What is Drug Tolerance and How Does It Develop?

Opiate Tolerance Definition

Drug tolerance happens when your mind naturally desensitises itself due to constant triggering of certain mechanisms, usually neurotransmitters or stimuli that can give your brain constant stimulation. It happens on many levels – a part of the homeostasis of the brain to constantly regulate pathways, of course to the great disadvantage to people who need manipulation of those pathways for health or pain relief reasons.

One should understand how closely intertwined drug tolerance is to psychological homeostasis, for example your body is wearing clothes most of the time – your clothes are constantly activating touch receptors in your skin. This constant stimulation leads to desensitisation of your touch receptors, as a result you don’t really feel the clothes on your body. It would make you nuts if your brain never adapted to the constant stimulation of clothes on your skin.

This means the brain is pretty much a natural genius at developing tolerance to many things, for example the fear of heights disappear when people spend enough time on high buildings. This is also why the “first time” of everything experientially feels so amazing, but then the interest and excitement slowly disappears, or why scarves feel uncomfortable when winter begins but feels okay afterwards.

Unfortunately because of this general balancing act of the brain regulating itself – the brain structurally cannot be aware that an opiate pain killer is stopping pain, or a drug is helping with memory and cognition, nor can it do anything about the fact that it will rebalance the receptors back if you press them enough. This creates the problem of opiate tolerance or indeed any drug tolerance.

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I believe this is likely a survival mechanism, if an prehistoric human ate a psychoactive or poisonous plant as food, it would greatly benefit the human to develop tolerance and not get drugged or incapacitated all the time.

Now onto an example of a one specific mechanism of drug tolerance in action in the brain (remember there are multiple pathways to drug resistance even including the liver):

Both amphetamines and opiates have similar mechanisms in how drug tolerance develops which is complicated and can be separate entire article itself. We will address an example what does happen after tolerance develops with the NDMA pathway.

Upon administration of opiate or amphetamines, a calcium ion (Ca2+) influx occurs in your brain and body, and this is one of the main pathways (but not all) of how your body signals tolerance. A large influx sends warning signs to your body of overstimulation so it responds to react less to reduce the effects.

This large influx produces an immediate defense response from the brain, any neurotransmitter effects (dopamine, norepinephrine, opiates and serotonin) are temporarily reduced and in the long term permanently reduced.

This mechanism takes time to develop, and varies greatly between individuals and is why drugs work wonderfully before people eventually stop getting effects from them.

That said – there are however multiple variations of similar mechanisms often happening in parallel, however the Ca2+/NDMA is worth talking about because it is fairly straightforward and also seem to play a major direct role in drug tolerance in a variety of drugs including benzodiazepines, opiates, nicotine and amphetamine. Other mechanisms such as the CCK path seem to attenuate this tolerance.

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What Can I Take to Reduce Opiate Tolerance?

The NMDA receptor is the site of calcium influx, the NDMA receptor is activated by glutamate and glycine. If the NDMA receptor is not activated – Calcium Ions (Ca2+) influx are limited. Thus the body would not reduce the effect of the opiate or amphetamine, and over time even reverse the tolerance to a degree (due to the mechanism no longer being as significant)

As such drugs that serve as NDMA antagonist like Memantine, Magnesium, Agmatine, DXM and Ketamine down regulates glutamate and thus puts a limit on Ca2+ influx and consequently influencing and reducing amphetamine and opiate tolerance.

There is an large amount of research on NMDA receptor antagonist reducing opiate tolerance and thus maintaining dosage effectiveness for patients.

There are also other pathways that attenuate (manage) tolerance indirectly without affecting the calcium channel and they too can be affected to reduce tolerance and keep the medicine’s effect.

Pathways for reducing opiate tolerance:

CRF-antagonists – Antalarmine is the most well known drug of this class

CCK antagonistsProglumide is the most well known one. People have reported it cutting their tolerance to half, it also has next to no side effects which makes it attractive.

Glutamate antagonists – NMDA antagonists such as Memantine are well known for blocking tolerance to opioids and other classes of drugs but it seems AMPA and kainate antagonists also block tolerance to opioids:


Sigma Antagonists:


Supposedly they potentiate opioid analgesia, don’t know if that applies to recreational effects or whether they counteract the onset of tolerance.

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Does it Work Forever?

Anti tolerance strategy does work, but it will not allow continued escalation of doses, initial tolerance will never be completely reversed, this is evidenced in that drugs never reproduce their initial effects ever again, even on a long period of abstinence, especially for drugs that have effects on dopamine, the brain is wired to react defensively to overstimulation of neurotransmitters.

What anti tolerance strategies can do though is to stabilize or reduce drug usage, and in another way enhance the effects of your current dosage – without a further increase of dosage for the same expects, preventing you from reaching a point where your dosage is simply unaffordable, ridiculous or causing excessive amount of side effects.

There are numerous things to try before getting to a dead end with increasing dosages – so always research as much as you can. For more information about how to reduce opiate tolerance please read the rest of the blog.

– Khemcorp


Disclaimer: All thoughts and advice expressed are the personal opinions and gatherings of the author and do not constitute medical advice. If you are seeking medical advice please consult a doctor.