Health - Cannabis & Cannabinoid Tolerance

[Shampoo]

Cannabis Tolerance: Basic Assay of Mechanisms, Actions and Results
By Shampoo

Due both to its common use as a recreational intoxicant and its employment in medicine, cannabis has been widely examined for its therapeutic potential and side effects. Among these side effects is tolerance, the regulation of cannabinoid uptake as a result of over stimulation. Tolerance is indicated by the requirement of larger doses to achieve a consistent desired effect, or when a given dose no longer provides it. Higher doses commonly result in the indication of higher impact of undesirable effects though, as with cannabinoids, tolerance can be achieved for many of these as well. Tolerance to cannabinoid stimulation results in withdrawal, most notably marked at 12 hours after cessation of “heavy” use by inner-unrest, increased activity and irritability. During a flushing period of 4 weeks following a 4 week daily ingestion period of 210 mg smoked THC, determined by Georgotas and Zeidenberg (comprehensive psychology), mild-withdrawal symptoms were reported to last between 5-7 days, with no inflammation or indication of desire for THC in the remaining 3 weeks.

Unlike the mythic ‘street-knowledge’ assay, which implies cannabinoid re-absorption through lipid deposits resulting in ‘occupied’ receptors due to constant stimulation, modern neuroassays have concluded tolerance to be based solely in receptor regulation. The cannabinoid content of endogenous lipid deposits has been shown to be less than active physiologically and psychologically.

A non-tolerant ingestion of smoked marijuana results in peak plasma concentrations of 90-95 ng/ml and peak effects lasting 75-90 minutes at which time plasma levels drop below psychoactive concentrations at 10 ng/ml. Plasma concentrations are unaltered by tolerance, indicating no change in endocannabinoid signaling, however cannabinoid stimulation, especially in ligand activation, decreases as a result of receptor based regulation. As has been widely explained and explored, availability of bonding-sites is reduced by down-tolerance and phosphorylation after prolonged or extreme exposure to cannabinoid agonists, resulting in a notable decrease in efficacy of stimulation and effects.

Down Regulation and Phosphorylation:
Importunate exposure of receptors to agonist behavior, both with respect to time and dose, results in the endogenous desensitization of Cannabinoid receptors. G protein receptors CB1 and CB2, the primary sites of action for Cannabinoid stimulation, recede from their bonding heights into the cell-membrane after prolonged agonist action. This recession, known as downregulation, is coupled with phosphorylation in the desensitization of overestimated receptors in the mechanistic action of Cannabinoid tolerance. Phosphorylation creates ‘rapid-tolerance’, or the tolerance normally experienced during a single smoke session, normally receding at an equally rapid rate.

Specific Activation:
Various Cannabanoids are active at different receptors, both by their affinity for CB1 or CB2 or their digested distribution. As a result, specific tolerance occurs effecting specific site of action.

-Tolerance to the pharmacological effects of ataxia, analgesia, motor inhibition, and anticonvulsant activity usually occurs within 3-7 days of administration, depending on dose and frequency, as a result of cerebellum based CB1receptor-binding and WIN55,212-2 stimulation.

-Long-term memory inhibition, as well as certain neuroendocrine actions (including neuroprotective), take several weeks to develop tolerance desensitization, the former in part due to anandamide’s relatively high endogenous availability. Anandamide levels in the striatum show reduction after prolonged exposure to cannabinoid receptor agonists, though the availability of the precursors was not diminished, suggesting a superficial alteration of productivity.

-More resistant populations of CB1 receptors, primarily located in the limbic regions responsible for emotional stimulation, were uniquely resilient in prolonging the onset of tolerance regulation. Tolerance to immunosuppressive effects of CP-55,940 through stimulation of CB2 receptors is largely insignificant even over extended periods of exposure.

-CB1 activation in Hipocampal neuron populations responsible for short-term memory develops down-tolerance within 24 hours of Δ9-THC administration and showed no impact (positive or negative) from increased anadamide availability or administration.

-Cannabinoid analogues WIN55,212-2, CP-55,940 and 11-hydroxy-Δ8-THC, more infinitively specific cannabinoid agonists take 7-9 days to develop normal tolerance shown to take 3-7 days in administration of less-specific agonists. Due to their specific affinity for bonding efficiently with CB1 receptors (predominant site of CNS stimulant and psychoactive activity), tolerance develops more slowly than with less accurately coupled agonists such as Δ9-THC, CBN and CBD.

-In vitro cultures of neuroblastoma cell line (N18TG2) exhibited rapid-tolerance to chronic exposure to cannabinoid agonist stimulation, showing a natural cellular response.

Tolerance as Dependence Indication:
Though tolerance and dependence often develop concomitantly, in the case of cannabinoid stimulation, since the primary actions of tolerance are neuroreceptive as opposed to adaptive endocannabinoid signaling, tolerance and dependence are independently significant. There is no scientific consensus on the implications of cannabinoid dependence and withdrawal. As there is no indication of somatic and/or neurovegetative periods after abrupt cessation of high-dose cannabinoid therapy, the criteria for physical dependence remain unfulfilled as defined by worldwide health ministries. Psychological withdrawal implications failed to appear in any animal study, though have occurred in human and some non-human primates, to a notably lesser degree than opiods. Primary indicated factors of “heavy” marijuana use behavioral withdrawal include irritability, sleep deficits, attentional deficits, and anxiety, and have been shown to noticeably recede within a 3-day period of cessation, dissipating completely within 1 week.

Application:
Recreational tolerance is relatively minute, if existent, in occasional users or ‘weekend-smokers’. Daily consumption for medicinal or recreational purposes however, can have greater, though still relatively diminutive, tolerance implications. Allowing receptor recuperation every 90 minutes could greatly decrease the impact of downregulation, and ingestion of appropriate doses rather than the commonly high recreational dose could aid in the resistance of phosphorylation tolerance. A recent study employing capsaicim antagonists and markers during Δ9-THC administration for analgesic property showed a low ceiling of consumption efficiency, followed by a rapid phosphorylation at high doses, implying a ‘sweet-spot’ theory, in which an exact dose is exponentially more efficient than an overdose. Recreational tolerance is relatively minute, if existent, in occasional users or ‘weekend-smokers’, due to the allowed recovery time. Daily consumption for medicinal or recreational purposes however, can have greater, though still relatively diminutive, tolerance implications. Forecasting scientific developments imply that through integration of specific agonists at specific bonding sites could reduce selective tolerance while achieving reasonable effects. The application of esoteric agonists could potentially alleviate tolerance based dosing and the complications it implies. Additionally, dosing with cannabinoid antagonists, such as CBD and CBG, can combat downregulation of receptors and expose increased availability.

For a full review of the lengthy cannabinoid tolerancedependence deliberation see:
H. Kalant, Adverse effects of cannabis on health: an update of the literature since 1996, Progressive Neuropsychopharmacol Biol Psychiatry 28 (2004), pp. 849–863

Other resources:

González, Sara, Maribel Cebeira, and Javier Fernández-Ruiz. "Cannabinoid Tolerance and Dependence." Pharmacology Biochemistry and Behavior 81 (2005).

Grotenhermen, Franjo, M.d., and Ethan, M.d. Russo. Cannabis and Cannabinoids: Pharmacology, Toxicology, and Therapeutic Potential. New York, London, Oxford: The Hawthorn Integrative Healing Press, 2002.

Gerhard A. Wiesbeck, Marc A. Schuckit, Jelger A. Kaljimin, Jayson E. Tipp, Kathleen K. Buchloz, Tom L. Smith. An evaluation of the history of a marijuana withdrawal syndrome in a large population. Addiction 91 (10), 1469–1478. Department of Psychiatry, University of San Diego, US (1996)

Georgotas, A. "Observations on the Effects of Four Weeks of Heavy Marihuana Smoking on Group Interaction and Individual Behavior." Comprehensive Psychiatry 20 (1979): 427.

Reputation Comments on this post:

	very good post as usual
	Good info
	thanks for posting this very interesting study
	nice article
	Fantastically informative post as always!

[enquirewithin]

Psychological withdrawal implications failed to appear in any animal study, though have occurred in human and some non-human primates, to a notably lesser degree than opiods. Primary indicated factors of “heavy” marijuana use behavioral withdrawal include irritability, sleep deficits, attentional deficits, and anxiety, and have been shown to noticeably recede within a 3-day period of cessation, dissipating completely within 1 week.

That sounds about right from anecdotal evidence.

[FuBai]

I know this thread is a bit old but I did have a question on it - does the loss of tolerance (or the reversal of down-regulation, not phosphorylation which, according to the above, can be resolved in a matter of 90 min) occur at a steady rate? Take a scenario in which a heavy smoker ceases use and it takes, say, 5 days for physical tolerance to leave him - does that tolerance decrease at a comparative rate each day so around a fith of the tolerance goes each day (if you can talk about tolerance in those terms), or does it decrease slowly at first, speeding up towards the third day and then slowing down again? Or does it decrease in a different pattern?

[purplehaze]

From what I have read here and elsewhere, tolerance decreases rapidly within the first week of abstinence and then gradually for the remainder of the month.

I'm not 100% when reading these kind of articles if im getting everything out of them, but I think I understand the most of it.

Nice article shampoo, I also would like clarification on the downgrade of tolerance.

[FuBai]

Originally Posted by purplehaze

From what I have read here and elsewhere, tolerance decreases rapidly within the first week of abstinence and then gradually for the remainder of the month.

I'm not 100% when reading these kind of articles if im getting everything out of them, but I think I understand the most of it.

Nice article shampoo, I also would like clarification on the downgrade of tolerance.

My understanding was that most physical tolerance was gone in 5-7 days...

[Shampoo]

Originally Posted by purplehaze

Nice article shampoo, I also would like clarification on the downgrade of tolerance.

Could you elaborate on this question? Hopefully I have an answer, but Im not sure exactly what about the degradation of tolerance you are looking for? Timeframe? Neurology? Testing? Fill me in and hopefully I can elaborate.

[purplehaze]

Example.

If someone smokes everyday for 1 year and they quit for 5 - 7 days will there tolerance be practically the same as if they had quit for a month? Were is the line, like if you stop smoking for X amount of days your tolerance returns to normal, as if you aren't a smoker.

If test1 smoked and built his tolerance up to 1gram each session to get him high, and done this for X ammount of time, say 1 year. If his tolerance slowly gained up to 3grams each session to get him high how long would it take him from not using before his tolerance returns to 1gram or a normal tolerance.

I know thats irrational or illogical ammounts but just to get the idea.

My understanding is that if test1 has a high tolerance and he quits for 7 days his tolerance returns to pretty low. If he continues to quit for 28 days his tolerance still goes down but does not go down at as rapid of a rate as the first 7 days, another words after the initial 7 days the tolerance goes slow until it is not present at day ~28 , but 7 days is plenty rewarding and any more would prove to not degrade ones tolerance to a notacibly more amount Ie you smoke a spliff at day 7 your high as fuck, Ie you smoke a spliff at day 30 and you dont get much more effect than you did at day 7.

This is just my understanding, I hope by this sloppy poorly constructed example you can correct me and give me a better understanding on how tolerance works.

Thanks, Payce.

[FuBai]

Originally Posted by purplehaze

My understanding is that if test1 has a high tolerance and he quits for 7 days his tolerance returns to pretty low. If he continues to quit for 28 days his tolerance still goes down but does not go down at as rapid of a rate as the first 7 days, another words after the initial 7 days the tolerance goes slow until it is not present at day ~28 , but 7 days is plenty rewarding and any more would prove to not degrade ones tolerance to a notacibly more amount Ie you smoke a spliff at day 7 your high as fuck, Ie you smoke a spliff at day 30 and you dont get much more effect than you did at day 7.

Why at day 28? I suspect you said this because you were refering to how long it takes for metabolites to cease to be present in urine, yet we know that the cannabinoids dissolved in fats can not contribute to tollerance because they are far below psychoactive levels, and it is these cannabinoids and thier metabolites which are detectable in urine. Tollerance is all about down-regulation and up-regulation of receptors, or so I understand, and I can't see how it could be effected by cannabinoids dissolved in fat.

[purplehaze]

Im not talking about passing a drug test at all, all im referring to is tolerance if smoked. Like if you quit for 7 days and then smoke you will get higher than if you hadnt quit for 7 days and continued to smoke everyday. But quiting 7 days your tolerance returns to a level that it isnt that much better to quit 28 days as far as high effect.

[Shampoo]

I think FuBai was reffering to your use of the standard '28 days' quota, which he pointed out is a measurement of metabolite presence, not psychoactive content, thus not effecting tolerance via down-regulation.

The example you gave is right on par. A heavy smoker (1 gram or 3 grams, down-regulation acts in the same manner) will see a rapid degradation of tolerance over the first 3-7 days of their smoking cessation. After this, their tolerance will continue to diminish slightly, but not to a noticeable degree. Down-regulation of CB receptors should be completely absent within 2 weeks at the most, never an entire 28 days, which is also only a rough estimate of the time it takes for metabolites like THC-COOH to leave lipid deposits.

Reputation Comments on this post:

Informative.

[CoryInJapan]

that sweet spot theory is more than a theory I belive.


When Swim smokes cannabis he used to smoke a lot all day...when ever he felt his high comming down it was time to redose.


Now swim smoke in intervals or longer peroids of time without smoking and has noticed tolorance has not gone up that much at all compared to old smoking habits.

Swim still smoke every day since Swim has Insomnia he has to smoke every night.

Swim used to smoke an ounce in less than 2 weeks, now swim can make a half eighth last the week.

wake n bakes and good night snaps only

with possibly a snap at 420 or around that time if desired...

So at most Swim is smoking maybe 3- 4 times a day spaced out pretty good and has noticed a dramatic difference in my tolerance being a lot lower.

[EscapeDummy]

Originally Posted by FuBai

My understanding was that most physical tolerance was gone in 5-7 days...

Anecdotally, from a personal friend named EscapeDummy, this is most certainly not the case. He smoked daily, missing a day here and there for about the last 8 months. For the last 6ish months, he hasn't gotten anywhere near as high as the first two months. He took a 10 day break from smoking weed, and on the 11th day, smoked again. He definetly got way more high than he was getting, but still not at the level he used to get to. Also, he noticed that his tolerance rapidly increased to its previous level after one week of smoking almost every day.


Then again, very likely this could just be his individual, esoteric reaction to the complex THC and CBD compounds.

[porchy]

Originally Posted by EscapeDummy

Anecdotally, from a personal friend named EscapeDummy, this is most certainly not the case. He smoked daily, missing a day here and there for about the last 8 months. For the last 6ish months, he hasn't gotten anywhere near as high as the first two months. He took a 10 day break from smoking weed, and on the 11th day, smoked again. He definetly got way more high than he was getting, but still not at the level he used to get to. Also, he noticed that his tolerance rapidly increased to its previous level after one week of smoking almost every day.


Then again, very likely this could just be his individual, esoteric reaction to the complex THC and CBD compounds.

What you said is exactly the same as what they were saying. It takes up to a month for the tolerance to be completely gone, for 7 days the tolerance decreases rapidly.

[4TwentyRM]

Swim was smoking bud constantly for at least 13 months, with not even a day break in between that time, and the last break before that was six days. But a few days a go swim came back from London where he had not smoked for six days. Swim was hoping to have some exotic strains waiting for him so he could get the most out of his longest break in the last year. Unfortunately it was only mid-grade, and while swim did get quite noticeably put under the stupor of THC, it was not like the six day break a year before. But then again, the break a year before swim had come back to some extreme 19%, so, don't know if it's quite comparable. But yes, definitely, swim realizes and is slightly upset at the fact that the real, visceral high does indeed take a cessation when overly indulged, and after the break and one starts back it, it quickly dissipates and lets the user know to restart the break/indulge process.

[swimsstrange]

Thank you, for this excellent post!
Swim has pushed use so far, that a bowl of high grade bud resulted in a mere nicotine effect. Thats really fustrating for him, since it rendered all attempts to get stoned futile. Even almost pure bowls wouldn't do a thing for him. Then it is time for a break resulting in severe insomnia, cold sweats, anorexia diarrhea and stomach pains.
After a few weeks tolerance levels, but the body and brain learns to become more effective in counteracting effects of exogenous cannabinoids, leading to complete tolerance even faster.
Never underestimate the power of the human body.

[enquirewithin]

Smoking for less time during the day is helpful. SWIM only smokes late at night and it works for him every day.

[rainsong]

swim think that a lot of his tolerance is of the cognitive sphere: he becomes desensitized to the ideas that marijuana inspires in him, ideas that form a sort of girding for the visionary/psychotic/whatyouwill-level cannabis experience. after using regularly, he finds he has to wait months to restore this primal power of the drugs, even longer.