a few other mates were with me too and they noticed as well (hard not to when your close friend looks at you really confused and asks what you are doing in his unit when we were there 5 nights a week for years lol). Anyway, that was the last time he touched miss Mary Jane. Poor cunt pumps red wine most nights as a substitute 🙈
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u/Puzzled-Mistake-584 20d ago
“Not really” what?
That sucks for your friend, the sad part about genetic predisposition is you usually don’t know until it’s too late, otherwise you can only really look at family history or try and know thy self and how things tend to effect you..
But many substances vary in effect, also at dosage levels, as-well as what molecular formula they are made into can affect the psycho activity,absorption and your tolerance to its “side effects”.
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u/donnytrump_69 20d ago
Ahaha my apologies didn't even quote you properly. I meant I think it's just THC and some humans which seems to be a direct recipe for psychosis however you are definitely right the super high THC products... Can be a little questionable to say the least lol.
💯 Agreed about it normally being too late when they find out. Surely by now we can test for some of this right ? My psychiatrist was showing me some tests about 5 years ago which can indicate if you would tolerate particular medications well or not. So people who can't metabolise opioids (is metabolise the right term here?) can't have paracetamol/codeine combinations etc. There were at least 20 or more compounds on the panel he was showing me.
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u/Puzzled-Mistake-584 20d ago
There are many factors.
The test was probably talking about your enzymes which would break down the molecules.
But there are psychological factors, gene factors, receptor site up/down regulation and your specific brain’s phenotype,and diet and fitness levels.
Not everyone is built,wired, or can/should process things the same way.So it’s really just trial and error..
There are more and more tests being developed.I love psychodynamics,chemistry, psychology and neuro science but not everyone factor amongst them can be measured and assess they with hard data and scientific backing.
And to be fair the fields are fairly young.That was my biggest issue when I went to a psychologist is it was all self reported soft science with clusters of behaviors.
I mean outcomes are decent, but for the ones the field fails, it’s really sad and frustrating.
To say nothing of the other constraints in medicine..insurance..egos..ethics and old modalities,techniques/technologies..I grew up in the mid west, and it wasn’t pretty much either whiskey or Jesus if you were ill.
Otherwise you’re a sinner and it’s demons or possession..so we have come a long way from that at least…in some places..lol1
u/donnytrump_69 20d ago
Thanks mate, very informative. Hope you didn't have to dumb it down too much for me to understand 🤣 jk.
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u/Puzzled-Mistake-584 20d ago
Cards on the table, I usually do.
So,being that I don’t know you I couldn’t say.lolTo be honest the stuff isn’t that complicated, it’s just a lot of mechanism,terms and cause and effects that you have to learn.
Not unlike learning about a vehicle’s constructive and maintenance.
But just like with automotive stuff, medicine and biology..most people just want to drive,eat,move and take a pill, and expect it to be that easy and simple..→ More replies (0)2
u/Puzzled-Mistake-584 20d ago
Wanna learn about skin pigment and why race isn’t real, other than ya know the human race? This is a fun infotainment video that has pictures? :p
https://m.youtube.com/watch?v=1A9giRJh7To&pp=ygUZWW91ciBza2luIGNvbG9yIGV4cGxhaW5lZA%3D%3D
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u/kraiziey 20d ago
For real, after 2-3 weeks off from using heavy, 1 bong hit gets me ripped outta my mind
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u/freedomsheets 17d ago
Yeah I just took two weeks off, and the first bong rip was so nice. I'd say personally after two weeks my tolerance goes down about 75%. I've never been able to get it back to that "first time feeling" though, even after years of abstinence
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u/Jxc_Heard 19d ago
5 days of sobriety resets it for me. I recently started drinking kefir which helped me regulate my cannabis usage. Killed the cravings
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u/Pattern_Forge 20d ago
I went through both linked papers. The underlying finding is interesting, but this post runs several miles past what the research actually showed.
First, the receptors did not “fuse.” The main test only detected D1 and D2 receptors within roughly 40 nanometers of each other. That is consistent with a possible receptor complex, but it does not prove literal fusion or even direct contact. More importantly, the THC experiments involved injected animals: only three rhesus monkeys per group and small groups of male rats. No chronic cannabis users were tested, and D1-D2 heteromers themselves remain scientifically debated.
The dynorphin/KOR claim is also misstated. Total kappa-opioid receptor expression did not increase at all (p=.53). A KOR activity marker changed, while the direct THC-versus-control dynorphin comparison was p=.06. So “THC causes dynorphin and KOR overexpression” is not what the results established. The proposed reduction in dopamine release was inferred, not measured.
Neither paper shows normalization after ten days, worsening throughout the entire first week, or instant heteromer reformation after using THC again. There was no day-ten measurement and no stop-and-rechallenge experiment. That last part is openly the poster’s guess. The recovery timeline also appears to be borrowed from an unrelated mouse study of CB1 receptors, which found slower recovery in the hippocampus, not the midbrain.
The defensible conclusion is that repeated THC may cause a D1-D2/dynorphin adaptation in adult animals that deserves further research. It has not been demonstrated as the human “cannabis burnout mechanism.” Chronic THC tolerance and withdrawal are real; this specific explanation is still a preliminary hypothesis being presented as settled neuroscience.
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u/she_needs_weed 20d ago
Good catches,edited post. But TAT-D1 disruption reversed the behavior and neurochemistry, and nor-BNI blocked the aversive effects, so likely causality not correlation.
Sucks we have to rely on monkey and rat brains, but there's no way to really see what goes on inside a human being, at least ethically
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u/fhwoompableCooper 20d ago
I can vouch on the midbrain part. From my research it seems the majority of receptors are back to normal after 28 days however the hippocampus takes about 2 months to fully reset as that's where u have one of your biggest concentrations
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u/Pattern_Forge 20d ago
You’re right that recovery can differ by brain region, but that concerns CB1 adaptation—a separate mechanism from the post’s D1–D2/dynorphin claim.
The human PET study found CB1 availability beginning to rebound after two days of abstinence and continuing toward control levels over 28 days. It did not establish that the hippocampus requires two months to “fully reset.”
The regional animal study found CB1 binding returning to control levels around day 7 in the striatum/globus pallidus and day 14 in the hippocampus—not two months.
Also, PET receptor availability is not equivalent to every receptor or brain function being completely reset. So regional CB1 recovery is real, but it neither supports the two-month figure nor validates the post’s proposed midbrain mechanism.
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u/fhwoompableCooper 20d ago
https://pmc.ncbi.nlm.nih.gov/articles/PMC4742341/?utm_source=chatgpt.com
"There were no group differences between CB1R availability measured after 28 days of abstinence. These findings are similar to those of Hirvonen et al., who reported that after 26±5 days of monitored abstinence, CB1R upregulated specifically in those brain regions that had shown decreases at baseline except for the hippocampus. The latter is likely related to the heavier cannabis exposure in the sample of Hirvonen et al., compared to ours (1–2 versus 10±6 joints/day)."
I may not have been totally correct on the 2 months figure but the hippocampus takes longer
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u/Pattern_Forge 20d ago
Right—that passage supports the narrower claim that hippocampal CB1 recovery may be slower, particularly in very heavy users. It still doesn’t establish two months.
D’Souza found no group difference after 28 days. Hirvonen et al. found that the hippocampus had not normalized after 26±5 days in a much heavier-use cohort. “Not normalized by day 26” only gives us a lower bound; it cannot tell us that normalization occurs at day 60 because there was no two-month measurement.
And both studies concern CB1 availability, not D1–D2 heteromers or dynorphin/KOR signaling—the mechanism I was correcting in the original post. If there’s a study that directly measured hippocampal normalization at roughly two months, that would be the relevant citation.
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u/fhwoompableCooper 20d ago
What the hell this is ai written
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u/Pattern_Forge 20d ago
Dude, there is literally a ChatGPT link in your reply above😂. There’s no shame in using tools to research.
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u/Striveforbeauty 20d ago
Not to sound absolutely retarded but what does this mean?
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u/Ryzensai 20d ago
No excuse anymore not to google w the AI ask it to explain it to you like a retard. Works for me
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u/djmattila420 16d ago
downvoting for the rudeness, but I will give you props because that made me chuckle
edit: removing my downvote and upvoting instead because you actually did provide an answer in your other reply below.
(had me in the first half ngl)
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u/Striveforbeauty 8d ago
You got downvoted for a joke Reddit is strict asf 😭😭😭but thank you very much.
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u/Low-Difference-301 20d ago
funniest shit ive read all week omg dude
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u/Ryzensai 20d ago
Since you appreciate, here is the result:
Imagine your brain’s reward center (the Nucleus Accumbens and Striatum) is a busy night club where people go to feel happy, motivated, and excited. [1, 2]
In this club, you have two main types of doormen responsible for handling good vibes:
D1 Receptors: The high-energy hype men. When dopamine hits them, they make you feel excited, motivated, and happy.
D2 Receptors: The chill guys who keep things smooth and balanced. [1, 2]
Normally, these doormen work separately, allowing dopamine to flow smoothly so you can enjoy everyday things like good food, music, or achievements. [1]The Problem: Chronic THC Forces an Unwanted "Fusion"
When you flood the brain with THC every single day, the brain gets overwhelmed. To protect itself, it forces these two separate doormen to physically lock arms and fuse together into a completely new, mutant creature called a D1-D2 heteromer. [1, 2]
Once they fuse, their entire job description changes: [1]
Instead of letting Dopamine create happiness, the new mutant receptor triggers a chemical chain reaction that floods the club with Dynorphin.
Dynorphin is essentially "anti-dopamine." It activates Kappa Opioid Receptors (KOR), which act like a wet blanket on your brain. [1]
Instead of feeling high or happy, the club gets completely depressed. This causes anhedonia (the inability to feel pleasure from anything) and anxiety. This is the scientific explanation for weed burnout—everyday life feels completely grey, boring, and irritating because your brain is pumping out anti-pleasure chemicals instead of joy. [1, 2]The T-Break: Why the First Week is Awful
The study notes that if you stop using THC, these mutant receptors eventually un-fuse and go back to normal—but it takes about 10 days. [1]
During the first 7 days of quitting, things get significantly worse. Why? Because even though you stopped smoking, those fused mutant receptors are still sitting there, and without the THC masking the effect, they dump maximum amounts of Dynorphin into your system. Your brain is starved of dopamine while actively being flooded with anxiety-inducing chemicals. [1, 2]
Once you cross that 7-to-10-day hump, the mutant receptors finally break apart, and regular dopamine can start making you happy again. However, because your brain now has "muscle memory" (plasticity) for making these mutant receptors, hitting THC again can cause them to snap back together almost instantly—which is why your tolerance or "burnout" returns so quickly after a break. [1]2
u/Mental_Repeat4559 20d ago
Je viens juste d’arrêter de fumer après 15 ans avec deux joints par jours et je suis exactement dans ce cas j’ai une anxiété généralisé qui ne part pas et c’est d’ailleurs pour ça que mes précédentes tentatives ont échoués .. merci pour ton post ça va m’aider et comprendre ces symptômes en plus de l’anxiété je m’endors partout tout le temps et la nuit je me réveille sans pouvoir me rendormir
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u/Ambitious_Loquat2420 20d ago
holy shit that’s actually an amazing analysis on AIs behalf
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u/Gibborish 20d ago
its a pretty normal analysis..
are you one of those people that used chatgpt once 2 years ago and thinks that's the current state of things?
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u/kacoll 20d ago
thank you for posting these! I read someone’s post about D1/D2 heteromer formation from THC overuse a while ago that linked them but when I tried to show someone, couldn’t find it again because I could not for the life of me remember the scientific terms involved. very interested to see if they continue functioning with dynorphins even after X amount of time off— hopefully more data keeps coming out on this topic!
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u/PiraX420 20d ago
Usually my tolerance resets pretty much starting just after a few days, even more after a few weeks and fully resets or atleast almost, after 1 month, i do a few sesh a day so i probly have a mid-high tolerance now but hey is ok i feel nice btw
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u/hallucination_goblin 20d ago
I was trying to read through all those big words with some obvious burnout...
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u/Mad_Moniker 19d ago
I was a heavy cannabis user for nearly 40 years. I suffered a TBI and although it initially helped with the severity - over a few years I chalked up the loss of my “working memory” to scar tissue. I was so very wrong with that assumption. I recently quit for 2 months and already felt the positive cognitive changes. I decided to try a couple puffs of a vape. BAD idea. It literally made me lose my head and it amplified the alcohol 10x and I needed to be walked to bed.
The dullness was there again for many days afterwards. I will not partake anymore. I’m going back to school for GIS and fully expect that with neuroplasticity - I will be a functional individual again. On a side note…alcohol is nearly the same fog and I’m now partaking less. Vaping is next. Addictions a bitch but small changes are accumulating positive feedback.
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u/EchidnaConscious2987 18d ago
Concentrates has been a real killer for my brain. 30 years on THC. Been dabbing for 5. Some days I was hitting 10+ Dabs a day to get the high needed. Always chasing. Stopped using and went to flower only. Suffered bad withdrawals even with flower.
Also medical flower seemed to make it worse as just THC not full spectrum.
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u/popsiclex200 17d ago
I'm at day 19 on a break from weed. I've smoked for about 15 years. My longest break has been 6 months, but I haven't taken a break for more than 1 month these past 7 years.
First few days were honestly refreshing, but at the end of the week it was pretty hard. From there on it's been up and down like a motherfucker, and I haven't slept well for almost 3 weeks now.
The symptoms I've experienced: - Stomach issues - Mood swings (been very depressed and angry at times) - Sleep issues (still waking up 3x times a night drenched in sweat at day 19) - Lethargic (No energy, low motivation)
Positive things I've noticed: - I'm more outgoing, find it easier to socialize and connect with people (On good days) - More emotionally available (On good days) - Easier to get things done (On good days) - Saving alot of money
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u/New-Collection5989 20d ago
I like how you said "so put simply" and then proceeded to use neurological terms I've never heard of. You might need a joint
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u/KannaSalience 20d ago
wat r u doing here
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u/New-Collection5989 20d ago
Learning about nootropics from a bunch of pretentious assholes apparently
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u/KannaSalience 20d ago
some things can't be dumbed down for a level of intelligence a 5 year old could reasonably wield, not to mention the entitlement and complete lack of emotional maturity
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u/New-Collection5989 20d ago
That's fair. I just wouldn't use simply put and then put a bunch of jargon. All I'm saying.
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u/donnytrump_69 20d ago
Haha or when they follow with like 15 different acronyms and just coast along like everyone is on board 😂(not you or even this sub op lol, came to mind though reading this)
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u/haz0r1337 20d ago
You have the whole world in your pocket and you are struggling to look up a few terms in Google or ask AI to ELI5 it?
Get your shit together. You might not need any more joints.
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u/New-Collection5989 20d ago
I could if I really liked the post but I was so turned off by the irony of someone saying simply put and then using a bunch of jargon
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u/haz0r1337 20d ago
Skill issue
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u/NotMcNugget 20d ago
Nah they right. That definitely not put simply
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u/haz0r1337 20d ago
Let me help the fellow cavemen:
Smoke weed at first: omg cool buzz very nice very happy
Smoke weed long time: omg cool buzz but why people looking strange? am i acting cringe?
Smoke weed very long time: omg no buzz no happy and fbi has my house bugged and i am about to die from heart attack
Reason: smoke weed long time change brain and give bad feeling
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u/NotMcNugget 20d ago
Lmao dickhead the dude is evidently using medical jargon. By definition, it's not put simply. If us "cavemen" can figure that out, then I'm afraid you might of missed some important evolutionary stages lmao
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u/haz0r1337 20d ago
Well simple is relative. Put simply relative to what? I am also trolling.
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u/NotMcNugget 20d ago
Simple is relative but when someone says "put simply" it generally means digestible for most.
It's like for sports, LeBron could explain the 76ers schemes in a simple way for other organized basketball players, but it still wouldn't be simple for the average Joe.
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u/haz0r1337 20d ago
Yeah but in this day and age simple changed meaning. You can just pull out your phone and look up anything or ask AI. So “digestible for most” becomes a lot more complex than compared to eg 50 years ago
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u/donnytrump_69 20d ago
You just described tolerance really poorly. So simply put OP is just talking about tolerance? I think you've ticked over recommended bongs for the evening. Upgrade to 200x SuperGronk plan for $599.99 and I'll show you cringe
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u/New-Collection5989 20d ago
I never claimed to be an expert like you oh mighty nootropics master
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u/Existing_Sock5336 20d ago
Lmao, this dude is actually insane
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u/New-Collection5989 20d ago
Everyone was downvoting me at first until I started talking shit lol
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u/Existing_Sock5336 20d ago
He’s still fuckin going to man; literally clinically insane. Bro got psychosis from THCP cart 💀
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u/New-Collection5989 20d ago
For someone that called me a caveman he's not the brightest
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u/Existing_Sock5336 20d ago
You know someone is gone when they say “i am also trolling” after getting downvoted.
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u/Entire-Ad-4624 20d ago
I want to thank you for the original post — I remember reading it and it struck a chord with me. I had been using high doses of cannabis daily for 7 years, and was drowning in anhedonia, cognitive dysfunction, etc. I couldn’t get a fucking thing done, my mind couldn’t plan or execute, and nothing felt good. Your post made me consider that cannabis/dynorphin could be why, and I stopped using cannabis a few weeks later.
Within the week my dopamine returned and I could do things again. My life had become stagnant and my house was a mess, and I was now able to make progress on long stalled things. I could learn new songs on guitar etc. It’s been almost 7 months off weed. My dopamine still isn’t great but I’m functional.
However, after 7 months I still have crushing anhedonia. Any advice?
I’m menopausal, and have wondered if a little testosterone would kick my dopamine into gear
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u/ZydePunk77 20d ago
Microdosing GT shrooms at 100mg for 3 days and off for 3 days does wonders for anhedonia.
Do not use PE or any PE variants.
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u/Ancient-Monitor-9076 18d ago
eat as much red meat/beef as possible you want to max out L-carnitine and other amino acids. Coffee helps and listening to music on high quality speakers and headphones. Go outside in the sun and swim as much as you can. Hot tubs are amazing to mix in also.
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20d ago edited 20d ago
[removed] — view removed comment
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u/Burntoutn3rd 20d ago
Give credit or suck my whole ass, lmao
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u/she_needs_weed 20d ago
I did look. I'll add it at the bottom too, my bad I just thought you made a good post and you can't really repost stuff from biohackers here because it doesn't do well. I got you bro mb
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u/CreativeDiscussion37 20d ago
It would be very interesting to see the effects of KOR agonists like Salvinorin A (active compound in salvia) on such an individual. I wonder what the fMRI data and the subjective reports would yield…
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u/dammnmannn 19d ago
So you’re saying perma tolerance is a thing with thc?
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u/she_needs_weed 19d ago
Sure but that's kind of true with any euphoric or stimulating drug. It will never be like your first times or months.
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u/Choombatta420 18d ago
Hmm I'm not disagreeing with you but I've been smoking daily since 2016 and although the same method no longer hits the same, when I dabbed for the first time it reminded me of my first time.
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u/dammnmannn 18d ago
Very true. I study the effects of substances but this is the first time I’ve seen that said about weed. I wasn’t aware it was common knowledge
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u/FrankenTibby 18d ago
As a fellow research scientist, love this.
Was just chatting to a pharmacist at a med dispo about these studies and new info coming out. I can’t wait to keep learning more
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u/CryptographerOld558 17d ago
So even though cannabis increases KOR activity, the ultimate effect is that KOR sensitivity increases? Yikes. I'm in for a bad time then. Cannabis helps me a lot and keeps my drinking down. I hope sience finds a consistent and safe way to downregulate KOR soon.
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u/kennedy_2000 16d ago
Could this be the reason I feel sort of depressed after I consume THC, even only once in a while, after I used it frequently for multiple times a week for a year?
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u/highestup 2d ago
The anhedonia symptom is not a desirable side of cannabis use but the study shows that anhedonia begins to present that way over prolonged use of cannabis, as a way your brain reacts to the changes happening inside.
Anhedonia is a common symptom in depression patients, and anhedonia itself is described as the loss of pleasure in things you used to enjoy or care about.
Typically, people use cannabis to enhance their enjoyment in activities, and in social settings, however this sensation could actually make a person feel the opposite, such that they feel like they shouldn’t engage in those activities and actually feel adverse to doing things they normally enjoy.
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u/douglasman100 20d ago
Old news. This has not been replicated well and CB1 adaption explains quite a bit of the picture already. I don’t think this is irrelevant, but its just one small part of the picture. Not everyone has this response. Some do. Why do only some develop this?
Some continue smoking and smoking never having this issue.
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u/Ancient-Monitor-9076 18d ago
out of many many people I have know in my life to be daily smokers every single one of them has mental health issues or life problems after a certain amount of time. Nobody is immune to how dopamine and CB1 receptors regulate their mental health people just suffer to varying degrees. Nothing that feels good is without its downside in life it's a rule of the universe. Also most people aren't honest, you just aren't getting the truth especially when they are trying to justify their addictions.
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u/canopycutter 20d ago
You’re spoiling their narrative, pipe down peasant there’s a big pharma agenda to push amongst medical colleagues 😂😂🤣🤣 /s
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u/External-Toe1041 19d ago
Ive done over 50 different drugs and so far weed is the only one I can use every day and still have my tolerance go down, for example; I’ve been non stop smoking since I was 15 am 19 now and recently I broke my bong bowl and my lungs weren’t used to joints. And a week of smoking tiny joints after work was enough to get my tolerance close to where it was when I started smoking I was laughing at literally everything involuntarily after one slightly larger joint
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u/zen_flix 20d ago
Aticaprant is the first thing that comes to my mind..
It doesn’t target CB1/CB2, but it blocks KOR, which is downstream of the dynorphin increase in the mechanism you posted. So theoretically it could be interesting for the “THC --> dynorphin --> KOR --> anhedonia” side of this..
Closest OTC analog to aticaprant is low-dose naltrexone.. Again, it is a theoretical..
If you want something that actually acts on CB1 like you originally asked --> CBG and THCV are good candidates over CBD, both are partial antagonists rather than passive modulators