My latest take on how tolerance works

[Chip (OP)]

Tolerance may develop when a drug is used repeatedly because metabolism of the drug speeds up (often because the liver enzymes involved in metabolising drugs become more active) and because the number of sites (cell receptors) that the drug attaches to or the strength of the bond (affinity) between the receptor and drug decreases.

This is my understanding of how tolerance works for psychoactive drugs as most people are either ignorant of (novices), confused or simply misunderstand:

It also determines your **withdrawal response**.

Tolerance action evolves differently for each drug and every time period involved will vary as will the responses to the various dosages and their rate of titration or increases. **Dose and frequency** are the two determinants of the gravity of your tolerance or **addictive response** but **frequency carries more weight**.

To further complicate this, **cross-tolerance** develops to different drugs when they share the same mechanism of action and/or by modulating the same neurotransmitter levels in the same way.

Lastly, the **ceiling effect** of certain drugs like the whole class of benzos, the opiate Codeine and the opioid Buprenorphine, **saturates the receptors** and jacks up tolerance to the whole of it's class .

Some non-psychoactive drugs like Paracetemol do not cause tolerance whatsoever.

> The only way to keep your tolerance naive indefinitely is to never poke it like you do when you use a drug more than once or twice contiguously before your physiological response returns to baseline -- and then waiting a little bit longer just to be safe, before your next session -- for example by using Heroin weekly or Methamphetamine no more than every 10 days. However, it always catches up with you eventually.

Everybody is different and their individual tolerances and withdrawal responses can vary significantly as is the case with amphetamines (as most never develop any issues at all but a small majority need regular breaks).

Tolerance is a mammalian homeostatic response to any external molecule that alters neurotransmitter levels or effects nerve transmission rates.

> Tolerance is the mechanism of addiction and is permanent because it's a learned response and is in your best interests for it to quickly try to rebalance your physiology due to the variations of drug-serum levels that happen when you use drugs.

But you can take a break to **reset** it however it not only goes back to where it was before you took that break, but it just goes a little bit faster every time, often imperceptibly.

You can eventually reach a point where it doesn't matter how long that break is so it can't be reset.

> The only way to keep your tolerance naive indefinitely is to never poke it like you do when you use a drug more than once or twice contiguously before your physiological response returns to baseline.ogical effect.

Also, with many drugs, the **range of effects between a perceptible sensation through to profound euphoria keeps narrowing** over time until it's no longer available, much to the disappointment of the user.

So you end up not feeling much at higher doses and as you keep increasing the dosage you then either go to the top end of that range (such as having a blackout like with alcohol) or hit a ceiling and then if you continue on you may suddenly and unexpectedly overdose due to the dimishing warning symptoms.

Understanding various tolerances and their evolution can save your life.

References:

* Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321276/

* What is a ceiling effect?

*In the context of opioid addiction treatment, the term "ceiling" refers to the ceiling effect, a pharmacological phenomenon that occurs when a drug reaches its maximum effect, and increasing the dose does not result in any further benefits or side effects. This concept is particularly relevant for medications like buprenorphine, which have a ceiling effect that reduces the risk of overdose. Specifically, buprenorphine’s safety is conferred by ceiling effects for respiratory depression, sedation, and subjective measures (euphoria), making it a very safe option for opioid use disorder (OUD) treatment.*

https://ophelia.com/glossary/ceiling-effect#:~:text=Ceiling%20effect-,What%20is%20a%20ceiling%20effect%3F,further%20benefits%20or%20side%20effects.