Yay, my first post here!
Wanted it to be about the recent study I did. While the results will have to be replicated with a follow-up experiment, with more animals, and additional groups for comparison, this results has never been seen before with this tumor type, which is 100% lethal and has no known case of spontaneous regression (i.e. disappearing on its own, without treatment). Basically, 2 out of 3 animals were fully cured in this experiment/study.
https://twitter.com/haidut/status/1751716166387597730

Human-equivalent doses for the substances were ~15mg/kg vitamin B1 (thiamine Hcl), 30mg/kg vitamin B3 (niacinamide), 1.5mg/kg vitamin B7 (biotin), and 15mg/kg aspirin. Administration was once daily, orally.

A very interesting study, and one of the few that I have seen openly acknowledge the existence of the Randle Cycle and its importance to human health. Namely, the study demonstrated that increased FAO is sufficient to cause cellular dysfunction, senescence and ultimately diseases and the process known as “aging”. It is starting to look more and more plausible that aging/disease are nothing but symptoms of increasingly reduced glucose oxidation and increased FAO. As the study says, increased FAO “muscles out” glucose in competition for access to the Krebs/TCA Cycle. This increase in FAO leads to overabundance of acetyl-CoA and the abudance of acetyl group is what the study claims increases the activity of a gene called “p16”, implicated in many chronic conditions associated with aging. However, the study mentioned another mechanism that is mostly ignored by medicine and that mechanisms is the increased reactive oxygen species (ROS) generated by FAO compared to glucose. As discussed on many podcasts, ROS is actually a misnomer and is a symptom of “reductive” rather than “oxidative” stress. In addition, more than 98% of the ROS are generated when there is blockage at one (or more) of steps of the electron transport chain (ETC) and the accumulated electrons start flowing backwards through the chain – i.e. reverse electron flow (REF). REF itself further contributes to the already present reductive stress (low mitochondrial NAD+/NADH ratio) since the actual process of REF further lowers the mitochondrial NAD+/NADH ratio, this lower NAD+/NADH ratio further limits oxidation of glucose and promotes FAO, thus creating a vicious cycle. The buildup of electrons as a result of increased FAO is handled by the cell through an emergency mechanism by converting some of the superfluous acetyl-CoA into citrate and using that citrate to synthesize fat, which is then fed into the beta-oxidation cycle and ends up again as acetyl-CoA – again, a vicious cycle and it just so happens that this metabolic phenotype is the very hallmark of cancer. Medicine now recognizes such metabolic derangement in cancer, but claims that the ETC blocks are due to external agents, cancerous mutations, or just aging in general. But the study below makes it quite clear that the truth is actually backwards and that all that it takes for the “cancer” metabolism to occur is simply a sufficient shift from oxidation of glucose towards FAO, as per the Rande Cycle. This increased FAO results in lowering of the FAD/FADH ratio and thus a functional (co-factor deficiency) block at complex II of the ETC, which ultimately leads to the electron buildup, REF and thus drop in NAD+/NADH ratio as well. In contrast, oxidizing mostly glucose does not generate REF (since it does not lower the FAD/FADH ratio) and when the electrons flow forward it accounts for less than 2% of the total generated ROS during OXPHOS (the other 98% being generated as a result of REF). In other words, all that it takes for both function and structural pathological changes to occur, as well as senescence/aging, is increased FAO at the expense of glucose, which results in a shift of the redox balance in favor of reduction, forming a vicious metabolic cycle.

An interesting finding of the study is that saturated fats (SFA), despite being much preferable than PUFA for oxidation, are also capable of affecting the Randle Cycle and shifting the redox balance in favor of reduction. The specific lipid used in the study to increase FAO at the expense of glucose was octanoate (caprylic acid), and providing sufficiently high concentrations of that SFA was sufficient to trigger the increased FAO and cause senescence. Ray mentioned this on a few podcasts when people asked him if keto diets would be OK if one ate 100% saturated fat. His answer was that a diet which contains only saturated fats in its lipid fraction is preferable to a “standard” Western diet (i.e. 30%+ PUFA on average), however long term consumption of a keto diet with 100% SFA in its lipid fraction is also not optimal since it would generate less CO2, more ROS and ultimately cause the same metabolic derangements as a standard Western diet. Thus, he said, oxidizing primarily glucose is of paramount importance when it comes to systemic health.

In addition, the study contains an interesting finding that a widely used cancer drug known as doxorubicin can produce the exact same metabolic derangements and senescence as the increased FAO, which is another way of saying that the drug is harmful and ultimately (oh, the irony!) carcinogenic. One of the hallmark side effects of standard chemotherapy is that it visibly ages the patient, and the study below provides an explanation why – i.e. most chemotherapy drugs are likely metabolic blockers like doxorubicin and as such not only lead to accelerated aging, but are direct causes of secondary diseases (including cancer), further ruining the patient’s health already compromised by the cancer and its diagnosis. The study exposed another widely used drug – the lipid lowering agent fenofibrate – as also being a pro-senescent agent, and this should not be surprising considering fenofibrate increases FAO. To make matetrs worse, unlike doxorubicin, fenofibrate is used by a much larger group of people as prevention for heart disease (CVD) with (again) the irony being that the drug likely promotes the very disease it is supposed to prevent.

The good news is that this vicious metabolic cycle caused by increased FAO can be broken through various methods that aim at either increasing glucose oxidation, reducing FAO or both. Aside from the increased supply of glucose, substances such as thiamine (vitamin B1), niacinamide (vitamin B3), biotin (vitamin B7), aspirin, oxidizing agents / quinones, thyroid, progesterone, DHEA, pregnenolone, testosterone, DHT, etc all work to increase glucose oxidation, while inhibiting FAO. It just so happens that the first four of the above mentioned substances are the cancer protocol I am using for the xenograft experiments that I have been running for the past 2+ years, and the results so far corroborate both the bioenergetic theory and the findings of the study below. Namely, everything in the body is controlled by metabolism/bioenergetics and oxidizing anything other than (primarily) glucose for an extended period of time ultimately leads to degeneration/disease, and is the primary driver of what we, perhaps mistakenly, call “aging”.

https://doi.org/10.1126/sciadv.ado5887

“…Recent studies have indicated that senescence contributes to aging and age-related diseases (1, 3). p16 expression increases in various tissues with age (7, 8). Increased p16 expression decreases the tissue-regenerative potential of pancreatic β cells and neuronal progenitor cells (2). Moreover, p16-expressing senescent cells that accumulate in the body impair heart and kidney function and shorten healthy lifespan (9). This impaired organ function may be due to the secretion of inflammatory cytokines and chemokines by senescent cells, a phenomenon termed the senescence-associated secretory phenotype (SASP) (10). The link between p16 and aging is further supported by the finding that the INK4/ARF locus, which encodes the senescence effectors p16, alternative reading frame (ARF), and p15, is a hotspot for susceptibility single-nucleotide polymorphisms associated with age-related diseases, such as atherosclerosis and diabetes (1). Therefore, elucidating the regulatory mechanisms of p16 expression may provide clues to understanding the mechanisms of aging. Numerous transcription factors and histone-modifying enzymes have been implicated in p16 expression (6).”

“…We found that upon DNA damage, BNIP3 is phosphorylated by ATM and contributes to an increase in the number of mitochondrial cristae. This increase in cristae enhances the oxidation of fatty acids to acetyl-CoA, an acetyl group donor, thereby promoting histone acetylation around the p16 transcription start site (TSS). Notably, pharmacological activation of FAO alone can induce senescence in fibroblasts, endothelial cells, and mouse liver.”

“…FAO activation decreases acetyl-CoA production from glucose (38). This effect, known as the Randle cycle, is primarily due to inhibitory phosphorylation of pyruvate dehydrogenase (PDH), the mitochondrial enzyme that converts pyruvate to acetyl-CoA (Fig. 4A). Isotope labeling with [U-13C]glucose indicated that the conversion of pyruvate to acetyl-CoA and then to citrate and acetylated amino acids decreased during doxorubicin-induced senescence (fig. S9A). In addition, doxorubicin treatment increased PDH phosphorylation (Fig. 4G and fig. S9, B to D). This increase was attenuated by the knockdown of CPT2, BNIP3, or ATM but not by knockdown of p16. In contrast to doxorubicin treatment, oncogenic RAS expression did not increase PDH phosphorylation (Fig. 4H), perhaps reflecting that PDH phosphorylation is not solely regulated by FAO (39). These results are consistent with FAO activation during DNA damage–induced senescence.”

“…To further investigate the importance of FAO in senescence induction, we used the medium-chain fatty acid octanoate. Unlike the more abundant long-chain fatty acids, octanoate freely crosses mitochondrial membranes (40). When added to cells, octanoate is readily oxidized to acetyl-CoA, an acetyl group donor, and promotes histone acetylation and the associated expression of lipid metabolism–related genes. Treatment of IMR-90 cells with octanoate increased p16, CPT2, and phosphorylated PDH levels and decreased lamin B1 levels (Fig. 5A). In contrast, the ATM-p53-p21 pathway and γH2AX foci were largely unaffected (Fig. 5, A and B). Octanoate treatment increased the percentage of SA-β-gal–positive cells (Fig. 5C). In addition, octanoate treatment decreased the percentage of EdU-positive proliferating cells and increased nuclear size (Fig. 5D and fig. S10A). These changes in cell proliferation and nuclear size were suppressed by p16 knockdown (Fig. 5D). Octanoate treatment increased the expression of inflammatory cytokines and chemokines (fig. S10B). Similar results were obtained with fenofibrate, a lipid-lowering drug that activates FAO through the transcription factor peroxisome proliferator–activated receptor α (PPARα) (Fig. 6, A to E, and fig. S10, C and D) (41). We confirmed that fenofibrate-induced p16 expression was attenuated by CPT2 knockdown (Fig. 6B). Treatment with octanoate or fenofibrate increased mitochondrial ROS levels, decreased mitochondrial membrane potential, and increased the number of cristae and mitochondrial length (fig. S10, E to I).”

“…In this study, we have shown that nuclear DNA damage signaling to mitochondria via BNIP3 induces senescence by activating FAO (Fig. 7L). Our results suggest that DNA damage–activated ATM translocates to mitochondria, where it phosphorylates BNIP3. BNIP3 increases the number of cristae and activates FAO. This activation may reflect an attempt to repair DNA damage through histone acetylation (44). If DNA damage persists, the resulting prolonged FAO activation appears to promote histone acetylation for p16 expression. However, histones are not the only proteins whose acetylation state is regulated by acetyl-CoA levels (45). In addition, FAO activation has effects other than increased acetyl-CoA levels (15, 38, 41). In particular, increased mitochondrial ROS production may contribute to the induction of senescence (12, 46). Further studies are needed to elucidate the mechanisms by which BNIP3 regulates cristae and by which FAO drives senescence. We used doxorubicin and oncogenic RAS, which cause DNA damage (1), to conclude that DNA damage–activated FAO drives senescence. However, we cannot completely exclude the possibility that doxorubicin activates FAO independently of DNA damage.”

Via: http://haidut.me/?p=2710

As many of my readers know, muscle spasticity is one of the main symptoms of low thyroid function and is present in many people with chronic conditions, especially neurological (e.g. multiple sclerosis). A number of remedies have been tried clinically, but there has been no breakthrough, except with quinine. However, for some reason, medicine has decided that quinine is “dangerous” and its use is discouraged clinically while also being regulated in the food supply. Tonic water, which traditionally has 300mg-500mg quinine per quart/liter, has been regulated in most Western countries to contain no more than 100mg per quart/liter. Be that as it may, I think the focus should stay on the fact that impaired muscle relaxation is core symptom of energetic deficiency. As an extreme example, Ray cited experiments from the early 20th century demonstrating that even “rigor mortis” can be prevented with injections of ATP directly into the muscle tissue. The study below found that just 180mcg vitamin K2 (MK-7) daily, for 8 weeks strongly decreased frequency and severity of nocturnal leg/muscle cramps (NLC), while also producing no notable side effects. In addition, the study cites a previous one where vitamin K was able to reduce muscle cramps in hemodialysis patients. The study attributes these effects of vitamin K to its ability to inhibit calcium uptake into the cell from the extracellular medium. I would take this a step further and point out that vitamin K can even reverse already established soft-tissue calcification, which is the reverse process – i.e. pushing calcium out of the cell after it had already accumulated in pathological amounts. However, I think the main mechanism of vitamin K has to be related to its ability to act as a quinone/oxidizer and speed up the flow of electrons through the OXPHOS pathway. In corroboration, T3 administered orally or by injection also has potent muscle-relaxing effects and T3 can also decalcify tissues by raising ATP production (and thus magnesium retention) and accelerating calcium efflux by raising CO2 production (which draws calcium out of the cell as CO2 is leaving the cell) thus achieving higher magnesium/calcium ratio inside the cell. Vitamin K also has this effect and this is probably how it also manages to decalcify cells (an effect already demonstrated in several human trials).

https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2825457

https://www.news-medical.net/news/20241030/Vitamin-K2-reduces-the-frequency-intensity-and-duration-of-nighttime-leg-cramps.aspx

“…Half of the confirmed participants were randomly assigned to receive a daily dose of 180 μg vitamin K****2, while the others received a placebo for eight weeks. The placebo and vitamin K2 capsules were identical in appearance and packaging, and both the research staff and participants were blinded to the assignment of groups. Participants consumed one capsule per night and tracked NLC events, pain level, and duration. Research staff contacted them weekly to ensure adherence, collect reports, and enquire about any side effects. The main outcome was the average number of NLCs experienced each week during the eight weeks of the study, with the severity (scored between 1 and 10) and the duration in minutes of the cramps as secondary outcomes.”

“…However, the group receiving vitamin K2 reported that their mean cramp frequency reduced to 0.96 events per week over the eight weeks, while the placebo group’s average number of events increased to 3.63. Statistical tests established that this difference was significant. Those receiving the vitamin capsule also reported greater reductions in the severity of pain and duration of NLC events. No adverse events were reported by the participants related to the consumption of vitamin K2. Following previous findings that vitamin K2 relieves hemodialysis-related cramps, researchers explored whether they can alleviate discomfort from NLCs. They found that from the first week of the trial, vitamin K2 reduced the intensity, duration, and frequency of NLC events. The mechanism could be the lowering of calcium levels, leading to muscle relaxation. Encouragingly, the therapy appeared safe for older adults, with no observed adverse effects during the study. However, it is not recommended for people on certain blood thinners, as it may interfere with its effects.”

Via: http://haidut.me/?p=2708

Yet another confirmation that cortisol, while being life-saving in acute stress situations, can shorten lifespan if chronically elevated. In fact, according to the study below, antagonizing the effects of even normal cortisol levels may extend lifespan. This corroborates Ray’s statement that all the symptoms of aging (and thus every chronic disease) can be reliably reproduced in even youthful organisms by the administration of sufficiently high doses of cortisol. An interesting finding of the study was that the anti-aging effects was due to improved mitochondrial function, so this suggests (again) that any benefit or risk from a specific substance is likely ultimately due to its effects on metabolism/mitochondria. And it just so happens that cortisol does suppress mitochondrial function, while simultaneously enhancing both fatty acid synthesis and fatty acid oxidation, as well as lipolysis. Finally, the study compared the effects of cortisol blocking to the effects of the well-known life-extension drug rapamycin, which works by blocking the mTOR protein. In fact, blocking cortisol extended lifespan by 40%+ more, compared to rapamycin and without the known (and very dangerous) side effects of rapamycin (immunosuppression). The two drugs were not synergistic when used together, suggesting they work through the same pathway.

The anti-cortisol drug the study used was the well-known Mifepristone/RU486. However, there is plenty of evidence that progesterone, DHEA, testosterone, DHT, etc are also capable of antagonizing the effects of cortisol. As a curious example, I would point to both Elon Musk and (especially) Jeff Bezos, who are some of the most well-known users of testosterone (TRT). Both have had doctors and the general public commenting that since starting TRT they have able to “age in reverse” and that is readily visible by comparing pictures from their younger years (20s and 30s) to recent ones. While medicine will probably attribute those beneficial effects on testosterone (T) being an “anabolic” steroid, in reality most of the “anabolism” stems from the anti-catabolic effects of T (it is a cortisol blocker at the receptor level, just like RU486). As such, OTC alternatives with known anti-cortisol effects such as progesterone/DHEA or pregnenolone may also be able to achieve the same effect.

https://doi.org/10.1080/19336934.2024.2419151

https://gizmodo.com/abortion-drug-mifepristone-might-have-unexpected-health-benefits-study-suggests-2000517292

“…The University of Southern California scientists directly compared the effects of mifepristone on female fruit flies with another drug that has shown anti-aging potential, the immunosuppressant rapamycin. They found that both drugs taken separately improved the flies’ longevity, though mifepristone performed a bit better, extending the flies’ lifespan by a median 114% compared to 81% for rapamycin. However, when both drugs were used together on the flies, the flies actually went on to have a slightly lower lifespan than normal—indicating that the drugs work in a very similar way to boost longevity, the researchers said. The team’s other experiments suggest that both drugs do this by improving the cells’ ability to clean up their damaged or dysfunctional mitochondria…”

Via: http://haidut.me/?p=2706

I know the topic of smoking and drinking is controversial, and I hope that this post is not taken as an invitation to start puffing packs a day and downing pints of beer like water. Yet, there is something in the habits of extremely long-lived and healthy people that flies in the face of mainstream medicine and piques my curiosity. On one hand, there is strong evidence that chronic exposure to the aromatic hydrocarbons present in any smoke is carcinogenic, confirmed in many thousands of people who have worked in forest management (controlled fires), furnace/metallurgy workers, chimney sweepers, etc. On the other hand, the evidence for natural tobacco (no additives) smoking is a lot less convincing, even if we factor in the obvious ghostwriting and sponsored studies by the Big Tobacco companies questioning the dangers of smoking. There is also the curious fact that the World Health Organization (WHO) deliberately excludes countries with high tobacco consumption from its reports on cancers and longevity. For instance, not many people know that Caribbean countries, on average, have some of the highest tobacco (and alcohol) consumption per-capita in the world, yet have much lower rates of lung and other cancers, and also have some of the highest numbers of centenarians per-capita in the world. Other countries with a high number of centenarians also seem to have higher rates of smoking (and drinking). In addition, many of the world’s so-called super-centenarians were heavy smokers (and drinkers) throughout their lifetimes. Perhaps the most famous example is former UK Primer Minister Winston Churchill who was a heavy cigar smoker all his life, detested exercise, and was a heavy drinker as well, yet lived well into his nineties despite many of his relatives dying much younger (so genes were probably not a factor).

https://www.scmp.com/news/world/article/1857713/secret-longevity-may-lie-long-lived-smokers-biologically-distinct-group

https://www.dailymail.co.uk/travel/article-7832443/Why-centenarians-abound-Dominica-location-Pirates-Caribbean-films.html

https://www.bbc.com/news/world-africa-44224484

https://www.biorxiv.org/content/10.1101/704080v3.full.pdf

“…The supposed enrichment for extreme-age survival in BZs is then subject to a host of secondary claims, each aimed at explaining the primary pattern of extraordinary longevity. Old-age survival in the BZs is supposed to result from diverse causes such as ‘moderate’ drinking at twice the NHS heavy-drinking guidelines[28], plant-based diets[25–27] and inbreeding[12,13].”

“…However, according to the national statistics bureau of Japan, only 3.9% of Japanese women and 19.3% of men over the age of 80 are smokers[56]. Tokyo centenarians therefore smoke at around twice the rate that could be expected in a younger, 80+year old cohort with an identical sex ratio. Likewise, 80% of the ‘exceptional’ health-status centenarian population were daily drinkers, followed by 49% of the ‘normal’ and less than 40% of the ‘frail or fragile’ centenarians, resulting in “a [significant] positive relationship between drinking habits and functional status”[55]. In contrast with these figures, Japanese government surveys estimate only 2.8% of women and 23% of men aged 80+ drink every day[56]. Daily drinking peaks at 36.7% in men aged 60-69, the heaviest-drinking cohort in Japan[56]. As such, Tokyo centenarians drink at higher rates than any other age group, and smoke at rates equal to a 45-year younger population[56].”

I think there is a play by Woody Allen about a man who falls in coma for decades only to wake up in a hospital at some point in the future and be presented with lit cigar/cigarette by a nurse and upon seeing his shocked face, the nurse exclaims something along the lines of “Please go ahead, it just tobacco. The healthiest remedy known to man.” On a more recent, and grim, note – we do have the extensive data from the COVID-19 pandemic demonstrating convincingly that smokers has a much lower chance of both falling ill with COVID-19, as well as deteriorating and dying from it.

https://pmc.ncbi.nlm.nih.gov/articles/PMC10306417/

“…A case-control study from Mexico included 32,583 patients (12,304 COVID-19 positive cases and 20,279 COVID-19 negative controls) of which 2.3% of cases were smokers and 4.3% of controls had a history of smoking [65]. This study not only concluded that active smokers had a decreased likelihood of developing COVID-19 (females, adjusted OR = 0.49, 95% CI: 0.31–0.78; males, adjusted OR = 0.64, 95% CI 0.51–0.81) but also suggested that nicotine in tobacco might have a therapeutic effect.”

And finally, there is the curious example of a medical student from the UK, who had debilitating ulcerative colitis (UC) – a disease considered “incurable” by medicine – that went away for good when he started smoking a few cigarettes a day.

https://www.dailymail.co.uk/health/article-2201475/Doctors-dont-know-best-Student-claims-cured-debilitating-bowel-disease-taking-smoking.html

“…Stephen Pendry, 23, struggled with crippling pain, tiredness, shortness of breath and dehydration since he was diagnosed with ulcerative colitis four years ago. But he is now completely symptom-free, thanks to a new four-a-day cigarette habit. Doctors are divided over benefits of patients smoking to combat symptoms – some believe nicotine is the healer so patches, and not cigarettes, are way forward”.

So, how can the bioenergetic theory attempt to explain any potential benefits of smoking? Well, for a start, many of the main psychoactive tobacco ingredients (e.g. nicotine, cotinine, anabasine) are aromatase inhibitors.

https://pubmed.ncbi.nlm.nih.gov/3711333/

In addition, it seems that most of the studies that demonstrated detrimental effects from tobacco or nicotine were in-vitro, yet the effects of nicotine/tobacco seem to be the opposite in-vivo, at least in amounts that would constitute smoking a few cigarettes a day. Perhaps most importantly, nicotine seems to be able to strongly blunt the systemic inflammatory effects of endotoxin/LPS, including in humans. Assuming endotoxin/LPS is the main driver of many/most chronic diseases, the anti-estrogenic and anti-endotoxin effects of nicotine (and some other tobacco ingredients) may explain its cumulative effects on promoting longevity, despite the known and undisputed carcinogenic effects of the actual smoke from the burning tobacco.

https://channel.ersnet.org/media-52743-converse-airway-effects-of-nicotine-iin-vitroi-and-iin-vivoi

https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.826889/full

https://pubmed.ncbi.nlm.nih.gov/17177960/

“…Because a prototypical ligand for this receptor is nicotine, we studied the in vivo human response to bacterial endotoxin or lipopolysaccharide (LPS) in the context of nicotine or placebo pretreatment. Twelve adult male normal subjects were studied prospectively. Six received overnight transcutaneous nicotine administration by application of a standard patch (7 mg). Six hours later, all subjects were given an intravenous dose of endotoxin (2 ng/kg) and were evaluated for an additional 24 h for circulating levels of inflammatory biomarkers, vital signs and symptoms. The nicotine subjects had elevated blood levels of the nicotine metabolite, continine, prior to and throughout the 24-h post-endotoxin exposure phase. Subjects receiving nicotine exhibited a significantly lower temperature response as well as attenuated cardiovascular responses for 2.5-6 h after LPS exposure. In addition, increased circulating interkeukin (IL)-10 and cortisol levels were also noted in nicotine subjects. These data indicate an alteration in LPS-induced systemic inflammatory responses in normal subjects exposed to transcutaneous nicotine. In this model of abbreviated inflammation, nicotine exposure attenuates the febrile response to LPS and promotes a more prominent anti-inflammatory phenotype.”

Interestingly enough, one of most renowned healers in the Amazonian region – the birthplace of tobacco – used tobacco almost exclusively to heal almost any disease known to man. A key fact to note in his work was that all the tobacco-based remedies he used were used orally and/or topically, but never through smoking.

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.594591/full

“…Harmful usage of tobacco is a public health problem of global concern and, in many countries, the main risk factor for non-communicable diseases. Yet, in the Peruvian Amazon, the geographical region believed to be tobacco’s historical birthplace, this plant is associated with a strikingly different usage and repute: Tobacco (especially Nicotiana rustica L.) in this area is described as a potent medicinal plant, used topically or via ingestion to treat a variety of health conditions. The goal of this transdisciplinary field study was to investigate clinical applications of the tobacco plant as per Amazonian medicine exemplified in the practice of a reputed Maestro Tabaquero, an Amazonian traditional healer whose medical specialization focuses on tobacco-based treatments…The current study described Amazonian therapeutic uses of tobacco (N. rustica L.) in the practice of a Maestro Tabaquero, an accomplished Amazonian healer specializing in tobacco-based treatments. The informant’s descriptions revealed refined knowledge on the plant’s therapeutic scope and properties, safety profile, and application techniques. A liquid remedy taken orally was his most commonly used preparation, with reported acute/sub-acute effects involving a pronounced psychoactive component (altered state of consciousness) and physiological response (emesis, intoxication, Spanish: “mareación”). A skilled tabaquero that knows how to diagnose, dose, administer, and intervene in case of adverse effects was described as imperative for safe treatment delivery; tobacco ingestion otherwise may be dangerous. The main indications mentioned by the informant included problems of the mind, of the respiratory system, parasitic illnesses (intestinal/skin), gout, and Amazonian epistemic conditions described as spiritual-energetic in nature.”

So, maybe that’s the main message here – unmodified tobacco may be indeed a highly beneficial natural remedy, with the benefits present mostly in using the plant through means that do not produce carcinogenic byproducts (e.g. smoking). However, even when smoked it seems that tobacco may still be a good “doctor” (see medical student with UC story above), despite doctors uniformly condemning tobacco/smoking as one of the biggest evils of the modern lifestyle. I wonder how many of the harms of even smoking are due not so much to the undeniably carcinogenic smoke, but to the toxic additives present in the vast majority of commercially sold cigarettes/cigars. The toxic ammonia and the carcinogenic flame retardants that are now mandated in commercial tobacco products by law may very well turn out to be a much bigger villain than the humble leaf from Amazonia.

Via: http://haidut.me/?p=2702

The topic of endotoxin/LPS, 5-HT and gut dysbiosis is a recurring one in the bioenergetic sphere and there is hardly a chronic (and acute – i.e. flu, COVID-19) disease that has not been at least partially linked to our gut bacteria overproducing endotoxin, which then acts on the gut lining – enterochromaffin cells (EC) – to trigger 5-HT, histamine and nitric oxide (NO) production, leading to GI and subsequently systemic inflammation and diseases. As such, keeping the gut bacteria (microbiome) under control with antibiotics, insoluble fiber, charcoal, etc is one of the main mechanisms for improving health in the bioenergetic sphere. Another important aspect in the bionergetic view is that one should consume foods that are easily digestible so that they are absorbs easily and early in the GI tract (stomach and upper small intestine) and do not reach the colon where they would feed the microbiome. There is also a focus on not consuming substances that physically or chemically irritate the intestine (e.g. silica, talc, titanium dioxide, gums, vegetable rennet, etc) since irritation (even without presence of food) would also trigger the same serotonin-histamine-NO-inflammation cascade.

Well, the study below demonstrates why keeping the microbiome in check may be a top priority. It shows that human gut bacteria, at least in babies, produces very high amounts of 5-HT independently of the EC in the gut. In fact, about half of the bacterial species contained in the microbiome (both animal and human) apparently produce 5-HT on their own. That bacterial-derived 5-HT has the role of an immunosuppressant for the baby to dampen allergic reactions. Aside from elucidating an additional major source of 5-HT int the human organism, the study also suggests that “exogenous” serotonin is also bioactive, which is something most doctors still refuse to believe. Namely, medicine has focused mostly on the 5-HT produced by the EC in the gut since they claim that mostly such 5-HT enters the circulation and is of systemic importance. Since the externally (bacterially) produced 5-HT in this study most certainly produced systemic (immune) effects, I think it is pretty clear that exogenous 5-HT matters. That corroborates Ray’s views that one should be careful when consuming foods naturally high in 5-HT such as kiwis, dates, and (unripe) bananas.

https://www.science.org/doi/10.1126/sciimmunol.adj4775

https://www.the-scientist.com/gut-serotonin-curbs-the-developing-immune-system-72265

“…The infant gut is packed with a medley of molecules that dictate development during a critical time in a newborns’ life. But how these molecules interact with and influence immune cells early in life isn’t fully understood. Now, in a study published in Science Signaling, a team of scientists revealed how one molecule produced in the gut, the neurotransmitter serotonin, activates a subset of T cells and dampens the immune system.1 The authors linked gut-derived serotonin to the creation of tolerance against allergens, suggesting that the pathway may play a role in the development of conditions such as asthma and food allergies.”

“…However, when Zeng and her team profiled the metabolites in the gut of neonatal mice, they found that the neonatal intestine had an unexpectedly high amount of the neurotransmitter serotonin. But the serotonin was not coming from the enterochromaffin cells, the cells that produce serotonin in adults, but rather from the gut’s resident bacteria. When they isolated bacteria from both neonatal mice and healthy human infants they found that around half of the microbes in their samples produced serotonin.”

Via: http://haidut.me/?p=2700

The study is very new so I can’t get access to its full contents yet, but I wanted to post about it ASAP as it is one of the first studies in a major journal that specifically targets cancer’s redox nature – i.e. “cancer” cells are in a highly reduced state and administering pro-oxidant therapy (i.e. oxidizing agents or NAD+ precursors) is likely to be therapeutic. As my readers know quite well, quinone molecules are some of the most widely used for basic research and redox modulation, and the naphthoquinone family has been studied extensively specifically for cancer. Vitamin K and its analogs are napththoquinones that have been getting a lot of attention lately, culminating in the FDA approval of a cancer drug called Apatone (combination of vitamin K3 and vitamin C), which works exclusively through redox/metabolic mechanisms. Well, the study below used just vitamin K3 specifically for its pro-oxidant effects and found that it greatly diminished prostate cancer growth. The mechanism of action was generic (i.e. redox state) and applicable to every cell, healthy or “cancerous” alike. The study had an in-vivo component, and since most prostate cancer mouse models are done with xenograft models (human tumor hosted by another organism), the findings of study suggests that the effects of vitamin K(3) are relevant for human cancer. Since I cannot get access to the full study, I don’t know what dose they used and for how long the administration lasted. However, most human studies with the closely-related vitamin K2 (MK-4) typically use 30mg-45mg for cancer, and there are already highly promising human cancer trials with vitamin K2 (MK-4). In fact, the rumor is that vitamin K2 (MK-4) may soon be approved as a prescription drug for preventing/treating liver cancer, as well as various blood cancers (leukemias, lymphomas, etc). So, it looks like medicine is finally waking up from its “slumber” and recognizing that metabolism and redox state sit at the very core of “cancer” and should be primary targets for its treatment.

https://pubmed.ncbi.nlm.nih.gov/39446948/

“…In this work, we show that a pro-oxidant vitamin K precursor [menadione sodium bisulfite (MSB)] suppresses PC progression in mice, killing cells through an oxidative cell death: MSB antagonizes the essential class III phosphatidylinositol (PI) 3-kinase VPS34-the regulator of endosome identity and sorting-through oxidation of key cysteines, pointing to a redox checkpoint in sorting. Testing MSB in a myotubular myopathy model that is driven by loss of MTM1-the phosphatase antagonist of VPS34-we show that dietary MSB improved muscle histology and function and extended life span. These findings enhance our understanding of pro-oxidant selectivity and show how definition of the pathways they impinge on can give rise to unexpected therapeutic opportunities.”

https://medicalxpress.com/news/2024-10-vitamin-supplement-prostate-cancer-mice.html

“…Prostate cancer is a quiet killer. In most men, it’s treatable. However, in some cases, it resists all known therapies and turns extremely deadly. Published in the journal Science, a new discovery at Cold Spring Harbor Laboratory (CSHL) points to a potentially groundbreaking solution. CSHL Professor Lloyd Trotman’s lab has found that the pro-oxidant supplement menadione (vitamin K3) slows prostate cancer progression in mice. The supplement is a precursor to vitamin K, commonly found in leafy greens. The story begins more than two decades ago.”

Via: http://haidut.me/?p=2698

As many of my readers know, the medical industry has been quietly increasing its interest in and clinical trials with so-called “neurosteroids”, most of them members of the pregnane family. I think the term “neurosteroid” as used by mainstream medicine is a misnomer as it is used selectively for only a few of all the known steroids, despite the fact that virtually all of them have been demonstrated to have a central (brain) effect. For example, currently the label “neurosteroid” is applied almost exclusively to steroids such as pregnenolone, progesterone, allopregnanolone and various of their synthetic derivatives, though steroid families such as estrogens, androgens, mineralo/gluco-corticoids, and even thyroid hormones have all been demonstrated to have potent and rapid central effects as well, with indisputable influence on mood, cognition, various neurological conditions, traumas (e.g. TBI) and even cancer.

Recently, the FDA approved the progesterone derivative allopregnanolone (3α, 5α-tetrahydroprogesterone), commonly known as Allo or AlloP, as a treatment for post-partum depression. In addition, multiple companies are running clinical trials with that steroid for wide range of other conditions including dementia (e.g. Alzheimer Disease), anxiety disorders, autism, psychotic states (e.g. schizophrenia), post-traumatic stress disorder (PTSD), and even direct brain damage states such as traumatic brain injury (TBI) as well as its chronic form known as chronic traumatic encephalopathy (CTE). As of now, the only condition for which AlloP has been approved is postpartum depression with expectations that the steroid will soon be also approved for depression of any origin. The currently approved formulation is through IV infusion, but some of the new formulations currently being tested are meant for oral use, and use a preparation very close to the ideas of Dr. Peat for using long-chain fats and vitamin E to circumvent first-pass metabolism of any steroid and ensure most of the steroid gets absorbed through the lymphatic system. As such, selling AlloP has become very legally risky.

Interestingly enough, the first commercial antidepressant of the SSRI class known as fluoxetine (Prozac) was found to increase the activity and expression of an enzyme called 3α-hydroxysteroid dehydrogenase (3α-HSD), which is one of the major steps in synthesizing allopregnanolone from progesterone.

https://www.ucsf.edu/news/1999/11/97489/scientists-identify-new-pathway-antidepressant-action

https://www.pnas.org/doi/10.1073/pnas.96.23.13512

Since levels of allopregnanolone have been consistently found to increase after fluoxetine administration, and allopregnanolone levels were found to be universally low in people with depression (as well as many other brain/mood conditions) the hypothesis was that it was allopregnanolone that was the true antidepressant, with fluoxetine functioning only as a trigger for the synthesis of that “neurosteroid”.

https://pubmed.ncbi.nlm.nih.gov/37746458/

However, this hypothesis is incomplete since fluoxetine was found to increase activity and expression of mostly 3α-HSD, and while this MAY results in higher allopregnanolone levels it does not guarantee it, since the cascade has to also pass through the enzyme 5α-reductase (5-AR) in order to synthesize allopregnanolone. In fact, the steps of allopregnanolone synthesis are as follows: progesterone -> 5α-dihydroprogesterone (5-AR activity) -> allopregnanolone (3α-reductase activity). If fluoxetine selectively increases the activity of only 3α-HSD, then the only thing that can be said for sure is that fluoxetine would increase the levels of a steroid that takes progesterone as input and produces a 3α-reduced steroid, which is a steroid with a hydroxyl group (OH) on position C-3, in the alpha configuration. Once progesterone goes through 3α-HSD, and produces a C-3-ol steroid, the reaction terminates there, since that output steroid cannot undergo processing by 5-AR, as the latter can only accept as input steroids with a keto group on C-3 (progesterone, testosterone, cortisol, etc). However, since the enzyme 3α-HSD is bi-directional (oxido-reductase), the end steroid output may get converted back to progesterone. The output of the progesterone being processed by 3α-HSD is the steroid 3α-Dihydroprogesterone (3α-DHP), and if fluoxetine works primarily by increasing 3α-HSD activity and levels, then a more appropriate hypothesis would be that the anti-depressant and anti-anxiety effects of fluoxetine may be due more to the increased levels of 3α-DHP, and not so much on the increased levels of allopregnanolone.

https://en.wikipedia.org/wiki/3%CE%B1-Dihydroprogesterone

Interestingly enough, 3α-DHP has been found to have the same affinity and strength as a GABA agonist as allopregnanolone, and the latter is known as the most potent endogenous GABA agonist agent. As such, multiple studies have demonstrated that 3α-DHP has similar anxiolytic, sedative and analgesic effects as allopregnanolone. In addition, levels of 3α-DHP have been found to be low in many conditions where allopregnanolone levels have also been found to be low.

“…3α-Dihydroprogesterone (3α-DHP), also known as 3α-hydroxyprogesterone, as well as pregn-4-en-3α-ol-20-one, is an endogenous neurosteroid.[1] It is biosynthesized by 3α-hydroxysteroid dehydrogenase from progesterone.[1] 3α-DHP has been found to act as a positive allosteric modulator of the GABAA receptor and is described as being as active as allopregnanolone in regard to this action.[1] In accordance, it has anxiolytic effects in animals.[2] 3α-DHP has also been found to inhibit the secretion of follicle-stimulating hormone (FSH) from the rat pituitary gland, demonstrating possible antigonadotropic properties.[1] Unlike the case of most other inhibitory neurosteroids, 3α-DHP production is not blocked by 5α-reductase inhibitors like finasteride.[1] No data were available on the progestogenic activity of 3α-DHP as of 1977.[3] Levels of 5α-DHP have been quantified.[4]”

Strong GABA agonists are known to have a cortisol-lowering effects and there are several published case reports showing successful treatment of Cushing disease/syndrome in some people using the anti-anxiety benzodiazepine drugs (also GABA agonists, but more selective). Being the strongest endogenous GABA agonist, allopregnanolone has also been demonstrated to have cortisol-lowering effects in humans.

https://pubmed.ncbi.nlm.nih.gov/20158297

https://pubmed.ncbi.nlm.nih.gov/8946427/

https://pubmed.ncbi.nlm.nih.gov/36139100

Cortisol is a proven causal factor in depression, confirmed by multiple studies demonstrating rapid antidepressant effects of glucocorticoid antagonists (e.g. Mifepristone/RU486) in both animals and humans, as well as by rapid depressive effects caused by synthetic (e.g. dexamethasone) and natural (e.g. cortisol) glucocorticoid agonists. Since allopregnanolone has been shown to lower cortisol in humans that may explain most of its anti-depressant effects, as well as its anxiolytic effects.

https://www.newscientist.com/article/dn9516-abortion-drug-could-rapidly-treat-depression/

https://med.stanford.edu/news/all-news/2002/08/stanford-researchers-study-controversial-drug-as-treatment-for-psychotic-major-depression.html

https://doi.org/10.1016/j.steroids.2022.109058

https://link.springer.com/article/10.1134/S2079059717010142

https://pubmed.ncbi.nlm.nih.gov/34071053

As the Wiki article above states, 3α-DHP is as effective as allopregnanolone in terms of GABA activity, and likely has the same mental/physiological effects. Also, unlike allopregnanolone, 3α-DHP is not affected by administration of 5-AR inhibitor drugs such as finasteride, and is not currently regulated by medical authorities (e.g. FDA) in the US or other any other of the 30+ countries I was able to check.

https://pubmed.ncbi.nlm.nih.gov/7914815/

“…The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to an aversive, anxiety-inducing, predator (cat) odor were examined in an odor preference test. Control untreated mice displayed an anxiogenic response to the cat odor, spending a minimal amount of time in a Y-maze in the vicinity of the cat odor. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP had an anxiolytic action, resulting in significant dose-related (0.01-1.0 micrograms) increases in the amount of time spent in the proximity of the cat odor. These anxiolytic effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP) having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the response to cat odor indicating that the anxiolytic actions of 3 alpha HP were unlikely to be related to any analgesic effects. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results indicate that the allylic neurosteroid 3 alpha HP has anxiolytic actions involving interactions with the GABAA receptor.”

https://pubmed.ncbi.nlm.nih.gov/9870343/

“…Here we show that brief exposure of male mice to an ELF magnetic field (30 min, 60 Hz, 141 microT peak) significantly reduces the analgesic effects arising from intracerebroventricular (i.c.v.) administration of the centrally produced allylic neuroactive steroid, 3alpha-hydroxy-4-pregnen-20-one (3alphaHP) and that the dihydropyridine (DHP) calcium channel antagonists, diltiazem and nifedipine, block the inhibitory effects of the 60 Hz ELF on 3alphaHP-induced analgesia. These results indicate that exposure to 60 Hz ELF affects the analgesic effects of neuroactive steroids such as 3alphaHP through alterations in calcium channel function. These findings raise the possibility that ELF magnetic fields may, in part, exert their actions through effects on diverse neuroactive steroid modulated processes.”

https://pubmed.ncbi.nlm.nih.gov/3147122/

“…This allylic steroid elicited significant, dose-dependent (0.001-1.0 micrograms) analgesic responses for 90-150 min after injection. These analgesic effects of 3A4P were stereospecific, the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3B4P) failing to affect the nociceptive responses. The analgesic effects of 3A4P were blocked by peripheral administrations of the GABA antagonists, bicuculline and picrotoxin, and reduced by the benzodiazepine antagonist, Ro 15-1788. The exogenous opiate antagonist, naloxone, and the putative endogenous opioid antagonist, Tyr-MIF-1 (Pro-Leu-Gly-amide), also reduced 3A4P-induced analgesia, while i.c.v. administration of 3A4P (0.001 and 0.01 micrograms) itself attenuated the analgesic effects arising from peripheral administrations of opiate receptor agonist, morphine. In addition, the calcium channel antagonists, nifedipine and verapamil, enhanced 3A4P-induced analgesia but had no evident effects on the actions of 3B4P. These results suggest that the central analgesic effects of the FSH-suppressing steroid, 3A4P, arise via benzodiazepine–GABA–opiate mechanisms and calcium channels.”

The interesting properties of 3α-DHP are not exhausted by its close mimicry/overlap with allopregnanolone. The studies below suggest that it has a number of other interesting effects, at least in animals, include unique anti-cancer effects NOT shared by allopregnanolone. Since one of the tumor cell lines used in many of those cancer studies was the estrogen-sensitive (ER+) line known as MCF-7, a reasonable conclusion may be that 3α-DHP has anti-estrogenic effects, not shared by its cousin allopregnanolone, as other estrogen antagonists have also showed anti-cancer effects in MCF-7 models. For the record, 3α-DHP also demonstrated inhibitory effects on tumor growth from estrogen- and progesterone-negative cell likes, which suggests its effects are generic/systemic and not only focused on a specific steroid pathway.

https://pubmed.ncbi.nlm.nih.gov/25927181/

“…Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.”

https://pubmed.ncbi.nlm.nih.gov/19931389/

“…The studies were conducted on tumorigenic (MCF-7, MDA-MB-231, T47D) and non-tumorigenic (MCF-10A) human breast cell lines, employing several methods to assess the effects of the hormones on cell proliferation, mitosis, apoptosis and expression of Bcl-2, Bax and p21. In all four cell lines, 5alphaP increased, whereas 3alphaHP decreased cell numbers, [(3)H]thymidine uptake and mitotic index. Apoptosis was stimulated by 3alphaHP and suppressed by 5alphaP. 5alphaP resulted in increases in Bcl-2/Bax ratio, indicating decreased apoptosis; 3alphaHP resulted in decreases in Bcl-2/Bax ratio, indicating increased apoptosis. The effects of either 3alphaHP or 5alphaP on cell numbers, [(3)H]thymidine uptake, mitosis, apoptosis, and Bcl-2/Bax ratio, were abrogated when cells were treated simultaneously with both hormones. The expression of p21 was increased by 3alphaHP, and was unaffected by 5alphaP. The results provide the first evidence that 5alphaP stimulates mitosis and suppresses apoptosis, whereas 3alphaHP inhibits mitosis and stimulates apoptosis. The opposing effects of 5alphaP and 3alphaHP were observed in all four breast cell lines examined and the data suggest that all breast cancers (estrogen-responsive and unresponsive) might be suppressed by blocking 5alphaP formation and/or increasing 3alphaHP. ”

https://pubmed.ncbi.nlm.nih.gov/15212687

“…Recent evidence suggests that progesterone metabolites play important roles in regulating breast cancer. Previous studies have shown that tumorous tissues have higher 5α-reductase (5αR) and lower 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO activities. The resulting higher levels of 5α-reduced progesterone metabolites such as 5α-pregnane-3,20-dione (5αP) in tumorous tissue promote cell proliferation and detachment, whereas the 4-pregnene metabolites, 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αDHP), more prominent in normal tissue, have the opposite (anti-cancer-like) effects. The aim of this study was to determine if the differences in enzyme activities between tumorous and nontumorous breast tissues are associated with differences in progesterone metabolizing enzyme gene expression.”

“…The study shows changes in progesterone metabolizing enzyme gene expression in human breast carcinoma. Expression of SRD5A1 (5αR1) and SRD5A2 (5αR2) is elevated, and expression of AKR1C1 (20α-HSO), AKR1C2 (3α-HSO3) and AKR1C3 (3α-HSO2) is reduced in tumorous as compared to normal breast tissue. The changes in progesterone metabolizing enzyme expression levels help to explain the increases in mitogen/metastasis inducing 5αP and decreases in mitogen/metastasis inhibiting 3αHP progesterone metabolites found in breast tumor tissues. Understanding what causes these changes in expression could help in designing protocols to prevent or reverse the changes in progesterone metabolism associated with breast cancer.”

Furthermore, another study demonstrated striking spermatogenic effects of 3α-DHP, which were much stronger than the spermatogenic effects of testosterone. However, unlike testosterone, DHT and other related steroids, 3α-DHP did not display androgenic effects. Assuming allopregnanolone has similar effects, I would not be surprised if we soon see clinical trials for allopregnanolone (and/or, God forbid, 3α-DHP) as treatments for infertility, especially considering the skyrocketing rates of this issue in most Western/developed countries.

https://pubmed.ncbi.nlm.nih.gov/2502196/

“…The effect of 3 alpha-hydroxy-4-pregnen-3-one (3HP), a Sertoli cell steroid, on spermatogenesis was examined in normal and gonadotropin-suppressed rats, through s.c. as well as direct intratesticular injections. Early experiments employing normal prepubertal male rats indicated that 3HP, when administered at 65 micrograms/100 g BW daily for 15 days, was capable of stimulating pachytene spermatocyte number to 149% of untreated control numbers. It was of interest to determine if this effect could be amplified in gonadotropin-suppressed animals. Neonatally estrogenized rats (500 micrograms estradiol benzoate in 0.1 ml oil at 2 days) were treated on alternate days with 3HP (100 micrograms/100 g BW) for 3 wk, starting at 7 days of age. This treatment significantly increased the number of spermatocytes per tubule cross section from 17.3 +/- 1.9 (in estradiol benzoate-only animals) to 47.1 +/- 7.9 (p less than 0.01). In a similar study, 100 micrograms/100 g BW of testosterone propionate could stimulate spermatocyte number to only 15.1 +/- 2.2 cells per tubule cross section versus estradiol benzoate-only numbers. A single intratesticular injection of 3HP (2 ng in 2.0 microliters oil) in Methallibure-treated rats resulted in a significant increase in late pachytene spermatocyte numbers from 0.77 +/- 0.12 in Methallibure-only-treated rats to 1.70 +/- 0.10 (p less than 0.001) cells per tubule cross section in 28-day-old rats. However, in this study, no other progesterone metabolite or androgenic steroid (testosterone, 5 alpha-dihydrotestosterone, or 5 alpha-androstan-3 alpha, 17 beta-diol) tested was capable of this level of germ cell stimulation. In conclusion, 3HP appears to have a direct effect on germ cell development within the testis at levels much lower than those shown to be effective for androgens. It does not appear that this effect is mediated through the conversion of 3HP to any C21 or C19 steroids, and appears to be the first report of a Sertoli cell steroid with a possible role in the process of mammalian spermatogenesis.”

https://pubmed.ncbi.nlm.nih.gov/3106016/

“…Treatment of young (15-day-old) intact males with either 3-HP or 17 beta-hydroxy-5 alpha-androstan-3-one (DHT) for 14 days showed that DHT resulted in significant increases in prostate and seminal vesicle weights, while 3-HP showed no apparent androgenic activity. ”

Finally, 3α-DHP seems to have pro-sexual effects (at least in males) as it increased the preference of treated males for the odor of estrous females. While the study discusses GABA agonism by 3α-DHP as the main mechanism in achieving this pro-sexual effects, I suspect there is more at play since the administered GABA abtagonists did not completely block the effect. In my opinion, given the similar structure between 3α-DHP and allopregnanolone, the pro-dopamine and anti-serotonin (5-HT3 blocker) effects of the latter are likely to both be present in the former, and both of those pathways have a known pro-libido and performance enhancing effects.

https://pubmed.ncbi.nlm.nih.gov/8055331/

“…The effects of the centrally produced allylic neurosteroid, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP), on the responses of male mice to the odors of estrous female mice were examined in an odor preference test. Control untreated mice displayed a significant preference for the odors of an estrous female, spending more time in a Y-maze in the vicinity of the odors of an estrous than a non-estrous female. Intracerebroventricular (i.c.v.) administrations of 3 alpha HP enhanced male preference for the odors of estrous females, causing a significant dose-related (0.01-1.0 microgram) increase in the amount of time spent in the proximity of the odors of the estrous female, while having no significant effect on the responses to the non-estrous female odors. These effects of 3 alpha HP were stereospecific, with the stereoisomer, 3 beta-hydroxy-4-pregnen-20-one (3 beta HP), having no significant effects on odor preferences. The analgesic, morphine, also had no significant effects on the responses to female odors suggesting that the enhanced preference for estrous female odors were unlikely to be directly due to any analgesic effects of 3 alpha HP. The effects of 3 alpha HP were significantly reduced by peripheral administrations of the GABAA antagonists, bicuculline and picrotoxin, but were unaffected by either the benzodiazepine antagonist, Ro 15-1788, or the opiate antagonist, naloxone. These results suggest that the neurosteroid 3 alpha HP has facilitatory effects on olfactory mediated male sexual interest or motivation that involve interactions with the GABAA receptor.”

All in all, quite an interesting substance, and given its non-regulated nature we decided to release it as a product to the general public.

The units listed on the label are just for measurement purposes. They do not indicate or suggest optimal dose. Please note that similar to the liquid products sold by companies like Sigma Aldrich, Spectrum Chemical, Alfa Aesar, etc, this product if for lab/research use only.

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3α-DHP is a liquid (very viscous) product containing a bioidentical endogenous neurosteroid known as 3α-dihydroprogesterone (3α-DHP). While that steroid has not been as extensively studied as the closely-related neurosteroid allopregnanolone, 3α-DHP can perhaps be best described as an allopregnanolone mimetic, with similar (though not identical) pharmacological profile and strength (especially on the GABA system). Some of the more unique and interesting properties of 3α-DHP include its anti-cancer effects demonstrated in animal studies, with the notable finding that those anti-cancer effects are NOT shared by neither allopregnanolone nor its precursor neurosteroid 5α-dihydroprogesterone (5α-DHP). In addition, 3α-DHP has demonstrated potent spermatogenic and pro-sexual effects in some animal studies, with the former fax exceeding the effects of any other known and tested steroid (e.g. androgens).

Drops per container: about 250
Each drop contains the following ingredients:

3α-dihydroprogesterone (CAS 25680-68-6): 1mg

Other ingredients: add product to shopping cart to see info
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REFERENCES:

https://pubmed.ncbi.nlm.nih.gov/11606426/

https://pubmed.ncbi.nlm.nih.gov/9295205/

https://pubmed.ncbi.nlm.nih.gov/8199276/

https://pubmed.ncbi.nlm.nih.gov/8275952/

https://pubmed.ncbi.nlm.nih.gov/1331405/

https://pubmed.ncbi.nlm.nih.gov/2031864/

https://pubmed.ncbi.nlm.nih.gov/2500330/

Via: http://haidut.me/?p=2691

Yet another study that will surely earn me even more hate from the vitamin A antagonist crowd:-) Yet, the findings of the study below are quite clear. Namely, retinoic acid receptor (RAR) agonists, of which retinoic acid is the primary endogenous one, may both prevent and treat a number of progressive and often lethal neurological conditions against which there is currently not only no cure, but there is also no effective “symptom management therapy” either. Perhaps the most dreaded example is amyotrophic lateral sclerosis (ALS), which is not only invariably lethal within 3-5 years of diagnosis but has seen its rates climb sharply in the last several decades. The study used the so-called “superagonist” of RAR known as ellorarxine, but as the study states all the findings apply equally well to vitamin A, but probably at higher than physiological doses. The mechanism of action of the drug was opined to be related to its ability to decrease systemic inflammation, as ascertained by biomarkers such as interleukins, TNF-a, NF-kB, etc. Interestingly, the patent on the drug (link above) also states that the pharma company developing the drug thinks it would be effective for psychiatric conditions as well, including schizophrenia. Btw, one notable study finding was that despite using a “superagonist” of RAR on mice and rats, the study did not observe any toxicity. So, if a super-potent vitamin A analog did not cause toxicity, maybe vitamin A is not quite the villain some people have presented it to be.

https://doi.org/10.3389/fnins.2024.1422294

https://medicalxpress.com/news/2024-09-super-vitamin-motor-neuron-disease.html

“…New research from the University of Aberdeen published today in Frontiers in Neuroscience, found, for the first time, that drugs that target the specific receptors necessary to activate vitamin A may be therapeutic for diseases that lead to deterioration of the brain. Specifically, when disease conditions were simulated in the laboratory, the team found that super-activation of the vitamin A signaling system helped protect against the type of damage that can occur in diseases such as MND. Professor Peter McCaffery, Chair in Medical Sciences at the University of Aberdeen, who led the study, explains, “We discovered that these drugs bind and turn on the ‘retinoic acid receptor,’ a key protein involved in activation of vitamin A in the body.” Azita Kouchmeshky, neuroscientist at the University of California, San Francisco, and first author, said, “We tested these drugs in a series of studies on neurons grown in a dish. Chemicals were added to the neurons that caused harm similar to the changes that occur in diseases such as MND or ALS. “Usually, these chemicals will cause the neurons to die. However, the application of the drugs that bind to the retinoic acid receptor significantly reduced the number of cells that died off. “The same drugs were also tested in mice and were found to induce changes that suggest they may also be effective in the body.”

Via: http://haidut.me/?p=2689

As my readers know from prior posts, Big Pharma has spared no resource in its quest to convince the public that taking aspirin is at least as dangerous as playing a Russian roulette. One of the most commonly cited (and fear-inducing) reasons doctors give to patients against using aspirin regular is the bleeding risk that allegedly aspirin increases. Multiple studies have come out in the last 10-15 years showing that the alleged risk has been dramatically overblown and does not correspond to the available data. In addition, several studied demonstrates that aspirin can reduce the risk of dying from a major bleeding event in the GI tract or brain. Those bleeding risks in GI tract and brain are even listed on aspirin products as official warnings by the FDA. The study below is perhaps the first to show that aspirin not only reduces risk of dying from a bleeding event, but actually reduces the risk of bleeding itself. At least when it comes to the brain, that is, which also happens to be the more feared bleeding risk type given the difficulty of controlling a bleeding event in the brain (as opposed to the GI tract). In addition, the hospitalized (cancer) patients taking aspirin had (juts like in the prior aspirin studies mentioned above) lower mortality, lower rate of strokes, shorter hospital stays and were easier to stabilize/treat. It looks like the study came dangerously close to showing that aspirin may cure the cancer of those patients as well, but given the low dosage such an outcome was not expected.

I would not be surprised if soon we see studies, which found that aspirin reduces risk of GI bleeding as well, and does not cause GI ulcerations, as currently claimed. But it looks like such studies may not be needed, as another recent study found that a majority of people over 50 take aspirin regularly despite their doctor’s advice (actually, orders would be a more appropriate word). As the former editor of the esteemed BMJ said – until serious evidence to the contrary is available, one should assume every public health warning/policy is fraudulent, as it is likely based on openly fraudulent research. The story of aspirin’s fear-porn  is perhaps one of the best examples of that.

https://www.mdedge.com/hematology-oncology/article/270699/all/could-aspirin-avert-bad-outcomes-leukemia

“…A new analysis hints that there may be a benefit from aspirin for hospitalized patients with leukemia. In a preliminary study, researchers found that aspirin users had much lower odds of intracranial bleeding, deep vein thrombosis, in-hospital mortality, and septic stroke. Aspirin users also spent less time in the hospital and had less costly care.  No one is suggesting that clinicians give aspirin to hospitalized patients with leukemia when the drug is not otherwise indicated. However, the findings, released at the Society of Hematologic Oncology (SOHO 2024) meeting in Houston, do indicate that more research is warranted, study lead author Jayalekshmi Jayakumar, MD, of the Brooklyn Hospital Center in New York City, said in a presentation.”

Via: http://haidut.me/?p=2687

A very interesting study, which is bound to be labelled as “controversial” and my post about it will probably get censored on Twitter/X and other social media if/when it gets shared there. Given that the mechanism of action reported by the study (dopamine enhancement) is so generic, the findings of the study possibly apply to other respiratory viral infections (URTI) too, which should not only make P5 a candidate for treating influenza, cold, and the rest of the viruses responsible for URTI, but may obviate the need for vaccines against those viruses if P5 intake is regular (as it is for most people who use it). Years ago, I posted about studies showing that cholesterol and progesterone also have protective effects in severe influenza infections, which suggests that one of the reasons for ever-increasing magnitude and severity of viral pandemics may be due to the widespread use of statins, as well as hormonal birth control in women. The reason I mention birth control is that despite most hormonal contraceptives containing synthetic progestins , most of those progestins have been found to behave nothing like bioidentical progesterone (which is very rarely used clinically) and (many/most) are in fact potent agonists of the estrogen receptor(s).

https://pubmed.ncbi.nlm.nih.gov/39201608

“…n the post-COVID-19 era, treatment options for potential SARS-CoV-2 outbreaks remain limited. An increased incidence of central nervous system (CNS) disorders has been observed in long-term COVID-19 patients. Understanding the shared molecular mechanisms between these conditions may provide new insights for developing effective therapies. This study developed an integrative drug-repurposing framework for COVID-19, leveraging comorbidity data with CNS disorders, network-based modular analysis, and dynamic perturbation analysis to identify potential drug targets and candidates against SARS-CoV-2. We constructed a comorbidity network based on the literature and data collection, including COVID-19-related proteins and genes associated with Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and autism spectrum disorder. Functional module detection and annotation identified a module primarily involved in protein synthesis as a key target module, utilizing connectivity map drug perturbation data. Through the construction of a weighted drug–target network and dynamic network-based drug-repurposing analysis, ubiquitin–carboxy-terminal hydrolase L1 emerged as a potential drug target. Molecular dynamics simulations suggested pregnenolone and BRD-K87426499 as two drug candidates for COVID-19. This study introduces a dynamic-perturbation-network-based drug-repurposing approach to identify COVID-19 drug targets and candidates by incorporating the comorbidity conditions of CNS disorders.”

“…Many candidate drugs have been proposed as repurposable drugs against SARS-CoV-2 infection, such as a group of kinase inhibitors [26,52], estrogen receptor modulators [53], microtubule-regulating agents [54], HCV inhibitors [55], and H1 antihistamines [27]. Notably, several drugs active in the CNS have been identified as repurposable for COVID-19, following SAveRUNNER analysis, such as dopaminergics and dopamine antagonists [56]. Herein, we proposed a series of dopamine-related drugs as potential drugs for COVID-19 treatment, especially pregnenolone and BRD-K87426499. Pregnenolone, as a dopamine release enhancer, is closely linked to the role of UCHL1 in regulating the dopamine system. UCHL1 may affect the function of dopaminergic neurons by participating in the processing of alpha-synuclein and reducing its accumulation, thereby inhibiting the production of alpha-synuclein aggregates in PD. Concurrently, it promotes dopamine release in the SCNS, which can alleviate local and systemic damage to the dopamine system and slow the progression of AD. This drug’s MOA in AD and PD suggests that pregnenolone and BRD-K87426499 may have a similar therapeutic effect in treating COVID-19.”

Via: http://haidut.me/?p=2685