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Bring the Dose Down: Reverse Tolerance and Cannabis

reverse tolerance cannabis
Written by Sarah Friedman

Have you ever had the experience with any drug or compound, where in the beginning you built up a nice big tolerance, just to find one day that you didn’t need as much to achieve the same effects? It happens in life. So what is reverse tolerance in cannabis, and is it actually a thing?

Reverse tolerance with cannabis doesn’t have to kill the experience, after all, it just means you need less! If you do find yourself unhappy with a reverse tolerance effect, maybe change up what you’re using. Today’s cannabinoid market offers all new things to try like delta-8 THC, HHC, and THCV, among a host of others. We’ve got great deals on all compounds in this growing market, so take a look at what we’ve got on offer to figure out what works best for you. Remember to subscribe to The THC Weekly Newsletter for deals on legal cannabis products, as well as all the latest news and industry stories. Also save big on Delta 8Delta 9 THCDelta-10 THCTHCOTHCVTHCP & HHC products by checking out our “Best-of” lists!


Tolerance

Drug tolerance is “a person’s diminished response to a drug, which occurs when the drug is used repeatedly and the body adapts to the continued presence of the drug.” This is different from drug resistance which “refers to the ability of microorganisms or cancer cells to withstand the effects of a drug usually effective against them.” For our purposes, we’re interested in tolerance.

What this means is that with repeated use of a drug (including cannabis), it requires larger doses to obtain the same high – or the same effects – that were once achieved at lower doses. This happens often as a result of how the drug is metabolized within the body, with repeated exposure allowing the body to essentially be more productive at getting the job done, which focuses mainly on liver enzymes increasing activity. Tolerance also occurs when the number of drug receptor sites decrease, as well as how strongly the bonds are made between the drug and the receptor.

The important thing to remember about most substances, is that we take them (and they are prescribed) within limits that are safe to take, at least in initial amounts. While prescription medication, especially drugs that are more dangerous, generally won’t be prescribed above a certain amount even with tolerance, what a person does on their own can often be more dangerous.

drug sensitization

The reason for this is that when we speak of ‘tolerance’, we’re speaking of the effects the drug has through receptors, and how it makes us feel. But drugs have other effects that we do not build tolerance to. For example, no matter how much fentanyl a person takes, they aren’t going to increase their bodies ability to deal with the effects to the autonomic nervous system, the part of the nervous system that controls things like breathing, body temperature, and heartrate. So, if a person must take a large dose of fentanyl to get high because of tolerance to its analgesic effects, this makes it that much easier for them to overdose, due to aspects of the drug which effect this part of the nervous system.

What is reverse tolerance?

I think we’re all relatively familiar with tolerance. The next question is, what’s reverse tolerance? The phenomenon of reverse tolerance, also known as drug sensitization, describes when a person has an increased reaction to the same amount of a drug, following regular use. Sensitization is the idea that the person is more sensitive to a substance than they were initially.

One of the examples often used to show this has to do with alcohol. For anyone who drinks out there, it’s understood that increased amounts are necessary to achieve the same feeling of drunkenness over time. However, because drinking leads to liver damage, and this can impair the liver, causing it to work in an impeded way, those with liver damage experience reverse tolerance. Since they can’t clear the alcohol from their system as fast, they can feel drunker off of smaller amounts.

Both tolerance and reverse tolerance are not specific to any one drug, nor do either apply to all. These things, similar to other issues involving the personal experience of drugs, can vary from user to user. Some will experience higher levels of tolerance to a substance that others might develop lower tolerance to, and some will experience reverse tolerance to substances that others never will for. Because of this last statement, it can often be hard to get a consensus on when and where reverse tolerance can be expected.

Reverse tolerance and cannabis

Currently, the jury seems to be out in the medical world as to whether reverse tolerance for cannabis exists. Some studies point to its existence, and others point to nothing. Perhaps, this itself simply backs up the idea that personal experience can vary greatly. Sometimes it will be seen, sometimes it won’t, so the idea the medical world would be split, is a good indication that though there is plenty of evidence to back it up, that it won’t always be seen.

In a 1971 study by Lemberger et al., study participants were given an IV injection of .5mg of THC. While subjects inexperienced with cannabis received no response to this small amount, experienced users reported a high lasting an average of 90 minutes, even when told beforehand they were being given a non-active version. Because of the IV administration, the idea of inexperienced smokers simply not knowing how to smoke correctly, is controlled for.

cannabis

Lemberger and team in 1971 and 1972, and Raphael Mechoulam in 1970, both posited that this was because of a possibility the enzymes for converting THC to other compounds, requires a person to have used it already. This wouldn’t back up that the study showed reverse tolerance, but it could help explain why the more experience a person has with cannabis, the more their body might be able to sensitize to it.

On the other hand, in 1972, Mendelson et al. conducted trials where no reverse tolerance was found in a population with an average of five years of marijuana use. In these trials, some users not only showed no reverse tolerance, but showed increased regular tolerance (not unexpected). Now, as there wouldn’t be an expected time frame for when reverse tolerance could occur, a study like this cannot, obviously, speak to any changes within users that might have happened with an average of closer to 20-30 years of use.

A little more data on reverse tolerance and cannabis

On a more chemical level, in 2004, this study came out: Reversal of Δ9-tetrahydrocannabinol-induced tolerance by specific kinase inhibitors, in which the investigators evaluated reverse tolerance through “kinase involvement in the expression of tolerance to the above four THC-induced behaviors.” These behaviors are: “Kinase inhibitors that specifically inhibit cyclic AMP-dependent protein kinase (PKA), cyclic GMP-dependent protein kinase (PKG), calmodulin-dependent protein kinase (PKC) and src tyrosine kinase”.

A kinase inhibitor is something that blocks enzymes called kinases, which are enzymes used to add phosphates to other molecules, and which are used to transmit signals and regulate many cellular processes. How they behave has an impact on the effects you get when using cannabis. And tolerance or reverse tolerance to them can change how a person experiences different effects of cannabis. Cannabis causes many effects beyond just getting high, so when speaking of tolerance, we’re speaking about all of these effects.

The results showed: “PKG and PKC inhibitors did not reverse tolerance in any behavioral measure. Src tyrosine kinase inhibition reversed tolerance to only the hypoactive effects of THC. PKA inhibition reversed tolerance to all measures, although the doses of inhibitor and time-course of inhibition varied among behaviors.” Regardless of how well your chemistry brain works, the takeaway is that some inhibitors caused a reverse tolerance reaction to THC, some didn’t, and there were not necessarily specific time frames for these reactions. This backs up the ability for reverse tolerance to at least some effects of cannabis.

On a last note, when looking for personal experiences on Reddit, I found a lack of general understanding for what reverse tolerance and sensitization are, so much so that even when this exact thing was being described, it seemed not to be understood by any responders.

reverse tolerance

This particular situation I’m noting actually sounds nearly identical to mine (read on), where a person required less and less to get to the point of THC overconsumption (seen in the form of anxiety/THC sickness). An issue not seen with repeated use until a certain point. Like with me, I can’t say this was exactly the case, but I did find it funny that responders were quick to give the opinion that reverse tolerance for weed doesn’t exist, while trying to figure out why this guy showed a massive increase in sensitization to it.

My own experience with reverse tolerance and cannabis

I actually brought up this subject today for a reason, as this issue of reverse tolerance and cannabis is one I seem to be experiencing. Whatever the cause, I can’t say, nor if it will last. But I can say that within the past six months or so, the larger amounts of cannabis I was smoking, now create too strong a reaction, and I can only use it in smaller amounts.

This is probably a good time to remind that there are different effects that tolerance can be built to, and different effects a person might become more sensitized to. I can get high off of a little less, for example, but that’s not the issue for me. The main thing I noticed was a sensitization to the effects of anxiety produced by the cannabis. And this for me has been intense, to the point of THC sickness.

I used to not have issues with cannabis causing major anxiety, nor have I often otherwise experienced THC sickness. In fact, though I got a little paranoid here and there, it was never a highly noticeable thing, and certainly not more than the standard paranoia of weed smoking. While I noticed this change in the past six months, I expect it’s been going on a bit longer, only getting to recognizable points in the last several months. After all, when you’ve never had an issue repeatedly using something before, it can take some time to make the connection that this thing is now causing a different response.

I don’t have to experience anxiety from cannabis – I actually tested it out. When taking extremely small doses (think micro-dosing or slightly above), I can experience whatever high comes from it, but without noticeably increased anxiety, and without feeling sick. Once I get anywhere near regular levels, or what I used to use, I’m going to feel it all throughout my body. Essentially, it starts to give me the feeling of THC overdose, at a much lesser amount than ever caused the reaction before.

Now, could this be issues of products and quality, of pesticides and additives (I do use oil vapes at times)? Could be. I performed no actual study, so all conclusions I’ve drawn are related to me paying attention to my own experience. Sure, it could be that I’ve had higher exposure to pesticides, and that that’s what’s causing the problem, but I’ve been a weed smoker for decades, have lived around the world, and somehow only have this problem now. I certainly can’t rule out other factors, but the best and most consistent answer I can find for myself involving cannabis, is that I’m experiencing reverse tolerance to the THC in the form of a massive sensitization to it.

drug tolerance

Conclusion

In my mind, it would be a hard argument to make that cannabis can’t cause reverse tolerance, though there is also nothing saying that it must. For all we seem to know about varying personal experience with compounds, this is not always taken into account in research. As more studies are done in the future showing this ability for variation on the subject of reverse tolerance, there will likely be a widening understanding of this phenomenon as it relates to weed.

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DisclaimerHi, I’m a researcher and writer. I’m not a doctor, lawyer, or businessperson. All information in my articles is sourced and referenced, and all opinions stated are mine. I am not giving anyone advise, and though I am more than happy to discuss topics, should someone have a further question or concern, they should seek guidance from a relevant professional.

About the author

Sarah Friedman

I look stuff up and and write stuff down, in order to make sense of the world around. And I travel a lot too.

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