The Drugs Don’t WorkOn
After a century and more of pharmaceutical medicine, we still have no reliable cures for any of the non-communicable diseases.
After a century and more of pharmaceutical medicine, public health continues to deteriorate at an alarming pace.
What is wrong with this picture?
Because Big Pharma only produces palliatives, and because the public grows ever sicker, the drug industry is enjoying significant growth. Earnings rose from $437 billion in 2012 to 1.4 trillion in 2021, and with a plethora of new biologicals in the pipeline are projected to grow even faster in future (1, 2). The drug industry has enough funds to rent politicians, subvert regulatory agencies, publish fake data in the most august peer-reviewed literature and warp the output of medical schools everywhere.
Their products are a common cause of death, particularly in the USA where frontier medicine is widely practiced and TV commercials for dangerous new drugs are broadcast every 20 minutes on all channels. Every year, America’s aggressively modern approach to disease kills over 100,000 in-hospital patients (3, 4) and twice that number of out-patients (5-7).
How did we get into this mess? More urgently, how can we get out?
Medicine made a series of wrong turns in the late 19th and early 20th centuries. Some of these were due to major scientific discoveries, from Leeuwenhook’s animalcules through Koch’s Postulates and from Pasteur to Ehrlich, Domagk and Fleming, Chain and Florey. Some were due to political corruption, financial greed and sociopathy; take a bow John Rockefeller, Mark Hegsted, Fred Stare. Others relate to our penchant for simple answers and our need for heroes.
Throughout history, infectious diseases had always been the major causes of illness and death. In 1900, for example, the leading causes of death were TB, pneumonia, diarrhoea and enteritis (8).
The first and greatest major advance against these was improved public sanitation. By 1940 (ie within a single generation), infectious deaths had fallen by 75% (9). Then came immunisation programmes and the antibiotics, which between 1940 and 1960 halved the death rates again (9).
These developments had a great impact on the public and medical perception of what medicine and indeed society could be. In 1900, a third of all deaths occurred in children under the age of 5. By 2000 this had fallen to 1.4% (10, 11), and the resulting 30-year increase in average life expectancy fed into the seductive and prevailing myth that we are all living longer; which is manifestly untrue (12-14).
If you start your life expectancy graphs at 1900, which was an historical low point, it looks as if we have made some progress. Among pre-modern hunter-gatherer societies, however, modal life expectancy is between 69 and 77 years (15), and would be higher still if not for high infant mortality. From this perspective, 20th century medicine’s crowning achievement appears to be the cancerous growth and metastasis of the pharmaceutical industry.
Improvements in sanitation, which were far more significant in pushing infections back than any medical developments (9), were driven by three remarkable men. The British lawyer Edwin Chadwick, the German polymath Rudolf Virchow and the American politician and statistician Lemuel Shattuck laid the foundations of public health infrastructure that enables today’s cities, but were largely forgotten. The great Claude Bernard, whose seminal work aligns with Virchow, was driven out of medical curricula and banished to the footnotes of biology schoolbooks.
Pasteur and to a lesser extent Fleming, whose later victories were less significant but more obvious, were lauded as messiahs. The magic bullets of immunisation and then antibiotics congealed into magical thinking, and the terrible beauty of the pharmaceutical industry was born. The non-communicable diseases (NCD’s) were becoming increasingly important due to dietary degradation (16), magic bullets were deemed to be the answer and only Big Pharma could produce them.
Infectious diseases such as TB, HIV, malaria and diarrhoea were still rife in the developing nations where they were no longer profitable; but even here, thanks to the Western junk foods which replaced Lord Amherst’s mythical pox-infected blankets (17) with genuine biowarfare (18), NCD’s took over early in the 21st century (19).
The modern, ultra-processed diet is the guts of it, as described in Barry Popkin’s nutrition transition (ie 20). The consequent malnutrition is a key risk factor for NCD’s (21), and because half of the world’s population now suffers from malnutrition (22-24), poor diet has become the leading cause of death world-wide (25).
It is time to bring Claude from the back of the hall to the dais, where he can legitimately stand shoulder to shoulder with Louis. Pasteur gave us the beginnings of an armory against infectious disease. Bernard bequeathed us the foundations of a defense against the NCD’s, which eventually lead, via Popkin’s work, to the four pillars of the Health Protocol.
To illustrate why we must push pharmacocentric medicine to the edge of the plate, consider Parkinsonism.
Like all NCD’s, this is a syndrome rather than a disease in the classic sense. It is a cluster of symptoms, all of which may vary in intensity, and which may be arrived at via a multiplicity of routes. The genetics, cytochemistry and intra- and extra-cellular machinery are extremely complex, and contain hundreds of links each of which, if damaged, may contribute to a clinically similar end-point.
The post-modern, ultra-processed diet creates the four major toxic pathogenic mechanisms of chronic inflammatory stress, Type B malnutrition, dysbiosis and failure of glycemic control. These in turn drive endoplasmic reticulum stress / proteostatic failure, immunological dysregulation and the integrated stress response, ALL of which are involved in Parkinsonism (ie 26-30). To this toxic list we must add exposure to carbamate and other widely used pesticides … (31).
There is thus not any single target that a pharmaceutical bullet can reach which will help more than a fraction of Parkinson sufferers. This is what the many clinical trials of anti-P drugs show; no matter how promising the putative mechanism of action (such as a disorder of calcium flux), initially promising pre-clinical and phase 1 / 2 studies inevitably run into the shallows of phase 3 disappointment, end-points not reached, trends failing to reach statistical significance (ie 32-38).
It is not for lack of trying. As Parkinsonism is increasing by leaps and bounds, and is on track to double by 2040 (39-41), the drug companies smell blood in the water. One review identified 193 ongoing trials targeting an extensive array of genes, enzymes, receptors and neurotrophic factors, as well as mitochondria, lysosomes, the microbiome and the lymphatic system (42).
Others are studying the impact of natural compounds ranging from wheat bran (43) to Hypoestes rosea leaf powder (44), and non-pharmacological treatments ranging from fecal transplants (45) to appendectomy (46) and ‘smart’ deep brain electro-stimulation (47).
I predict that the researchers will all fail to find more than the usual trend toward significance, because they are treating a heterogynous population who have, effectively, a wastebasket diagnosis. They are all labelled with Parkinsonism because they have some or all of the characteristic symptoms, but they ended up there from many different starting points and were driven there by multiple pathogenic mechanisms.
There are two very different approaches to this problem.
We could screen each individual PD patient minutely to see which of the many possible lesions is driving their condition, and then provide tailored therapy to each patient. The industry’s preferred approach, it is labor- and cash-intensive and probably useless as a public health tool.
It is still possible that somewhere in the tangled webs of biochemistry and cytology that culminate in clinical Parkinsonism, there is a universal or at least frequent convergence point which could usefully be targeted. The synthetic molecule NPT200-11, developed by Neuropore Therapies to enter the brain and inhibit the agglomeration of alpha-synuclein, has generated significant positive results in a murine model (48). Re-named UCB0599, it is now in Phase 1 and 2 clinical trials, along with several other drugs which act at the same point.
Other interesting targets include the kinase LRRK2, a multi-functional enzyme whose variants are one of the more common risk factors for clinical Parkinsonism, and which is implicated in some pre-clinical models (49); and sigma-1, which controls the rate of synthesis of chaperone proteins and reduces endoplasmic reticulum stress (50).
As a pharmacologist I admire the science, and these approaches may turn out to have some degree of effectiveness in slowing disease progression in some or even many cases. But I suspect they will never be more than disease modifying drugs with limited applications, the usual slew of adverse effects and unsuitable for prophylactic use. They will not stop the incoming tides of Parkinsonism, and the neuro-degenerative diseases in general.
Alternatively, we could characterise PD as a largely post-transitional disease, and re-establish pre-transitional nutritional values in our patients. This can be easily achieved through dietary improvement and/or pharmaconutritional tools, which allow us to impact safely on multiple targets and rectify the multiple metabolic and microbiotal distortions caused by the post-transitional diet.
This idea was substantially reinforced by a recent study which showed a strong correlation between following different forms of the Mediterranean diet, and a delay in the onset of Parkinsonism of up to 17 years (51, see also 52 and 53).
The same principles apply to Alzheimer’s (AD) which, like heart disease, is reduced in those eating a Mediterranean diet (52), is rare in pre-transitional societies (54, 55), and has a pathology that overlaps substantially with Parkinsonism (56-59).
Back in 2006, data emerged that increased intake of fruit and vegetable juices was protective against AD (60), and subsequent studies implicated the anti-inflammatory polyphenols (ie 61-64). Not only are they anti-inflammatory, they also reduce the aggregation of malfolded proteins which characterise Alzheimer’s, Parkinsonism and other prion-like and prionic diseases (65), which may include Covid (66).
The incidence of dementia is also reduced by consuming a diet that more closely approximates to a pre-transitional diet (63); my friend Dr Dale Bredesen even showed that Alzheimer’s, if caught early enough, can be reversed using dietary tools (67, 68). I should add that a very thorough (and thoroughly mis-directed) RCT showed limited improvements in AD, using a considerably less sophisticated nutrient intervention (69).
If that is not enough to persuade you, consider this. Hippocampal atrophy, a critical element in the development of Alzheimer’s, is common in those who eat an ultra-processed, junk food diet (70); but hardly occurs in pre-transitional societies (55).
There is currently no pharmaceutical cure for Alzheimers or Parkinsonism, nor can there be when these syndromes are in most cases driven by multiple metabolic distortions caused by today’s diet. The brain is so very complex, and it can go wrong in so many ways; the idea that we can find a magic bullet for either of these syndromes is ill-informed and philosophically mired in the past.
It is also dangerous. There is a significant sub-group of dementia sufferers whose conditions are driven and exacerbated by phamaceuticals. Chronic use of a number of commonly prescribed drugs (anticholinergic antidepressants, anti-psychotics, bladder antimuscarinics, anticonvulsants and ironically, antiParkinson drugs), increases the risk of dementia by roughly 50% (71, 72).
Big Pharma’s ability to subvert the regulatory authorities is, in the long term, even more dangerous. The recent FDA approval of Biogen’s drug aducanumab is a scandal; not one member of the FDA Advisory Committee voted to approve this ineffective product (73-75), and three of them resigned in the aftermath of the FDA’s edict.
This ‘anti-Alzheimer’s’ drug, which will earn Biogen $56,000 / patient / year, was licensed for financial reasons; it reduced amyloid plaque but was clinically ineffective. So did the eagerly awaited gantenerumab and solanezumab, but they too failed to produce any significant clinical benefit (76).
The higher road to better public health is via food. Safe and delicious, if you know just a little about cooking, this road is genuinely protective, and cheap. This is why regulatory agencies, pwned by the drug companies, have made open discussion about natural pharmacology effectively impossible.
I will finish with Walter, the Parkinsonian patient I last wrote about in July 2020.
It is now 4 years since his initial diagnosis, and when I put him on a program to restore pre-transitional nutrition. After two years his only remaining symptoms were micrographia and poor performance on the spiral test. After four years he now has no symptoms at all, and was recently discharged by his neurologist. At 82, Walter is so good at what he does (forensic accountancy) that he is repeatedly called back out of retirement to repair the problems created by millennials.
He is just one specific illustration of one ‘incurable’ syndrome, but I believe we can do the same for most of the other NCD’s that cast a lengthening shadow over our middle and old age.
There will always be a role for drugs, but not the central role they occupy today. To provide safe and cost-effective risk management for the greatest number of people we need a multi-layered approach, starting with dietary improvement and then reserving drugs (better than the ones available today) for the minority with specific genetic and/or environmental risk factors in whom foods are not enough.
Next week: The Walking Dead: Why are humans are so badly maintained?
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