Addiction-brain effects – Tolerance, sensitization, and withdrawal

If you’ve been with us for any length of time, you’ve already read about the addiction-brain effects for specific drugs. I think it’s important to understand some of the more general changes that occur in the addicted brain regardless of the specific drugs used.

One of the most common effects of long term drug use is something called tolerance, or the reduced effect of a drug dose. A lot of people know about this one, especially if they’re users and have found themselves needing to use more and more to get the same effect. However, while this is the most known, it is not the only change in the body, or brain’s, response to drugs with repeated use. The other effect, known as sensitization, is characterized by the exact opposite reaction – an increase in the response to the drug.

Tolerance & Withdrawal in the addicted brain

toleranceThe exact mechanism by which tolerance occurs is different for each drug, but the overall concept is the same. With repeated drug administrations, the body adjusts its internal processes in an attempt to return to its initial level of functioning. Drug use normally causes greater quantities of neurotransmitters like dopamine, serotonin, the opioids, and adrenaline to be present in the drug user’s synapses (see here for a review). The body counters this by reducing its own release of these chemicals, reducing the numbers of receptors that can be activated by the neurotransmitters, and increasing functions known as “opponent processes” that are meant to counter their activity.

The interesting thing about tolerance is that by reducing the level of these important neurotransmitters, addicts are left with another, possibly more important effect, which is the loss of the addicted brain’s ability to respond to any reward, including natural ones like food, sex, enjoying a good football game, or anything else. Essentially, this sort of cross-tolerance leaves the addict less able to respond to rewards in general.

The reduced response to drugs, and the corresponding changes in the body and brain’s own functioning, have long been thought to be a major cause of addiction. The withdrawal that results once drug taking stops is closely linked to the development of tolerance. Still, we now know that tolerance and withdrawal are not necessary, and certainly not sufficient for the development of addiction. Nevertheless, they are referred to as the physical dependence portion of addiction and are often are part of the overall picture.


Sensitization is the term used for an increased response to the same dose of a drug. That might sound a little oxymoronic after the tolerance discussion we just had, but bare with me.

Tolerance commonly develops when drug use is constant, or ongoing. It’s an aspect of chronic, long-term, use. On the other hand, sensitization is likely to occur when a user engages in intermittent, binge-like, drug use happening either once daily, or with even greater spacing (as in once every few days) and in large quantities. When you combine chronic use with binge behavior, you can actually get both responses.

Sensitization to drugs has been shown for physiological responses like heart-rate, blood pressure, and movement in animals and humans. More importantly, sensitization plays a part in increasing the motivation for drug use. Just like sensitization increases the physical response to drugs, there is a corresponding increased response in the addicted brain in areas important for motivation (like the NAc and VTA for instance). If an addict responds more to their drug of choice after repeated use, it should come as no surprise that sensitization has also been hypothesized to play an important role in the addiction process.

Drugs cause brain changes that drive addiction

opponent processesWhen both tolerance and sensitization develop in someone who has been using drugs, they’re left with a reward system that is less responsive to rewards in general while being more responsive to the drugs they’ve been binging on and to cues (or triggers) that are associated with those drugs. If that sounds like a recipe for disaster, it is. If you’re an addict yourself, you don’t have to imagine this, you’ve lived it – A state where nothing seems rewarding without being high.

The problem is that both tolerance and sensitization are examples of changes in response to drugs that are completely outside of the control of the user. There’s no doubt that the average drug user doesn’t think about, or even recognize, that as they continue to use drugs, their body adjusts in multiple ways that can make it that much harder for them to stop use at a later point. It should be clear that this is not an issue for everyone – both tolerance and sensitization require repeated administration of drugs that are pretty close together. But they don’t require hundreds of uses, a few days with continuous, or intermittent use, are often enough to bring about these changes in the addicted brain.

We often hear that even the first hit of a drug can cause someone to be addicted. While there’s little doubt that even a single drug administration can change brain response in important ways, I can say with absolute certainty that using a drug repeatedly cause long-lasting changes in the brain chemistry that make future drug use more likely.

3 responses to “Addiction-brain effects – Tolerance, sensitization, and withdrawal”

  1. One the Sub talk zone fails to mention is ibogaine…..yes, in the states its class one but for most a one time dose and done with withdrawl and a window of time without cravings. This is not replacement therapy. Not a Medication that one would abuse. Most do not want to repeat it.

    This medication would not numb one from real life, zap your sex drive nor do you have to go thru withdrawl to end the use of it.

    I heard Dr Scanland say that suboxone numbs one from 80% of feelings…..he also said he would rather detox someone from Herion then suboxone. But the pharm. companies will keep making money off the souls that have an opiate addiction either from Methadone or suboxone….its a guarrantee of “keep coming back”.

    • Dear Sista,
      While Ibogaine can seem promising, the only evidence I can find in terms of research work has to do with a single study of 30 or so patients who were only followed for 48 hours after Ibogaine administration. They reported reductions in withdrawal symptoms AND in cravings, which is great, but 48 hours is nothing in the grand scheme of things and it seems that no one has ever studies this stuff for a longer period of time. If you can point me to anything that shows that it works from day 3 on and that people don’t simply go back to using opiates immediately, you’ll be able to count me as a supporter.

      When it comes to the Dr. Scanland quote, I’m not sure what “80% of feelings” really means… When it comes to withdrawing patients from suboxone versus heroin, I don’t have much experience there, but it’s true that most people remain on maintenance, rather than detox, replacement therapy. Still, if someone makes money and an addict can return to normal life, that’s a result I like. Obviously, removing all drug use from the equation AND returning to normal life would be a better result, but the statistics there with opiates are pretty poor and like I said, there’s nothing showing that Ibogaine works in the long term.

Leave a Reply