statins, low cholesterol make some people crazy

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"The medications that change who we are" by By Zaria Gorvett, BBC Future,
8th January 2020

The article discusses effects of drugs such as statins, paracetamol, L-dopa or antihistamines on personality disorder and character changes. Particulary interesting are statins side effects since these type of drugs are routinely prescribed with the intention of continous usage.

Quote:

“Patient Five” was in his late 50s when a trip to the doctors changed his life.

He had diabetes, and he had signed up for a study to see if taking a “statin” – a kind of cholesterol-lowering drug – might help. So far, so normal.

But soon after he began the treatment, his wife began to notice a sinister transformation. A previously reasonable man, he became explosively angry and – out of nowhere – developed a tendency for road rage. During one memorable episode, he warned his family to keep away, lest he put them in hospital.

Out of fear of what might happen, Patient Five stopped driving. Even as a passenger, his outbursts often forced his wife to abandon their journeys and turn back. Afterwards, she’d leave him alone to watch TV and calm down. She became increasingly fearful for her own safety.

Then one day, Patient Five had an epiphany. “He was like, ‘Wow, it really seems that these problems started when I enrolled in this study’,” says Beatrice Golomb, who leads a research group at the University of California, San Diego.

... Over the years, Golomb has collected reports from patients across the United States – tales of broken marriages, destroyed careers, and a surprising number of men who have come unnervingly close to murdering their wives. In almost every case, the symptoms began when they started taking statins, then promptly returned to normal when they stopped; one man repeated this cycle five times before he realised what was going on.

Golomb first suspected a connection between statins and personality changes nearly two decades ago, after a series of mysterious discoveries, such as that people with lower cholesterol levels are more likely to die violent deaths. Then one day, she was chatting to a cholesterol expert about the potential link in the hallway at her work, when he brushed it off as obviously nonsense. “And I said ‘how do we know that?’,” she says.

Filled with fresh determination, Golomb scoured the scientific and medical literature for clues. “There was shockingly more evidence than I had imagined,” she says. For one thing, she uncovered findings that if you put primates on a low-cholesterol diet, they become more aggressive.

Golomb remains convinced that lower cholesterol can cause behavioural changes in both men and women
There was even a potential mechanism: lowering the animals’ cholesterol seemed to affect their levels of serotonin, an important brain chemical thought to be involved in regulating mood and social behaviour in animals. Even fruit flies start fighting if you mess up their serotonin levels, but it also has some unpleasant effects in people – studies have linked it to violence, impulsivity, suicide and murder.

If statins were affecting people’s brains, this was likely to be a direct consequence of their ability to lower cholesterol.

Since then, more direct evidence has emerged. Several studies have supported a potential link between irritability and statins, including a randomised controlled trial – the gold-standard of scientific research – that Golomb led, involving more than 1,000 people. It found that the drug increased aggression in post-menopausal women though, oddly, not in men.

In 2018, a study uncovered the same effect in fish. Giving statins to Nile tilapia made them more confrontational and – crucially – altered the levels of serotonin in their brains. This suggests that the mechanism that links cholesterol and violence may have been around for millions of years.

Golomb remains convinced that lower cholesterol, and, by extension, statins, can cause behavioural changes in both men and women, though the strength of the effect varies drastically from person to person. “There are lines of evidence converging,” she says, citing a study she conducted in Sweden, which involved comparing a database of the cholesterol levels of 250,000 people with local crime records. “Even adjusting for confounding factors, it was still the case that people with lower cholesterol at baseline were significantly more likely to be arrested for violent crimes.”.

Reference:

"Cholesterol and violence: is there a connection?", by
Golomb BA., Ann Intern Med. 1998 Mar 15;128(6):478-87.

animal fat is low cardio vascular risk, carbs are high risk

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A 2016 Czech study of 42 European countries

"Food consumption and the actual statistics of cardiovascular diseases: an epidemiological comparison of 42 European countries", by Pavel Grasgruber,* Martin Sebera, Eduard Hrazdira, Sylva Hrebickova, and Jan Cacek; Food Nutr Res. 2016; 60: 10.3402/fnr.v60.31694.

Quote:

The mean consumption of 62 food items from the FAOSTAT database (1993–2008) was compared with the actual statistics of five CVD [CVD=Cardio-Vascular Disease] indicators in 42 European countries. Several other exogenous factors (health expenditure, smoking, body mass index) and the historical stability of results were also examined.
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The most significant dietary correlate of low CVD risk was high total fat and animal protein consumption.

Additional statistical analyses further highlighted citrus fruits, high-fat dairy (cheese) and tree nuts. Among other non-dietary factors, health expenditure showed by far the highest correlation coefficients.

The major correlate of high CVD risk was the proportion of energy from carbohydrates and alcohol, or from potato and cereal carbohydrates. Similar patterns were observed between food consumption and CVD statistics from the period 1980–2000, which shows that these relationships are stable over time.

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Our results do not support the association between CVDs and saturated fat, which is still contained in official dietary guidelines. Instead, they agree with data accumulated from recent studies that link CVD risk with the high glycaemic index/load of carbohydrate-based diets. In the absence of any scientific evidence connecting saturated fat with CVDs, these findings show that current dietary recommendations regarding CVDs should be seriously reconsidered.
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Low cholesterol levels correlate most strongly with the proportion of plant food energy in the diet (r=−0.87, p less than 0.001 in both sexes) and with sources of plant carbohydrates represented by items such as % PC CARB energy (r=−0.87 in men, r=−0.83 in women; p less than 0.001) (Fig. 2), % CA energy (r=−0.85 in men, r=−0.81 in women; p less than 0.001), and cereals (r=−0.74 in men, r=−0.73 in women; p less than 0.001). Smoking correlates quite strongly with lower cholesterol as well, but in men only (r=−0.62, p less than 0.001).

Remarkably, the relationship of raised cholesterol with CVD risk is always negative, especially in the case of total CVD mortality (r=−0.69 in men, r=−0.71 in women; p less than 0.001)

Most interesting is the discussion section at the end of the paper:

Discussion

Raised cholesterol correlates negatively with CVD risk

The results of our study show that animal fat (and especially its combination with animal protein) is a very strong predictor of raised cholesterol levels. This is in accordance with the meta-analyses of clinical trials, which show that saturated animal fat is the major trigger of raised cholesterol (6, 16). Interestingly, the relationship between raised cholesterol and CVD indicators in the present study is always negative. As shown in Figs. 3 and ​and Supplementary Figs. 1 and 2, this finding is visually less persuasive in the case of CVD mortality, where factors such as the quality of healthcare come to the foreground, but it is quite unambiguous in the case of women's raised blood pressure.

The negative relationship between raised cholesterol and CVD may seem counterintuitive, but it is not at variance with the available evidence. The largest of the recent worldwide meta-analyses dealing with cholesterol and CVD risk (17) observed a positive relationship between raised cholesterol and CVD mortality at younger ages, but this association gradually started to reverse in seniors, where the number of deaths is the highest. In fact, the relationship between raised cholesterol and stroke mortality in seniors was slightly negative. Both this study and other studies dealing with blood profiles of patients hospitalised with CVD events (18–22) demonstrate that low HDL (high-density lipoprotein associated) cholesterol (around ~1.0 mmol/L), or high total cholesterol: HDL-cholesterol ratio are the best indicators of CVD risk. Total cholesterol is usually normal or slightly elevated (4.5–5.5 mmol/L), and hence it cannot serve as a predictor of CVD events. Some other authors also point to high plasma triglycerides (which correlate with low HDL-cholesterol levels) (23), or to the ratio between triglycerides and HDL-cholesterol (24) as another useful risk indicators.

In this context it is important to note that saturated fat is not only the key trigger of high total cholesterol, but even high HDL-cholesterol and LDL (low-density lipoprotein associated)-cholesterol (16). Saturated fat also decreases triglyceride levels, but the total cholesterol: HDL-cholesterol ratio remains stable. The main sources of saturated fatty acids are red meat and milk products (whole fat milk, cheese, butter) (see Supplementary Table 1). Therefore, in Europe, where the consumption of animal products is the highest in the world, we can assume a strong connection between total cholesterol and HDL-cholesterol. Understandably, this relationship may not be so strong outside Europe and it may also vary depending on the individual diet. This could explain regional and individual differences in the relationship between total cholesterol and CVD risk.

Although the concurrent increase of LDL-cholesterol levels is often taken out of context and used as an argument against the intake of saturated fats in dietary recommendations (25), saturated fat is primarily tied to the less dense, large LDL particles (26), whereas cardiovascular risk is connected with the denser, small LDL particles (27), which accompany carbohydrate-based diets. There is also no evidence that the reduction of saturated fat intake (on its own) would decrease CVD risk (28). On the other hand, it is true, that so far, there is no clear evidence that saturated fat would be beneficial for the prevention of CVD. The only possible exception among the sources of saturated fat is dairy (29–31).

Major correlates of high CVD risk

Carbohydrates

The results of our study show that high-glycaemic carbohydrates or a high overall proportion of carbohydrates in the diet are the key ecological correlates of CVD risk. These findings strikingly contradict the traditional ‘saturated fat hypothesis’, but in reality, they are compatible with the evidence accumulated from observational studies that points to both high glycaemic index and high glycaemic load (the amount of consumed carbohydrates × their glycaemic index) as important triggers of CVDs (1, 32–34). The highest glycaemic indices (GI) out of all basic food sources can be found in potatoes and cereal products (Supplementary Table 2), which also have one of the highest food insulin indices (FII) that betray their ability to increase insulin levels.

The role of the high glycaemic index/load can be explained by the hypothesis linking CVD risk to inflammation resulting from the excessive spikes of blood glucose (‘post-prandial hyperglycaemia’) (35). Furthermore, multiple clinical trials have demonstrated that when compared with low-carbohydrate diets, a low-fat diet increases plasma triglyceride levels and decreases total cholesterol and HDL-cholesterol, which generally indicates a higher CVD risk (36, 37). Simultaneously, LDL-cholesterol decreases as well and the number of dense, small LDL particles increases at the expense of less dense, large LDL particles, which also indicates increased CVD risk (27). These findings are mirrored even in the present study because cereals and carbohydrates in general emerge as the strongest correlates of low cholesterol levels.

The authors discuss the reason behind the origin of the now discredited cholesterol-heart disease hypothesis prompted by Ancel Keyes' ‘Seven Countries Study’:

Discrepancy in the old statistics: The root of the ‘saturated fat hypothesis’?

The paradoxical results of our historical comparison (men's statistics from 1980 and 1990) have an interesting analogy in the ‘Seven Countries Study’, which stood behind the current ‘saturated fat paradigm’. The authors of this longitudinal ecological research, finished in the early 1980s, concluded that men's CHD [CHD=Coronary Heart Disease] mortality in seven countries correlated positively with high blood pressure, high cholesterol, and high saturated fat intake, but the relationship of high blood pressure and high cholesterol with men's stroke mortality (in 12 cohorts from six countries) was strongly negative (54). Because CHD mortality was the central CVD [CVD=Cardio-Vascular Disease] indicator in this study, we think that the authors did not pay sufficient attention to this discrepancy and they contented themselves with the fact that stroke mortality was positively associated with high blood pressure at the individual level. Ironically, in the following decades, the ecological relationship of CHD with risk factors completely reversed.

...Second, the effect of increased longevity in highly developed countries, after the eradication of serious infectious diseases after World War II, led to a temporary epidemic of CVDs, which also coincided with rapidly improving living standards and the increasing consumption of animal food. Because of the chronic nature of CVDs, this dietary change may have brought health benefits only after several decades and as a result, the relationship of CVD indicators to animal products has reversed with a certain delay (Supplementary Figs. 42–47). In the eastern half of Europe, this phenomenon started to fully manifest only very recently (possibly in combination with heavy alcohol drinking), which led to the increase of CVD rates.

The obvious fallacy of the ‘saturated fat hypothesis’ can be demonstrated by the example of France – a country with the highest intake of animal fat in the world and the second lowest CVD mortality (after Japan) (56). In fact, if we use a limited sample of 24 countries (without the former republics of USSR, Czechoslovakia and Yugoslavia, and Luxembourg), a summary mean of food consumption from the last half-century (1961–2008) produces very similar results like the mean for the period 1993–2008 (Table 4), reaching r=0.82 between % CA [CA=carbohydrates] energy and raised blood pressure in women.

A short summary of the paper can be read in the following article:

New study finds wheat and carbs biggest risk for heart disease, red meat and saturated fat has no direct effect

anti-seizure effect of keto diet mediated by gut bacteria

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Gut bacteria play key role in anti-seizure effects of ketogenic diet
May 24, 2018 , University of California, Los Angeles

Quote:

UCLA scientists have identified specific gut bacteria that play an essential role in the anti-seizure effects of the high-fat, low-carbohydrate ketogenic diet. The study, published today in the journal Cell, is the first to establish a causal link between seizure susceptibility and the gut microbiota—the 100 trillion or so bacteria and other microbes that reside in the human body's intestines.
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In a study of mice as a model to more thoroughly understand epilepsy, the researchers found that the diet substantially altered the gut microbiota in fewer than four days, and mice on the diet had significantly fewer seizures.

To test whether the microbiota is important for protection against seizures, the researchers analyzed the effects of the ketogenic diet on two types of mice: those reared as germ-free in a sterile laboratory environment and mice treated with antibiotics to deplete gut microbes.

"In both cases, we found the ketogenic diet was no longer effective in protecting against seizures," said lead author Christine Olson, a UCLA graduate student in Hsiao's laboratory. "This suggests that the gut microbiota is required for the diet to effectively reduce seizures."

The biologists identified the precise order of organic molecules known as nucleotides from the DNA of gut microbiota to determine which bacteria were present and at what levels after the diet was administered. They identified two types of bacteria that were elevated by the diet and play a key role in providing this protection: Akkermansia muciniphila and Parabacteroides species.

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How do the bacteria do this? "The bacteria increased brain levels of GABA—a neurotransmitter that silences neurons—relative to brain levels of glutamate, a neurotransmitter that activates neurons to fire," said co-author Helen Vuong, a postdoctoral scholar in Hsiao's laboratory.

"This study inspires us to study whether similar roles for gut microbes are seen in people that are on the ketogenic diet," Vuong said.

Reference:


"The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet", Christine A. Olson, Helen E. Vuong, Jessica M. Yano, Qingxing Y. Liang, David J. Nusbaum, and Elaine Y. Hsiao; 2018, Cell 173, 1728–1741