Time = Less Tolerance?Why

[Prelude2TragedyII]

Okay,yeah, I read some stuff about letting your tolerance drop by waiting a while..What is it exactly that happens over that week or month that makes your tolerence level drop?

 

[Pimp Lazy]

What I understand about many drugs is that the receptors in your brain get damaged and take time to repair or in some cases destroyed completely. Thats whats actually happening when people get used to them. Part of it is mental. Thats why a heroin addict can OD on a lower than normal dose if they're in a setting that they aren't used to. From what I understand cannabis doesn't destroy the receptors but it does 'dull' them. Whether thats because they are damaged or whether they shut down a little I'm not sure. However, I have read many times that the receptor sites are not destroyed. I'd enjoy hearing a better answer myself, but thats the basic one. Peace.

 

[Lawrence Arms]

I always thought it had something to do with thc being stored in your fat cells, and as the days go by, you burn the fat cells, thus getting rid of the built up thc? That sounds wrong when i say it, but thats what i always thought.

 

[Pimp Lazy]

The active thc is gone when you stop feeling the effects but the thc is stored in fat as your body burns the fat they are released. You know as I'm saying this it makes more sense to me but seems to be against what I've heard in the past but don't remember figures huh? But then there's the question of why am I not constantly high for a month if it takes me that long to burn it off? I think part of its because the chemical structure is changed slightly so its not pyschoactive… but then why the tolerance? Random fact here in place of a scientific reason. The half-life of cannbis is between 0.8 and 9.8 days so if you have the slowest metabolism possible by this scale half the amount of weed you smoke at your highest tolerance will get you just as high after 9.8 days. Peace.

 

[FieryTemplar]

pimp and lawrence, are you guys being serious?

 

[Ninjagirl69]

ok well, i have by my side booklets that my mum got from the alcohol and drug addiction centre for me (lol she thought i had a marijuana problem anyways) and they say that thc is stored in your fat cells, that slowly as the thc is eaten away by your fat, thus after a while you build up a "tolerance" (i use the term very loosely) however if you leave smoking for a few days, weeks, months (depending on how often you smoke) that the body has more of a chance to get rid of the old thc and makes room for the new stuff lol so yea.....

 

[Grignard]

Well from my understanding of it, the most likely cause of a decrease in tolerance is about the same with many other substances, a decrease in novelty with prolonged use, and down-regulation of the appropriate receptors.

And both of these things take time to correct, though whether or not the experience becomes novel again really depends on the individual and their psyche.

However I haven't done a complete and thorough search of all possible resources, so don't quote me on those reasons just yet.

 

[stiphout]

For a long time I also believed you had to burn fat in order to get rid of the THC in your body as fast as possible. But I've heard theories of others saying there is not actually a tolerance to pot. It seems like it, but in reality it is all about getting used to it.

Maybe I can best compare it with taking a ride in a rollercoaster. The first time is magnificient, the second is also great but if you continue stepping into the rollercoaster its effects decrease en you get used to it. There is no thrill anymore at the end of the day (after 20 rides or so). If you pause for a week and then step into the rollercoaster again the effect is great again.

The same goes for the pot I guess. It is not real tolerance but just getting used to it (this is not a fact, just my opinion

 

[BilZ0r]

There is definatly tolerance to THC, and there are withdrawals too, the two go together. Meanwhile, yes, tolerance (at least in the short term) happens because of receptor (CB1) downregulation. This will probably involve the receptors being 'internalized', that is to say, taken into the cell, so they aren't expressed on the surface. The body will probably break down a propotion of those, and return some of the rest to the surface.

It is likely, that in really long term, chronic use (chronic chronic use.. lol), you might get physical changes in the actaul structure, position and nature of synapses. But that is theoretical.

 

[Blowmonkey]

^ I highly doubt that..

 

[Pimp Lazy]

I've read reports that say cannabinoid use doesn't hurt the receptors at all. Thats a large part of why cannabis is so safe to use and doesn't cause dependance in most of the people who use it even those who smoke everyday. I, however, am one of those people who feels dependance. It sucks. Its all in the genes I'm pretty sure. Some are addicts and some are not. Peace.

 

[Psilo707]

I doubt the permanent change in receptors due to massive cannabis use as well... it could be true I guess... but I still can't see it. I'm suprised there still isn't a clear cut answer to this.

 

[BilZ0r]

No, It's seems preety certain that CB1 agonists at reasonable concentrations cause downregulation and internalization of receptors. 3 month treatment to rats, of quite high doses of THC caused measureable changes in the morphology of the hippocampus. And really quite high doses of THC caused desensitization to CB1-, Adenosine A1- and GABAB-Mediated Adenylyl Cyclase Inhibition.

 

[Blowmonkey]

3 month treatment to rats, of quite high doses of THC caused measureable changes in the morphology of the hippocampus.

And this was after the rats abstained from THC for over a long period of time? Permanent..?

 

[Lawrence Arms]

I dont think anyone knows the answer

 

[BilZ0r]

Lets see. Scallet et al., 1987 had a 7 month washout phase.
Landfiled et al., 1988 had no washout phase
Lawston et al., 2000 had no whasout phase.

On the otherhand

Westlake et al., 1991 found no change in the number of CB1 receptors in rats treated with THC for 3 months, after a 2 month washout phase and...
Chan et al., 1996 dosed rats with the MASSIVE (and I mean stupidly, who the fuck let you give rats such a big fucking dose, you're one crazy fuckedup cunt, massive dose) of 500mg/kg THC FIVE TIMES A DAY!!! and he found no changes, but he wasn't really looking for them, and he only looked in rats that were have constant seizures because of the THC.

Now I'm not saying that you get the kind of large scale neuronal shrinkage or loss that they saw in rats, happening in humans, or that in doses more compariable to human ones, it even happens in rats. But the thing about these studies is that the methods used are very gross.

I mean, nearly all agonists induce changes in the brain on a pharmacological level, and I personally feel it would be reasonable to hypothesize, that a long term change in the pharmacology of a synapse would eventually lead to a change in the structure of the synapse. And when we're talking about a receptor that is believed to play an important role in normal physiological neuronal plasticity, that alters Ca2+ dynamics and is involved in the ERK pathway, I think it makes if even more likely.

 

[stiphout]

I look at it like jumping into a cold swimming pool. You jump in the first time and it's really cold! You stay in (keep smoking) and it warms up. The longer you're in the more your body gets used to it. Get out and jump back in and it's like you never got out. Your body is still used to the cold water (being high). But if you get out and stay out for a long period of time and jump in, it's cold again.

That's my take on it anyways.

I couldn't agree with you more! (see my rollercoaster explanation)

 

[Blowmonkey]

You're talking about this, right..?

Neuronal Morphology
The classic first step when investigating whether or not a given chemical is
neurotoxic, is to give it to an animal and then investigate, using histological methods, whether there has been any cell death or at least alteration of cellular morphology. The first study into the effect that cannabinoids have on neuronal morphology was Harper et al., (1977). This study reported that rhesus monkeys exposed to the smoke of 1 to 3 cannabis cigarettes a day for 6 months showed widening of the synaptic cleft, material in the synaptic cleft and nuclear inclusion bodies after a 8-month washout phase. Unfortunately there were many methodological problems with this study. There were no statistical analysis, the small sample sizes were extremely small, consisting of one active cannabis smoke treated animal, one IV treated animal and the controls were two completely untreated monkeys and one monkey who smoked alcohol extracted cannabis leaf which was presumed to be THC free. Indeed, the apparatus in which the animals were placed in order to administer the cannabis smoke, a procedure that most of the control animals were free of, seemed to be so constrictive and unnatural, that it could be a serious source of bias. Scallet et al., (1990) repeated this experiment, with larger sample numbers and showed that after a wash out phase of 7 months, rhesus monkeys who were exposed to the smoke of a single cannabis cigarette containing 2.6% THC, every day for 12 months,showed no statistically significant changes in synaptic characteristics, neuronal size, the number of apical or basilar dendrites or the number or length of dendritic branches, in comparison to monkeys who were either non-exposed or smoked ethanol-extracted cannabis. Andrews et al., (1989, as cited by Scallet et al., 1991) also found no neurohistological changes after dosing moneys IV with either 0.1 or 1mg/kg of THC for 90 days. Scallet et al., (1987) examined the hippocampal morphology of rats that had been dosed orally with THC 5 days a week for 90 days with 20mg/kg Monday to Thursday and 60mg/kg on Friday. After a 7 month washout phase, the THC treated animals were found to have a significant decrease in the cross sectional area of neurons and their nuclei, as well as a decrease in the synaptic density in the CA3 region of the hippocampus, in comparison to vehicle treated controls. Cerebellar Purkinje cells were unaffected. A second group of animals was dosed with either 10mg/kg or 20mg/kg THC, 5 days a week for 90 days. After an 8-week washout phase Golgi impregnation showed a reduction in the length of the outermost branchlets of CA3 neurons. Interestingly, in the second group of rats, there was no reduction in the size of neurons or synaptic density.
Landfield et al., (1988) treated rats 5 days a week for 8 months, with either
4mg/kg or 8mg/kg of THC orally. The 8mg/kg group originally received 10mg/kg but this dose was lowered during the first month because the animals found it aversive. Directly after the last dose of THC the CA1 region of the hippocampi from the high dose animals were shown to have a decreased number of pyramidal cell per area of section. Whether this reduction in pyramidal cell density was due to decreased cell volume oractual loss of cells was not explored. It was also shown that there was an increase in dark membranous inclusions in hippocampal astrocytes in THC treated animals. Lawston et al., (2000) showed that rats that were subcutaneously injected twice daily with 2mg/kg of the synthetic CB1 receptor agonist WIN 55,212-2 for 21 days, exhibited cellular alterations in the hippocampus. Using MAP-2 antibodies, which act as a dendritic marker it was shown that there was increased staining in the subiculum and CA3 region of the hippocampus, as well as increased staining in the lower blade of the dentate gyrus in comparison to vehicle treated controls. It was also shown that there was a decrease in MAP-2 staining in the CA1 region of the hippocampus and an increase in cresyl violet staining in the lower blade of the dentate gyrus. The authors also stated that the dendrites of CA1 neurons in treated animals appeared as disjointed segments, which seemed twisted or broken with a beaded aspect, rather than continuos smooth, structures, as was seen in their controls animals. Although this is an intriguing claim, there are no statistics associated with it, and so the definitiveness of this claim can not be verified.

Really, I'd like to see these results verified by other studies before I think it would be "reasonable" to hypothesize.. Though it looks like you're right, exceptionally chronic usage is more likely to be responsible for neuronal changes, though I expect them to be minimal.

 

[Vaya]

To the best of my understanding, it is because with continued use over prolonged periods of time the endogenous cannabinoid receptors in one's brain become saturated with THC. Obviously, this affects the absorption of THC in the brain by disallowing the molecules to bind to the receptors as easily - thus, tolerance, or needing more THC in the brain than before to increase the likelihood of receptor binding.

Given a period of non-smoking, I would suspect the receptors slowly rid themselves of their THC-saturation, and after enough time, are back to normal; remember, cannabis hasnt been shown to be neurotoxic, and receptor damage is a sign of neurotoxicity. Receptor saturation isn't.

 

[nowonmai]

^^
Given the timeframe relative to the timeframe usually associated with down/upregulation of receptor sites this seems like the most reasonable explanation.