In the observable pharmaceutical industry, there are two trends that are unfavourable. The first is the number of new chemical entities (what is required for high profit margin patents) are hitting a wall. They are running out of useful substrates that bind to receptors in a useful way – that is the truth. Drug companies are running out of things to try, as drugs become more exotic and tunnel specific.

In the recent past drug companies have managed to keep in the game by using rapid screening techniques, but this is yielding fewer and fewer candidates that meet the development criteria. As drugs become more exotic and specific, side effects also tend to increase and magnify. As a result too many drugs are just too toxic to develop.

As a result pharmaceutical companies are basically resorting to the strategy of branding and marketing to keep high profit margins to the drugs they have already developed and patented. This also means they have a need to hard sell drugs without fully communicating tolerance and side effects via means of covert information control and direct sales to medical professionals. In some cases drugs are simply discontinued and a more expensive formula is developed to retain profits (such as creating an extended release version).

For example statins regularly cause more deaths than they save, but this fact is cleverly hidden by pharmaceutical companies who continue to push these drugs to doctors who push them to patients.

This is a stark contrast to the massive pharmaceutical boom of the post world war period. The problem is twofold. One is that it is genuinely becoming harder to create new drugs, and two pharmaceutical companies have very little incentive to develop new drugs when they are already making so much money from the medicines created by the last generation.

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There had previously been in both the experimental community and pharmaceutical massive hopes for specific powerful receptor agonists and antagonists ligands which binds powerfully to only 1 or 2 receptor types.

Unfortunately ,the more novel drugs that hugely modulate receptor functions are not too dissimilar in ways of which why potassium cyanide or tetrodotoxin is poisonous, the complete inhibition or agonism of receptors often affect many critical body functions thus causing severe or sometimes fatal side effects. Many receptors have more than one single function in the body.

The irony is that the current generation of drugs that work very well such as Memantine tend to be partial agonists or antagonists which interfere much less with natural receptor functions, so making more powerful drugs is not really an option for the fight against tolerance.

As for the promise of new drugs –  it is highly likely the development of nanotechnology and AI computational chemistry. Continued breakthroughs in drugs will be made once this barrier is broken.


This does not solve the fundamental problem of drugs that act to change body/mind function. No matter what the drug is, as long as it has unnatural effects on the body the body will “naturalise” the drug via homeostasis and render the drug ineffective. It’s the elephant in the room nobody in the pharmaceutical industry would like to talk about.

Homeostasis is the main enemy of all drug applications, it is well known that opiate tolerance developed in a matter of days, the most potent drugs often illicit the most potent response from the body to counter the offset the drug has created, which is probably a desirable effect for example Morphine in the use of pain treatment. The bodies adaptation to dealing with drugs by developing tolerance and increasing the ability of the body to withstand drugs, also make drugs generally more prone to being fatal, and is a key part of how physical and psychological dependence develops.

This is why tolerance reversal or mediation is the elephant in the room nobody wants to talk about. Substances such as Memantine and Proglumide and Agmatine have no profit value in the views of the pharmaceutical companies (due to the patents already expiring) which develop and research the potent drugs. On the contrary the more drugs are needed, the more the companies make, so it makes no sense for pharmaceutical companies to push drugs that would essentially cannibalise their own industry.

Unfortunately that also means apart from the most severe cases, tolerance reversal or prevention is generally poorly understood and ill researched.

In the past we could always rely on the industry to develop the next big drug and then cycle to that until that stops working, but with the pharmaceutical companies scratching their heads being unable to find new more exotic drugs that can safely pass clinical trials.

The answer we believe is understanding the importance of dosage control, withdrawal alleviation such as using CES electroceuticals to alleviate pain withdrawal, understanding what our bodies need to naturally reverse tolerance (protein modifying processes). We won’t have the complete answer, but the opposite which is increasing doses until the side effects exceed the main effects, and until the effects become just to sustain “feeling normal” is not an answer.

– Thoughts from Khemcorp

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