“Helplessness is a state in which nothing a person opts to do affects what is happening. It is the quitting or the give up response that follows the conviction that whatever a person does doesn’t matter.”

— Sivakumar Nuvvula

It is not a characteristic trait or a fixed state. It is a learned response, and like most learned responses, it can be unlearned.

The concept has implications that extend well beyond psychology. It touches on how the brain responds to stress at a biological level, how environment shapes physiology, and what conditions are required for an organism to function at its full capacity. It is also one of the more well-documented phenomena in behavioral science, with a research history stretching back to the 1950s.

This article covers that history, the biology behind it, and one researcher’s broader interpretation of what learned helplessness reveals about stress, the nervous system, and how we live.

The Original Research

The groundwork was laid not by Martin Seligman, who is most commonly associated with the concept, but by Curt Richter, a Johns Hopkins researcher who published a paper in 1957 titled “On the Phenomenon of Sudden Death in Animals and Man.” [1]

Richter wanted to understand why animals sometimes died suddenly under conditions of extreme stress—not from physical injury, but from what appeared to be a kind of psychological collapse. To study this, he placed rats into jars half-filled with water and observed how long they would swim before giving up. Wild rats, despite being physically capable swimmers, died within minutes. Domesticated rats fared somewhat better but still showed rapid deterioration under certain conditions.

The critical finding came when Richter introduced an intervention. Before placing rats in the water, he repeatedly held them briefly and then released them—giving them a direct experience of escape from restraint. Rats that had been through this procedure swam dramatically longer than those that had not. The experience of having once been rescued appeared to eliminate the hopelessness response entirely. As Richter described it, after the elimination of hopelessness, the rats did not die. They became aggressive, continued to struggle, and showed no signs of giving up.

Richter also made an important physiological observation. The hearts of the rats that died quickly slowed down before death and remained relaxed and full of blood—indicating dominant activity of the vagal nerve and the parasympathetic nervous system, rather than the sympathetic fight-or-flight response that would be expected under stress. This was an early indication that the biology of hopelessness was not simply a matter of exhaustion.

A decade later, Martin Seligman at the University of Pennsylvania formalized the concept through a series of controlled experiments with dogs. [2] In the most well-known of these, dogs were divided into three groups. One group received no shocks. A second group received shocks they could stop by pressing a lever. A third group received the same shocks as the second group but had no control over when they stopped. The shock ended only when their paired dog in the second group pressed its lever.

When all three groups were later placed in a shuttle box, a chamber where they could escape shocks by jumping a low barrier, the results were clear. Dogs in the first two groups quickly learned to escape. Most dogs in the third group simply lay down and accepted the shock, making no attempt to escape even though the barrier was easily cleared. They had learned, through prior experience, that their behavior had no effect on outcomes—and that learning transferred to an entirely new situation

Seligman found one reliable cure. Experimenters physically moved the dogs through the motions of escape—picking them up and guiding their legs over the barrier. This had to be done at least twice before the dogs began jumping on their own. Threats, rewards, and demonstrations had no effect. The experience of successful escape had to be physically enacted to break the pattern.

Subsequent research confirmed that the same phenomenon occurs in humans. In one experiment, people performed cognitive tasks while exposed to distracting noise. Those who had access to a switch to turn off the noise performed significantly better than those who did not—even when the switch was never actually used. The mere presence of control was enough to change the outcome.

The Non-Fearful Rat

The image circulating in certain corners of the internet is a satirical but scientifically grounded portrait of the opposite of the helpless rat. It draws directly from the research tradition described above, particularly the enrichment experiments conducted at the University of California starting in 1960, and from Richter’s hopelessness work. [3]

The image attributes to this rat a set of characteristics that, taken together, describe the biological and behavioral profile of an animal that has been raised in a stimulating environment, has had repeated experiences of successful escape, and has developed both the neurological and physiological capacity to resist stress. Among the traits listed: cholinesterase levels at eight times the normal range, hypermetabolic and hypergonadal physiology, perfect memory, explorative and inquisitive behavior, and the ability to inspire similar resilience in other rats simply by being present.

The cholinesterase detail is not arbitrary. The Berkeley enrichment experiments found that rats raised in larger, more complex environments showed increased cholinesterase activity in their brains—the enzyme responsible for breaking down acetylcholine. This was associated with better learning, larger brain mass, and thicker cortical tissue. The offspring of these rats inherited similar advantages. [3] The non-fearful rat, in this framing, is the living product of an enriched environment—the biological inverse of the helpless one.

Ray Peat’s View

Ray Peat, a physiologist and independent researcher who wrote extensively on stress biology until his death in 2022, approached learned helplessness from a direction most mainstream psychology has not explored: the cholinergic nervous system.

Peat’s central argument was that the biological substrate of learned helplessness is an overactivation of the parasympathetic, cholinergic nervous system—the branch of the autonomic nervous system that governs rest, digestion, and repair, and which operates in opposition to the sympathetic fight-or-flight response. Richter’s observation that the hearts of hopeless rats slowed before death—indicating vagal, cholinergic dominance—was central to Peat’s interpretation.

Under normal conditions, the enzyme cholinesterase breaks down acetylcholine, keeping cholinergic activity in check. The Berkeley enrichment experiments showed that a stimulating environment increases cholinesterase activity, which Peat read as evidence that enrichment protects against the accumulation of acetylcholine that characterizes helplessness and stress-induced degeneration. Deprivation, in his view, does the opposite—it reduces cholinesterase activity and allows acetylcholine to accumulate, producing the biological conditions for passivity, cognitive impairment, and ultimately cell death. [4]

Peat drew a further line between the cholinergic system and thyroid function. During the development of learned helplessness, circulating T3 (the active form of thyroid hormone) decreases. [5] Removing the thyroid gland in animal models produces the escape deficit characteristic of learned helplessness. [6] Supplementing with T3 before exposing animals to inescapable shock prevents the development of helplessness, and after it has developed, T3 supplementation reverses it. [7, 8] Peat viewed this as evidence that thyroid function and cholinergic tone are deeply interrelated, and that conditions which suppress thyroid activity (e.g. chronic stress, nutrient deficiency, darkness) are also conditions that increase susceptibility to the helpless state.

“Environmental conditions that are favorable for respiratory energy production are protective against learned helplessness and neurodegeneration.”

— Ray Peat

Progesterone featured prominently in Peat’s framework as well. One of progesterone’s established functions is to increase cholinesterase activity, breaking down acetylcholine in the uterus to prevent premature contraction during pregnancy. Peat argued this function is general, not specific to reproductive tissue. Progesterone has been shown to protect against organophosphate poisoning, which works by inhibiting cholinesterase, and to improve recovery from traumatic brain injury.

Estrogen, by contrast, decreases cholinesterase activity, increasing cholinergic tone. Peat saw this as one of several reasons to view estrogen not as a uniformly beneficial hormone but as one that, in excess, tilts the biological environment toward stress, inflammation, and passivity. [9, 10]

The broader implication of Peat’s framework is that learned helplessness is not purely psychological. It is a physiological state with measurable biological correlates, and one that is influenced by the hormonal and metabolic environment of the organism. An enriched environment, adequate thyroid function, appropriate progesterone levels, and sufficient light exposure all work, in his account, against the conditions that produce helplessness. A depleted environment—one that restricts choice, limits stimulation, and produces chronic low-grade stress—does the opposite.

What This Means

The research on learned helplessness points to something that is both straightforward and underappreciated: the experience of control matters. Not just psychologically, but physiologically. The brain and body respond differently to conditions in which escape is possible than to conditions in which it is not, and repeated exposure to inescapable adverse conditions produces lasting changes in how an organism responds to adversity in general.

The cure, in both the animal models and the human literature, is consistent: a direct experience of successful escape or control. Not reassurance, not observation, but enacted experience. Richter’s rats needed to be rescued. Seligman’s dogs needed to be physically guided through the escape. The pattern breaks when the organism has an unambiguous experience of its own agency.

Peat’s contribution is to situate this in a broader biological context—one in which environment, hormones, metabolism, and the nervous system are all part of the same system, and in which the conditions that produce helplessness are the same conditions that impair thyroid function, suppress cholinesterase, and compromise cellular energy metabolism. On this view, the question of what produces a resilient organism is not separable from the question of what produces a healthy one.

[1] Richter (1957), On the Phenomenon of Sudden Death in Animals and Man

[2] Seligman & Maier (1967), Failure to Escape Traumatic Shock

[3] Krech et al. (1960), Effects of Environmental Complexity and Training on Brain Chemistry

[4] Anisman et al. (1981), Cholinergic Influences on Escape Deficits Produced by Uncontrollable Stress

[5] Helmreich et al. (2006), Peripheral Triiodothyronine Levels During Escapable and Inescapable Footshock

[6] Levine et al. (1990), Thyroparathyroidectomy Produces a Progressive Escape Deficit in Rats

[7] Brochet et al. (1987), Triiodothyronine Potentiation of Antidepressant-Induced Reversal of Learned Helplessness in Rats

[8] Massol et al. (1988), Triiodothyroacetic Acid Potentiation of Antidepressant-Induced Reversal of Learned Helplessness in Rats

[9] Jeyarasasingam et al. (2000), Tacrine, a Reversible Acetylcholinesterase Inhibitor, Induces Myopathy

[10] Franco et al. (2006), Hypothyroid Phenotype is Contributed by Mitochondrial Complex I Inactivation Due to Translocated Neuronal Nitric-Oxide Synthase

Along the way, I have come across a large number of research papers that have surprised me, challenged what I thought I knew, or simply made me think differently about something.

These are the ten that I found most interesting:

1. Testosterone administration reduces lying in men

2. Avoidance of sun exposure is a risk factor for all-cause mortality

3. A wandering mind is an unhappy mind

4. The serotonin theory of depression: a systematic umbrella review of the evidence

5. Minocycline, a microglial inhibitor, reduces ‘honey trap’ risk in human economic exchange

6. Progress on mitochondria and hair follicle development in androgenic alopecia

7. The tenacious brain: how the anterior mid-cingulate contributes to achieving goals

8. Refined carbohydrate consumption and facial attractiveness

9. Meal timing trajectories in older adults and their associations with morbidity, genetic profiles, and mortality

10. Emotional suppression and mortality risk over a 12-year follow-up

For each paper, I have outlined the study design, the primary findings, and what the data actually shows.

1) Testosterone administration reduces lying in men

Type of study: Double-blind, placebo-controlled trial
Sample size: 91 healthy young men
Duration: 2 days
Intervention: 50 mg transdermal testosterone gel vs. placebo
Key finding: Testosterone administration significantly reduced self-serving lying behavior

This study investigated whether testosterone has a causal effect on dishonest behavior in men. Prior research had established correlations between testosterone levels and various social behaviors, but most of that evidence was observational. This paper aimed to establish causation using a controlled experimental design.

91 healthy young men participated in a double-blind, placebo-controlled trial conducted over two consecutive days. On day one, subjects were randomly assigned to receive either 50 mg of Testogel (a transdermal testosterone gel) or a placebo gel applied to the upper right arm. The testosterone was allowed to absorb for 21 to 24 hours before any behavioral tasks were administered. On day two, subjects completed a die-rolling task and a post-experiment questionnaire, after which a blood sample was taken to verify testosterone levels.

The die-rolling task worked as follows. Each subject rolled a six-sided die in private and self-reported the result into a computer. The payout was equal to the number reported in euros for rolls of one through five, and zero euros for a six. Because only the self-reported number was recorded, and not the actual roll, subjects had a clear financial incentive to lie, and no risk of being caught doing so individually. Lying could only be detected at the group level by comparing the distribution of reported outcomes to what a fair die would be expected to produce.

The placebo group reported an average payoff of 4.18 euros. The testosterone group reported an average of 3.33 euros. This difference was statistically significant (p = 0.005). The gap was most pronounced at the highest-value outcome: 62.2% of placebo subjects reported a roll of five, compared to 34.8% of testosterone subjects—a result that was also statistically significant (p = 0.012). Both groups lied more than chance would predict, but the testosterone group lied substantially less.

A correlation analysis across the full sample found that higher testosterone levels were associated with lower reported payoffs (Pearson’s r = −0.22, p = 0.035), meaning the relationship held not just between groups but within the pooled data as well. OLS regressions confirmed the treatment effect was robust after controlling for age, personality variables including the Big Five and Machiavellianism, and economic preference measures including risk tolerance, impulsivity, and reciprocity.

One concern with placebo-controlled hormone studies is that subjects may guess which condition they are in and adjust their behavior accordingly. The researchers addressed this directly. Among the subsample asked, there was no correlation between actual and perceived testosterone administration (p = 0.94), and subjects who believed they had received testosterone did not report higher payoffs than those who believed they had received placebo (p = 0.179). A pure expectation effect is therefore unlikely to explain the results.

The authors propose two main interpretations. The first is that testosterone directly increases prosocial preferences—in this case, honesty. The second is that testosterone heightens status concerns and pride, making dishonest behavior feel dishonorable even when undetectable. This second interpretation is consistent with prior work suggesting testosterone motivates dominance-seeking behavior, which in certain contexts expresses itself as prosocial rather than aggressive conduct. The researchers could not distinguish between these two mechanisms.

2) Avoidance of sun exposure is a risk factor for all-cause mortality

Type of study: Prospective cohort study
Sample size: 29,518 women
Duration: 20 years (1990–2011)
Population: Swedish-born women aged 25–64
Key finding: Avoiding sun exposure was associated with a twofold increase in all-cause mortality

Most public health messaging around sun exposure has focused on its risks—primarily skin cancer, and melanoma in particular. This study took the opposite angle, asking whether avoiding sun exposure carries its own mortality risk. It is one of the few large-scale longitudinal studies to treat sun avoidance as an independent risk factor rather than a protective behavior.

The data came from the Melanoma in Southern Sweden (MISS) cohort, initiated in 1990. Approximately 30,000 Swedish-born women between the ages of 25 and 64 were recruited from the general population registry of South Sweden, representing around 20% of women in those age groups in the region. At enrollment, participants completed a detailed questionnaire covering sun exposure habits, smoking, alcohol consumption, marital status, education level, income, BMI, physical exercise, and number of pregnancies. A follow-up questionnaire was administered between 2000 and 2002. Deaths and cancer diagnoses were tracked through the National Cancer Register, the Cause of Death Register, and the National Population Register up to January 2011.

Sun exposure was assessed using four questions: how often subjects sunbathed in summer, whether they sunbathed during winter holidays, how often they used tanning beds, and whether they traveled abroad to swim and sunbathe. Each question was coded as yes or no, and a composite score from zero to four was created based on the number of affirmative answers. Women who answered no to all four questions were classified as sun avoiders and used as the reference group.

There were 2,545 deaths across 540,577 person-years of follow-up. The relationship between sun exposure and all-cause mortality followed a clear dose-dependent pattern. Compared to women with the highest sun exposure, those who avoided sun entirely had double the mortality rate (HR 2.0, 95% CI 1.6–2.5). Those with moderate exposure had a 40% higher mortality rate (HR 1.4, 95% CI 1.1–1.7). This gradient held after adjusting for age, smoking, education, income, marital status, comorbidity, BMI, and physical exercise.

One of the more striking findings involved the comparison between sun avoiders and smokers. Nonsmokers who avoided sun exposure had a similar life expectancy to smokers with the highest sun exposure. The authors concluded that sun avoidance appeared to carry a mortality risk of comparable magnitude to smoking in terms of life expectancy—a finding with significant public health implications.

Sun exposure did increase the incidence of melanoma. However, women with higher sun exposure who developed melanoma did not have worse survival outcomes. Sun-associated melanomas tended to be thinner and less aggressive, consistent with prior research linking higher vitamin D levels to less aggressive melanoma at diagnosis. The overall case fatality rate among women who developed melanoma was not significantly different between sun exposure groups.

The authors propose several mechanisms through which sun exposure may reduce mortality. Vitamin D synthesis via UVB radiation is the most discussed candidate, given established associations between low vitamin D and cardiovascular disease, cancer, and metabolic dysfunction. UVA radiation has also been shown to increase nitric oxide bioavailability in the skin, which may lower blood pressure and reduce cardiovascular risk. UVB exposure additionally stimulates cutaneous endorphin release, which may have independent physiological effects.

3) A wandering mind is an unhappy mind

Type of study: Experience sampling study via smartphone application
Sample size: 2,250 adults
Population: Adults aged 18–88 from 83 countries
Key finding: Mind wandering occurred in nearly half of all samples and was a stronger predictor of unhappiness than the activity people were engaged in

This study examined the relationship between mind wandering—thinking about something other than what one is currently doing—and emotional wellbeing in everyday life. Prior research on mind wandering had been conducted almost entirely in laboratory settings with small samples, limiting what could be said about its real-world emotional consequences. The authors addressed this by developing an iPhone application that contacted participants at random moments during waking hours and collected real-time reports of thoughts, feelings, and activities.

The application presented three questions at each contact: a happiness question answered on a continuous scale from 0 (very bad) to 100 (very good), an activity question in which participants selected from 22 options adapted from the day reconstruction method, and a mind wandering question asking whether participants were thinking about something other than what they were currently doing. If yes, they indicated whether the content was pleasant, neutral, or unpleasant. The database contained nearly a quarter of a million samples collected from approximately 5,000 people across 83 countries. The analytical sample for this paper consisted of 2,250 adults with a mean age of 34 years.

Three findings emerged.

First, mind wandering was extremely common. It occurred in 46.9% of all samples and in at least 30% of samples during every activity measured except one (making love). The frequency was substantially higher than rates typically observed in laboratory experiments, suggesting that controlled settings underestimate how often the mind actually wanders in daily life. The type of activity had only a modest effect on whether the mind wandered and almost no effect on what it wandered to.

Second, people were consistently less happy when their minds were wandering than when they were not, regardless of what they were doing—including during activities they rated as unenjoyable. This held even when mind wandering was to pleasant topics. People thinking about pleasant things were no happier than people focused on their current activity (b = −0.52, not significant). People thinking about neutral topics were meaningfully unhappier (b = −7.2, p < 0.001), and people thinking about unpleasant topics were considerably unhappier still (b = −23.9, p < 0.001). Time-lag analyses—which examined whether unhappiness preceded mind wandering or followed it—suggested that mind wandering was more often the cause of unhappiness than its consequence, though the authors acknowledge this cannot be established with certainty from observational data.

Third, and perhaps most striking, what people were thinking was a better predictor of their happiness than what they were doing. Activity type explained 4.6% of within-person variance in happiness and 3.2% of between-person variance. Mind wandering explained 10.8% of within-person variance and 17.7% of between-person variance. The two were largely independent of each other, suggesting they operate as separate influences on mood rather than one driving the other.

4) The serotonin theory of depression: a systematic umbrella review of the evidence

Type of study: Systematic umbrella review
Sample size: 17 studies included (studies ranged from n = 75 to n = 115,257)
Population: Adults with depressive disorders
Key finding: No consistent evidence that depression is associated with lower serotonin activity or concentrations

The idea that depression is caused by low serotonin—commonly referred to as the “chemical imbalance” theory—has shaped psychiatric practice and public understanding of depression for decades. SSRIs, the most widely prescribed class of antidepressants, were developed on the basis of this theory. This umbrella review set out to systematically evaluate whether the evidence across all major areas of serotonin research actually supports it.

An umbrella review synthesizes existing systematic reviews and meta-analyses rather than individual studies, placing it among the highest levels of evidence synthesis available. The authors searched PubMed, EMBASE, and PsycINFO through December 2020, identifying 17 eligible studies across six research domains: serotonin and its metabolite 5-HIAA in body fluids, serotonin 5-HT1A receptor binding, serotonin transporter (SERT) levels, tryptophan depletion studies, SERT gene associations, and SERT gene-environment interactions. Two independent reviewers extracted data and assessed study quality using established rating tools. The certainty of evidence in each domain was evaluated using a modified GRADE framework.

The findings across all six domains failed to support the serotonin hypothesis.

On serotonin and its metabolite 5-HIAA: Two meta-analyses covering 19 studies found no association between 5-HIAA concentrations in cerebrospinal fluid and depression. A separate meta-analysis of cohort studies found no significant relationship between plasma serotonin and depression. Notably, antidepressant use was independently associated with lower serotonin levels, raising the possibility that some prior findings of reduced serotonin in depressed patients reflected medication effects rather than the underlying condition.

On serotonin receptors: Two meta-analyses of 5-HT1A receptor binding found either no difference between depressed and non-depressed individuals, or lower levels of these inhibitory receptors in depressed patients—which would imply higher, not lower, synaptic serotonin activity. Both analyses were complicated by the fact that most participants had recently used antidepressants or other psychiatric medications.

On the serotonin transporter: Three overlapping meta-analyses found possible reductions in SERT binding in some brain regions, but the results were inconsistent across studies, and most participants had a history of antidepressant use. If the findings do reflect a real effect independent of medication, they would suggest increased rather than decreased synaptic serotonin in depression—the opposite of what the hypothesis predicts.

On tryptophan depletion: Artificially lowering tryptophan—the dietary precursor to serotonin—did not reliably lower mood in healthy volunteers. One small meta-analysis found a minor effect in people with a family history of depression, but the sample was only 75 individuals. Eight of ten recently published depletion studies in healthy volunteers showed no mood effect. The authors note that the most recent comprehensive systematic review of this area was conducted in 2007, leaving a significant gap in the literature.

On genetics: The two largest and highest-quality genetic studies—one involving 115,257 participants and one a collaborative meta-analysis of 43,165—found no association between the serotonin transporter gene (5-HTTLPR) and depression, and no interaction between that gene, stress exposure, and depression risk. Earlier smaller studies had suggested such an interaction, but these were not replicated at scale.

The authors conclude that the evidence does not support the hypothesis that depression is caused by reduced serotonin activity or concentrations. They note that most of the included non-genetic studies were of low methodological quality, did not adequately control for prior antidepressant use, and were based on relatively small samples. The genetic studies were the strongest in the review and provided the clearest negative evidence.

One implication raised in the discussion concerns antidepressant use itself. Evidence from several included studies suggested that long-term antidepressant use may reduce serotonin concentrations—the opposite of their presumed acute mechanism. The authors flag this as an area requiring further investigation, particularly regarding the consequences of prolonged use.

5) Minocycline, a microglial inhibitor, reduces ‘honey trap’ risk in human economic exchange

Type of study: Double-blind, randomized, placebo-controlled trial
Sample size: 98 healthy adult males
Duration: 5 days
Population: Japanese male university students aged 20–30
Key finding: Minocycline eliminated the effect of female physical attractiveness on male trust behavior in an economic exchange

This study examined whether minocycline—a tetracycline antibiotic with known effects on brain immune cells—could reduce a specific bias in male decision-making: the tendency to extend trust to physically attractive females without adequately evaluating their trustworthiness. The researchers called this the “honey trap” effect.

Participants were recruited from Kyushu University and screened by a psychiatrist prior to enrollment. Those with a history of antibiotic side effects, severe organ disease, allergic conditions, or psychiatric disorders were excluded. 101 males were enrolled and 98 completed the full protocol. Participants were randomly assigned in a double-blind manner to receive either 200 mg per day of minocycline or a matched placebo for four days, taken in two daily doses. On day five, approximately three hours after their final dose, participants completed a trust game.

The trust game worked as follows. Each male participant was given 1,300 yen and shown photographs of eight young women, one at a time. For each female partner, the participant decided how much of his 1,300 yen to transfer. Any amount transferred was tripled, after which the female partner would decide whether to split the total equally or keep it all. Crucially, all eight female partners had decided in advance to keep the entire amount—participants were not told this. The amount each male transferred served as the behavioral measure of trust. After each decision, participants rated their female partner on both physical attractiveness and perceived trustworthiness using an 11-point scale.

The results confirmed the honey trap effect in the placebo group. Placebo participants gave significantly more money to partners they rated as more attractive, regardless of perceived trustworthiness (p = 0.0004). The minocycline group showed no such pattern—attractiveness had no significant effect on the amount transferred (p = 0.223). A significant interaction between drug condition and attractiveness was detected (F(1,776) = 7.78, p = 0.005). For highly attractive partners specifically, placebo participants offered significantly more than minocycline participants (p = 0.0004). For less attractive partners, there was no difference between groups (p = 0.590). Anxiety scores did not differ between conditions, suggesting the effect was not mediated by differences in general anxiety state.

The authors propose that the effect operates through minocycline’s inhibition of microglial activity. Microglia are the brain’s resident immune cells, and minocycline is the most commonly used pharmacological tool for suppressing their activity in both animal and human research. Prior clinical work has shown that 200 mg per day of minocycline suppresses microglial activation in regions including the putamen, thalamus, and frontal cortex. The amygdala—a region heavily implicated in evaluating facial trustworthiness—is also reported to be among the brain areas most affected by minocycline. The authors suggest that microglial activity in the amygdala may modulate the cognitive and emotional processes through which attractiveness influences trust judgments, and that minocycline disrupts this pathway.

Alternative mechanisms are acknowledged. Minocycline also affects glutamate and dopamine neurotransmission and has direct effects on neuronal cells, so the observed behavioral change cannot be attributed solely to microglial inhibition. Prior research has also shown that minocycline attenuates the subjective high associated with dextroamphetamine, suggesting a broader capacity to reduce arousal-driven responses—which may partly explain its effect here.

6) Progress on mitochondria and hair follicle development in androgenetic alopecia

Type of study: Narrative review
Scope: Mechanisms linking mitochondrial dysfunction to hair follicle biology, with a survey of existing and emerging treatments for androgenetic alopecia
Key finding: Mitochondrial dysfunction plays a central and underappreciated role in the pathogenesis of androgenetic alopecia, and represents a viable therapeutic target

Androgenetic alopecia (AGA) is the most common form of hair loss, affecting up to 80% of men and 40% of women over a lifetime. The conventional explanation centers on androgens—specifically dihydrotestosterone (DHT), which binds to receptors in hair follicles and causes progressive miniaturization. This review argues that this framing is incomplete, and that mitochondrial dysfunction is a significant and largely overlooked contributor to follicle deterioration.

The authors begin by outlining the basic biology of the hair follicle cycle. Hair follicles pass through three phases: anagen (active growth), catagen (regression), and telogen (rest). The length of the anagen phase determines hair shaft length, and most clinically significant hair loss conditions involve its premature termination. The follicle is maintained by two primary cell populations: hair follicle stem cells (HFSCs), which drive regeneration, and dermal papilla cells (DPCs), which regulate HFSC activation through secreted signaling molecules. Several signaling pathways govern this process, including Wnt/β-catenin, which promotes growth, and TGF-β/BMP, which promotes regression.

Mitochondria intersect with each of these pathways. The review details how mitochondrial reactive oxygen species (ROS) are in fact required for normal Wnt/β-catenin signaling in hair follicles. In mouse models deficient in mitochondrial transcription factor A (TFAM), keratinocytes fail to generate mitochondrial ROS, which disrupts Wnt signaling, reduces β-catenin levels, and causes premature entry into catagen. The same TFAM-deficient models show impaired Notch signaling, with reduced expression of Notch target genes essential for keratinocyte differentiation. Mitochondrial morphology also matters: disruption of the fission protein DRP1 leads to hyperfused mitochondria and inactivates Notch signaling in follicle cells.

The review also covers the role of SIRT1, an NAD-dependent deacetylase that protects HFSCs from inflammation-induced damage via the MAPK-ERK-Mfn2 signaling axis. In AGA specifically, DHT induces mitochondrial dysfunction in DPCs, accelerating their aging and impairing their ability to support HFSC activation. Reduced SIRT1 expression compounds this by triggering a TNF-α-mediated inflammatory stress response in HFSCs. The authors present this as a plausible mechanistic link between androgen exposure and the cellular energy deficits observed in miniaturizing follicles.

Several mitochondrial proteins are discussed in relation to follicle health. CRIF1, a mitochondrial ribosomal protein, is required for oxidative phosphorylation and β-catenin signaling—its absence in mouse models produces abnormal hair morphology and delayed hair cycle progression. Apoptosis-inducing factor (AIF), located in the inner mitochondrial membrane, facilitates the anagen-to-catagen transition through caspase-independent apoptosis. Impaired AIF activity produces irregular follicle cycling. MPZL3, a nuclear-encoded mitochondrial protein, regulates ROS production and lipid metabolism in sebaceous glands, and its disruption causes premature anagen entry and seborrheic dermatitis-like inflammation. Krtap11-1, a mitochondrially located protein, modulates Wnt and BMP signaling and peaks in expression during catagen and telogen—its dysfunction leads to weak hair shafts and increased oxidative stress.

The thyroid axis is also discussed. Thyroid hormones stimulate mitochondrial biogenesis and prolong the anagen phase by promoting keratinocyte proliferation and keratin expression. Expression of the mitochondrial protein MTCO1 is upregulated in scalp hair follicles under the influence of the hypothalamus-pituitary-thyroid axis, supporting follicle growth. Mitochondrial dysfunction arising from hormonal imbalance can impair ATP production and compromise the energy supply available for follicle maintenance.

On the treatment side, the review surveys both established and emerging approaches. Minoxidil is discussed in the context of mitochondrial function—it may act partly by elevating intracellular calcium levels and increasing ATP synthase activity, though this mechanism remains incompletely characterized. Low-level laser therapy is proposed to work by stimulating mitochondrial photon absorption, increasing ATP production and nitric oxide release, and improving local blood circulation. Melatonin is highlighted for its antioxidant and DNA repair properties, reducing ROS and supporting SIRT1-mediated protection against oxidative damage in follicle cells. N-acetylcysteine (NAC) is noted as a mitochondria-targeted antioxidant that improved hair growth in men with early-onset AGA in at least one trial. Cyanidin-3-O-arabinoside (C3A) is identified as a compound that reduces DHT-induced slowing of hair growth by preventing mitochondrial calcium accumulation.

The review also covers novel drug delivery approaches, including microneedle patches integrated with cerium nanozymes capable of delivering antioxidants approximately 300 microns into the skin, and mitochondria-targeted antioxidants such as MitoQ and SkQ1, which are designed to accumulate preferentially within mitochondria. Mitochondrial transfer—transplanting functional mitochondria from healthy donor cells into damaged cells—is discussed as an experimental direction, with early evidence from non-hair contexts showing restoration of bioenergetic capacity and reduced oxidative stress.

7) The tenacious brain: how the anterior mid-cingulate contributes to achieving goals

Type of study: Narrative review
Scope: Neuroanatomy, functional neuroimaging, lesion studies, and stimulation studies examining the role of the anterior mid-cingulate cortex in tenacity, motivation, and goal-directed behavior
Key finding: The anterior mid-cingulate cortex functions as a central hub for integrating cost-benefit computations that underlie persistence in the face of challenge, and its structure and function predict outcomes across health, aging, academic achievement, and neuropsychiatric illness

This review argues that a specific brain region—the anterior mid-cingulate cortex (aMCC)—is the neurological seat of tenacity. The authors define tenacity as a bias in effort computations by which the costs of effort are devalued and the value of long-term rewards is emphasized, driving persistence in the face of difficulty. The paper synthesizes evidence from neuroanatomy, functional imaging, lesion studies, and direct brain stimulation to support this claim.

The aMCC sits at the intersection of at least five partially overlapping intrinsic brain networks, including systems involved in executive function, autonomic regulation, interoception, motor control, and attention. Structural connectivity analyses show the aMCC has strong connections with the dorsal prefrontal cortex, anterior and posterior insula, thalamus, amygdala, hypothalamus, premotor cortex, and periaqueductal gray. Network analyses consistently identify it as one of the most broadly connected regions in the brain—a structural and functional hub in the same class as other high-traffic regions known to coordinate activity across otherwise segregated systems.

Functionally, the aMCC is among the most consistently activated regions in the fMRI literature. A meta-analysis of over 5,600 studies found it to be one of the most frequently reported activation sites across diverse task domains including pain, negative affect, reward processing, memory, cognitive control, motor planning, social cognition, and autonomic reactivity. The authors argue this cross-domain engagement reflects a single underlying function: computing the expected energetic cost and reward value of potential actions, and allocating physiological and attentional resources accordingly.

The case for the aMCC’s role in tenacity specifically rests on several converging lines of evidence.

On lesion studies: damage to the aMCC or its connections consistently produces motivational impairment. In a case study of a patient with an aMCC lesion, the individual could perform cognitively demanding tasks at a relatively normal level but reported no subjective sense of effort and showed no increase in skin conductance as task difficulty increased—suggesting the aMCC is specifically required for registering the cost of effort rather than performing the task itself. In animal models, inactivation of the homologous region reduces willingness to expend mental effort and decreases the energy expenditure animals are prepared to commit to obtain a proportional reward.

On neuroimaging: several studies have linked aMCC structure and function directly to measures of tenacity. Spontaneous aMCC activity predicts grit scores. Greater functional connectivity between the aMCC and the striatum predicts both grit and growth mindset. Stronger structural and functional connectivity between the aMCC and the supplementary motor area predicts lower levels of apathy. aMCC activity during effort-based decision tasks predicts willingness to choose more demanding options and predicts trait-level persistence. Greater gray matter volume in the aMCC also predicts persistence as measured by personality inventory.

On stimulation: direct electrical stimulation of the aMCC in human patients produces what has been described as an increase in the will to persevere. In a well-controlled study across 329 patients and 1,789 cingulate stimulation sites, stimulation of the aMCC reliably elicited goal-oriented behaviors and a subjective sense of preparation for challenge. One patient described the feeling as: being headed toward a storm and having to figure out how to get through it. Transcranial stimulation targeting the aMCC has also been shown to reduce self-reported appetite in women with obesity, suggesting that augmenting aMCC activity can modulate self-regulatory behavior.

The review draws out several applied implications. In depression, aMCC volume reduction predicts severity of apathetic symptoms, and depressed individuals show reduced aMCC activation during planning tasks and impaired error-related aMCC responses—consistent with the view that motivational deficits in depression reflect disrupted aMCC function rather than hedonic processing alone. In neurodegenerative disease, apathy across Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease is linked to abnormal aMCC metabolism and connectivity in each case. In aging, a subgroup of older adults known as superagers—whose episodic memory performance matches that of much younger adults—show aMCC cortical thickness and network connectivity equivalent to young controls, and this preserved structure predicts memory performance. The authors propose that superagers may persist longer on cognitively demanding tasks due to superior aMCC function, effectively training the region through continued challenge.

On exercise and obesity, aMCC metabolism correlates with exercise intensity and is more strongly coupled in individuals with greater exercise capacity. Regular aerobic exercise has been associated with increased gray matter volume in frontal regions including the aMCC, raising the possibility that the region can be structurally strengthened through sustained physical training. Individuals who have successfully maintained weight loss after obesity show substantially enhanced aMCC activation in response to food cues compared to controls, suggesting that aMCC-mediated cognitive control is a distinguishing feature of sustained behavioral change.

8) Refined carbohydrate consumption and facial attractiveness

Type of study: Observational cross-sectional study
Sample size: 99 subjects (50 women, 49 men), 150 attractiveness raters, 222 age-estimation raters
Population: Caucasian university students aged 18–26
Key finding: Higher between-meal glycaemic load was associated with increased facial attractiveness ratings by opposite-sex raters in both men and women

This study examined whether refined carbohydrate consumption is associated with facial attractiveness. The rationale was physiological: chronic consumption of refined carbohydrates generates hyperglycaemia and hyperinsulinaemia, both of which interfere with sex hormones and growth factors that influence facial morphology and skin aging. If these downstream effects are visible in the face, they may be detectable by opposite-sex raters.

Subjects were recruited from the University of Montpellier. All reported European ancestry across all four grandparents. Standardized frontal facial photographs were taken under controlled conditions—neutral expression, no glasses or earrings, uniform gray background, and consistent camera settings. Physical characteristics including height, weight, smoking status, scholarship level, and contraceptive pill use in women were recorded as control variables.

Dietary assessment focused on three meals considered to carry higher glycaemic risk: breakfast, afternoon snack, and between-meal snack. These meals tend to be higher in refined carbohydrates and lower in fat, protein, and fiber—a composition that produces larger glycaemic and insulinaemic responses. For each food and drink item consumed at these meals, glycaemic load (GL) was calculated using established international tables. Glycaemic load accounts for both the glycaemic index of a food and the quantity consumed, making it a more precise proxy for glycaemic and insulinaemic response than glycaemic index alone. Separate GL scores were computed for breakfast (GL1), afternoon snack (GL2), and between-meal snack (GL3).

Two separate panels of raters were recruited from public places in Montpellier. One panel estimated the apparent age of subjects from their photographs. A second panel assessed attractiveness by choosing the more attractive face from pairs of same-sex photographs, with all pairs rated by opposite-sex raters. Raters with poor reliability—based on repeated trials built into the procedure—were excluded. The final attractiveness analysis included 150 raters evaluating 99 subjects.

A facial femininity/masculinity index was computed using geometric morphometric analysis of 142 facial landmarks, which was then reduced to a single discriminant score separating male and female facial morphology. This index served as a control variable in the attractiveness models.

The primary finding was that GL3—the between-meal glycaemic load—significantly predicted attractiveness in both sexes. Men with higher GL3 were preferred by female raters (β = 0.564, p = 0.001), and women with higher GL3 were preferred by male raters (β = 0.468, p = 0.007). GL1 and GL2 showed no significant effect in either sex. The direction of this result—higher refined carbohydrate consumption associated with greater attractiveness—was the opposite of what the authors predicted based on known physiological effects, particularly for women, where hyperinsulinaemia-driven androgen elevation would be expected to increase facial masculinity and reduce attractiveness.

Structural equation modeling was used to explore whether GL3 acted on attractiveness indirectly through the control variables. For men, higher GL3 was associated with an increase in apparent age relative to chronological age, and appearing older within the 18–26 range was independently associated with higher attractiveness among female raters, which is consistent with prior evidence that women prefer men who display cues of resource acquisition and social status. For women, higher GL3 showed a marginally significant association with increased facial femininity (p = 0.056), which the authors suggest may reflect hyperinsulinaemia-driven sex hormone changes, though they acknowledge this runs counter to expectation and requires further investigation.

The authors offer an evolutionary interpretation for the unexpected direction of the effect. In pre-industrial environments, foods that generate hyperglycaemia (e.g. ripe fruit, honey) were scarce and seasonally limited. The ability to access them may have served as a reliable signal of foraging success or resource quality, making facial cues of such consumption attractive to potential mates. In the modern dietary environment, where refined carbohydrates are ubiquitous, this preference may represent a maladaptation—a response calibrated for scarcity that no longer tracks actual resource quality.

9) Meal timing trajectories in older adults and their associations with morbidity, genetic profiles, and mortality

Type of study: Longitudinal cohort study
Sample size: 2,945 community-dwelling older adults
Duration: Up to 34 years of follow-up (1983–2017)
Population: Adults aged 42–94 at enrollment
Key finding: Later breakfast timing was associated with increased physical and psychological illness, evening chronotype genetics, and higher all-cause mortality risk

This study examined how meal timing changes across older adulthood and what those changes mean for health and survival. Most prior research in chrononutrition—the study of when food is eaten and its effect on health—has focused on younger adults or cross-sectional snapshots. This paper used nearly four decades of longitudinal data to track meal timing trajectories in the same individuals over time.

Participants were drawn from the University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UMLCHA), which enrolled 6,375 adults starting in 1983. Of these, 2,945 had complete meal timing data at baseline and at least one follow-up assessment. Participants completed a Personal Details Questionnaire up to five times across the study period, reporting the times they ate breakfast, lunch, and dinner, as well as when they went to bed and woke up. From these responses, the researchers derived several variables: the interval between waking and breakfast, the interval between dinner and bed, the daily eating window, and the eating midpoint. Mortality data were obtained from the NHS Digital death registry through August 2017.

Health status was assessed using the Cornell Medical Index, a validated instrument covering 19 areas of physical and psychological symptomatology, administered on four occasions. A multimorbidity index was calculated by summing the number of conditions reported at each assessment. A subset of 1,226 participants also provided blood samples for genetic analysis, from which polygenic scores for evening chronotype and obesity were derived.

On meal timing trajectories, the data showed that with each additional decade of age, breakfast shifted later by approximately 8 minutes in the unadjusted model and 3 minutes after full adjustment. Dinner also shifted later with age, and the eating midpoint moved later while the total daily eating window shortened. Lunch timing remained stable across the follow-up period, likely because of limited variability in midday schedules across the sample. Across the full age range of participants, the cumulative shift in breakfast timing amounted to approximately 45 minutes.

Latent class analysis identified two distinct subgroups: an early eating group of 1,391 participants who maintained consistently earlier meal times with age, and a late eating group of 1,554 participants whose meal times shifted progressively later. These groups showed meaningful differences in survival.

On morbidity, later breakfast timing was associated with depression, fatigue, hypochondria, and multimorbidity. Anxiety was associated with a shorter eating window. Oral health problems were associated with earlier dinner and a shorter eating window. These associations held after adjusting for lifestyle factors including sleep duration, smoking, alcohol, employment status, and marital status.

On genetics, each standard deviation increase in the polygenic score for evening chronotype was associated with breakfast being later by 7.2 minutes, lunch by 3.1 minutes, and dinner by 3.9 minutes. The obesity polygenic score was not associated with meal timing after adjustment, suggesting that genetic predisposition toward evening behavior—rather than body weight genetics—is the stronger driver of late eating patterns in this population.

On mortality, 2,361 deaths were recorded over 63,388 participant-years of follow-up. Each additional hour of later breakfast timing was associated with an 11% increase in mortality risk in the unadjusted model (HR 1.11, 95% CI 1.03–1.18) and an 8% increase after full adjustment (HR 1.08, 95% CI 1.00–1.17). The 10-year survival rate was 89.5% in the early eating group compared to 86.7% in the late eating group. No significant mortality associations were found for lunch timing, dinner timing, eating window length, or proximity of dinner to bedtime.

The authors are careful about directionality. Because the study is observational, the more plausible interpretation is that illness drives later meal timing rather than the reverse—depression, fatigue, and poor oral health make it harder to eat at regular times, and those same conditions predict higher mortality. Later breakfast may therefore function primarily as a marker of underlying health decline rather than a direct cause of increased mortality risk. The authors suggest this still has clinical value, as shifts in breakfast timing could serve as an early, easily detectable indicator of health deterioration in older adults.

10) Emotional suppression and mortality risk over a 12-year follow-up

Type of study: Prospective cohort study
Sample size: 729 adults
Duration: 12 years (1996–2008)
Population: Nationally representative sample of non-institutionalized US adults aged 18 and over
Key finding: Higher emotion suppression was associated with a 35% increase in all-cause mortality risk and a 70% increase in cancer mortality risk

This study examined whether the tendency to suppress emotional expression is associated with a higher risk of death over a 12-year follow-up period. Prior research had suggested a link between emotion suppression and chronic disease, but evidence on mortality specifically was limited, methodologically contested, or drawn from non-representative samples. This paper used a nationally representative US dataset linked to official death records to provide a more rigorous test of the association.

Data came from the 1996 General Social Survey (GSS), an annual nationally representative study of US adults conducted by the National Opinion Research Center. In 1996, a six-item emotion suppression scale was administered to 737 respondents. The scale asked participants to rate their agreement with statements such as “I keep my emotions to myself,” “When I’m angry I let people know,” and “I try to be pleasant so that others won’t get upset.” Responses were made on a five-point Likert scale, with higher scores indicating greater suppression. The GSS data were subsequently linked to the US National Death Index, which records cause of death with a verified accuracy rate of 99.8%. Of the 729 participants with complete data, 111 died during the follow-up period—37 from cardiovascular disease and 34 from cancer.

Mortality associations were assessed using Cox proportional hazards models adjusted for age, sex, minority race and ethnicity, education, and self-rated health. Suppression scores were scaled by the interquartile range, so reported hazard ratios reflect the difference between someone at the 75th percentile of suppression versus someone at the 25th percentile—a practically meaningful comparison rather than a theoretical one-unit shift.

The primary finding was that higher emotion suppression was associated with a 35% increase in all-cause mortality risk (HR 1.35, 95% CI 1.00–1.82, p = 0.049). For cancer mortality specifically, the association was larger—a 70% increase in risk (HR 1.70, 95% CI 1.01–2.88, p = 0.049). The association with cardiovascular disease mortality was in the same direction but did not reach statistical significance (HR 1.47, 95% CI 0.87–2.47, p = 0.148). When deaths in the first year were removed to reduce the possibility that pre-existing illness drove the results, the effects strengthened: all-cause mortality risk increased to 42% (HR 1.42, p = 0.028) and cancer mortality risk to 108% (HR 2.08, p = 0.013).

Exploratory analyses of individual scale items found that higher anger suppression, specifically disagreeing more strongly with “When I’m angry I let people know,” was associated with elevated risk across all three mortality outcomes. Disagreeing more with “I’m not afraid to let people know my feelings” was significantly associated with cancer mortality. Both items involve emotional expression toward others, which the authors interpret as consistent with research on the health-protective effects of social support and interpersonal emotional disclosure.

The authors propose two broad mechanisms through which suppression may influence mortality. At a behavioral level, suppression may lead to unhealthy coping behaviors (e.g. overeating, social withdrawal) as substitutes for emotional expression. At a physiological level, suppression has been associated with greater autonomic reactivity to stress and with elevated levels of catecholamines and glucocorticoids, suggesting that habitual suppression may dysregulate neuroendocrine systems in ways that contribute to disease progression over time.

If any of these papers changed how you think about something, that is exactly the point. There is considerable value in developing an independent relationship with scientific literature. Reading original research provides a more complete and accurate picture than someone else’s interpretation. The papers are out there, and most are freely accessible. The only requirement is your willingness to look.

Thank you for reading.

A plethora of hormones, herbal extracts, drugs, nutrients, and proprietary blends are used with the hope of finally fixing all of our health problems and reaching that theoretical state of optimal health.

This is not an unreasonable place to end up.

The environment we live in does not support health by default, and in many respects it works against it. There are a large number of cases where supplementation addresses something that diet alone cannot, and I believe certain unnatural interventions are often necessary to counteract the accumulated damage of an environment that is, in many ways, making us sick.

However, this is not what this article is about.

The goal of this article is to demonstrate that a well-constructed diet can cover the full spectrum of essential nutrients without supplementation, and that understanding this has a practical benefit beyond nutrition alone…

It reduces the number of supplements required.

Why is this important?

The vast majority of supplements contain excipients (e.g. fillers, binders, colourants, preservatives, flow agents) that are classified as inert despite evidence to the contrary.

A systematic screening of 3,296 excipients in the FDA inactive ingredient database identified 38 that interact with 134 human enzymes and receptors, with an additional 109 interactions found between 32 excipients and human protein targets used to assess drug safety.

Silicon dioxide, titanium dioxide, magnesium stearate, maltodextrin, carrageenan, and polyethylene glycol appear across the majority of commercial supplements, often in multiple products taken simultaneously. The long-term biological effects of daily exposure to these compounds have not been studied and are more than likely harmful.

Dr. Raymond Peat observed this directly:

I believe that diet builds the foundation of health.

Everything else—every supplement, every intervention, every protocol—is built on top of it, and none of it functions as intended when the foundation is weak.

The foods covered below provide the full spectrum of essential nutrients, with each section covering what a given food provides and the mechanisms behind why it matters.

Liver

Liver is the most nutrient-dense food available.

No other single food covers as many essential nutrients at the concentrations it provides, and no supplement stack comes close to replicating what a regular serving of liver delivers in the context of a whole food with intact cofactors and synergistic compounds.

100g of beef liver provides approximately:

• Vitamin B12: 2,471% of the daily value. B12 is required for DNA synthesis, red blood cell production, myelin integrity, and the conversion of homocysteine to methionine. Its neurological role is particularly significant with deficiency producing subacute combined degeneration of the spinal cord, peripheral neuropathy, cognitive decline, and in severe cases demyelination of neurons. These effects are not always accompanied by anaemia, meaning deficiency can be neurologically advanced before it is detected on standard blood panels. B12 is found exclusively in animal-derived foods, making liver one of the most concentrated and reliable sources available.

• Vitamin A (retinol): 552% of the daily value. Liver provides preformed vitamin A not beta-carotene, which requires enzymatic conversion to active retinol. This conversion is highly variable across individuals, with some studies finding that up to half of subjects are poor converters, and the conversion rate is further reduced in hypothyroidism, as thyroid hormone is required to drive it. Retinol is required for vision, immune function, skin cell turnover, thyroid hormone signalling, and reproductive function. Vitamin A deficiency leads to keratinization disorders, impaired immune response, and night blindness.

• Copper: 1,084% of the daily value. Copper is a structural component of cytochrome c oxidase—the terminal enzyme of the mitochondrial electron transport chain—and is directly required for mitochondrial ATP production. It is also a cofactor for ceruloplasmin, the ferroxidase that oxidizes ferrous iron into ferric iron for transport in the bloodstream, meaning copper status directly affects iron metabolism. Additional copper-dependent enzymes include lysyl oxidase, which is required for collagen cross-linking and connective tissue stability; superoxide dismutase, a primary antioxidant enzyme; dopamine beta-hydroxylase, which converts dopamine to noradrenaline; and monoamine oxidases involved in neurotransmitter degradation. Copper deficiency impairs all of these simultaneously.

• Vitamin K2 (MK-4): Approximately 10–15mcg per 100g, making liver one of the better animal-derived food sources available. MK-4 is a cofactor for the carboxylation of vitamin K-dependent proteins. The two most clinically relevant are osteocalcin, which binds calcium to bone matrix, and matrix Gla protein (MGP), currently considered the most potent known inhibitor of arterial calcification. When K2 is insufficient, both proteins remain undercarboxylated and inactive—calcium accumulates in soft tissue and arterial walls rather than being directed to bone. Undercarboxylated MGP has been consistently associated with accelerated vascular calcification across multiple patient populations.

• Riboflavin (B2): 263% of the daily value. Riboflavin is the precursor to FAD and FMN, two coenzymes that are required by flavoproteins throughout the cell. FMN is a direct component of complex I of the mitochondrial electron transport chain. FAD is the prosthetic group in complex II. Beyond the electron transport chain, FAD-dependent acyl-CoA dehydrogenases drive fatty acid beta-oxidation—the primary pathway by which fatty acids are catabolized for energy. Riboflavin deficiency depletes both coenzymes simultaneously, impairing mitochondrial energy production, fatty acid oxidation, and the metabolism of other B vitamins including B6 and niacin, which require FAD for their activation.

• Folate (B9): 63% of the daily value. The folate in liver is in its natural polyglutamate form—reduced and already partially active—rather than synthetic folic acid, which is fully oxidized and requires multiple enzymatic conversion steps to reach the active 5-methyltetrahydrofolate (5-MTHF) form. This conversion depends on the MTHFR enzyme, which is functionally reduced in a significant proportion of the population due to common genetic variants. In these individuals, synthetic folic acid from supplements accumulates in its unmetabolized form rather than being converted to active folate. Natural dietary folate from liver does not present this problem. Folate is required for DNA synthesis, DNA methylation, homocysteine metabolism, and red blood cell production.

• Pantothenic acid (B5): 142% of the daily value. Pantothenic acid is the sole nutritionally essential precursor to coenzyme A—the cofactor required for the citric acid cycle, fatty acid synthesis, fatty acid beta-oxidation, steroid hormone synthesis, and the acetylation of proteins and neurotransmitters. It is also a structural component of the acyl carrier protein involved in fatty acid synthesis.

• Iron: 82% of the daily value in heme form. Heme iron from animal tissue is absorbed through a dedicated active transport pathway involving heme oxygenase in intestinal enterocytes, at a rate of 15–35% of intake. Non-heme iron from plant foods and most supplements is absorbed at 2–20%, and its absorption is further reduced by dietary inhibitors including phytates, polyphenols, and calcium. Heme iron accounts for only 10–15% of total dietary iron intake in most Western populations but contributes more than 40% of total iron absorbed, due to its absorption advantage. Iron is required for haemoglobin synthesis, oxygen transport, energy production, DNA synthesis, and immune function.

• Zinc: 48% of the daily value. Zinc is a cofactor in over 300 enzymatic reactions, including those involved in DNA synthesis, protein synthesis, immune cell development, and wound healing. It is required for the biosynthesis, storage, and secretion of testosterone—zinc is concentrated in Leydig cells, and deficiency is consistently associated with reduced testosterone levels and impaired spermatogenesis. It also serves a structural role in zinc finger proteins involved in gene expression and DNA repair.

• Selenium: 66% of the daily value. Selenium is incorporated into approximately 25 selenoproteins in the human body, two of which are directly relevant to thyroid function: glutathione peroxidase, which protects the thyroid gland from the oxidative stress generated during thyroid hormone synthesis, and iodothyronine deiodinase, the enzyme responsible for converting T4 into the active thyroid hormone T3. The thyroid contains the highest concentration of selenium per gram of any tissue in the body. Deficiency impairs both antioxidant defence and thyroid hormone activation simultaneously.

• Choline: Liver is the richest dietary source of choline in the human diet. Choline participates in three primary metabolic pathways. Through phosphorylation, it is the precursor to phosphatidylcholine—the dominant phospholipid in cell and mitochondrial membranes and a structural requirement for every cell in the body. Through acetylation, it is converted to acetylcholine in cholinergic neurons, where it serves as the primary neurotransmitter for memory consolidation, neuromuscular signalling, and autonomic function. Choline availability in nerve terminals is the rate-limiting step in acetylcholine synthesis. Through oxidation, choline is converted to betaine, which donates methyl groups to the methylation cycle and supports epigenetic regulation. In the liver specifically, phosphatidylcholine is required for the assembly and export of VLDL—the lipoprotein that transports triglycerides out of the liver. Choline deficiency causes fat and cholesterol to accumulate in the liver, which is a well-established cause of non-alcoholic fatty liver disease.

Here are a couple of ways I like to prepare liver:

Oysters

Oysters are the single richest food source of zinc and one of the most concentrated sources of several nutrients that are consistently deficient in modern diets.

A 100g serving of cooked wild eastern oysters provides:

• Zinc: 555% of the daily value. As covered in the liver section, zinc is a cofactor in over 300 enzymatic reactions including DNA synthesis, protein synthesis, immune cell development, testosterone production in Leydig cells, and structural function in zinc finger proteins involved in gene expression and DNA repair. Oysters are the most concentrated dietary source of zinc available.

• Vitamin B12: 538% of the daily value. As covered in the liver section, B12 is required for DNA synthesis, myelin integrity, neurological function, and red blood cell production.

• Copper: 493% of the daily value. As covered in the liver section, copper is a structural component of cytochrome c oxidase, ceruloplasmin, lysyl oxidase, superoxide dismutase, and dopamine beta-hydroxylase.

• Selenium: 56% of the daily value. As covered in the liver section, selenium is required for glutathione peroxidase activity in the thyroid and for the conversion of T4 to active T3.

• Iron: 40% of the daily value in heme form. As covered in the liver section, heme iron is absorbed at 15–35% compared to 2–20% for non-heme iron from plant foods and supplements.

• Iodine: Approximately 20–30% of the daily value per serving. Iodine is a structural component of thyroid hormones—T3 contains three iodine atoms and T4 contains four. Without sufficient iodine, the thyroid cannot synthesize hormones regardless of selenium or TSH status. Iodine is taken up from the bloodstream by the thyroid gland via the sodium-iodide symporter and incorporated directly into thyroglobulin, the protein matrix from which T3 and T4 are cleaved.

• Taurine: Oysters are one of the richest dietary sources of taurine—the sulfur-containing amino acid covered extensively in my articles/posts. Taurine is found in high concentrations in the brain, heart, muscles, and retina, and is involved in bile acid conjugation, calcium signalling, cellular hydration, mitochondrial function, and neurological protection. Endogenous synthesis from cysteine declines with age and is impaired under conditions of high oxidative stress, illness, and metabolic dysfunction.

• Biotin (B7): Oysters are one of the best food sources of biotin, providing over 50% of the daily value per serving. Biotin is a cofactor for five carboxylase enzymes in the human body, each involved in a distinct metabolic pathway: pyruvate carboxylase in gluconeogenesis, two forms of acetyl-CoA carboxylase in fatty acid synthesis, propionyl-CoA carboxylase in the catabolism of branched-chain amino acids and odd-chain fatty acids, and beta-methylcrotonyl-CoA carboxylase in leucine catabolism. Biotin deficiency impairs all five pathways simultaneously, disrupting glucose metabolism, fatty acid synthesis, and amino acid catabolism.

• Manganese: Approximately 20% of the daily value. Manganese is the metal cofactor at the core of manganese superoxide dismutase (MnSOD), which is the primary antioxidant enzyme in the mitochondrial matrix, where superoxide is generated continuously as a byproduct of electron transport chain activity. MnSOD catalyses the dismutation of superoxide radicals into hydrogen peroxide, preventing oxidative damage to mitochondrial DNA, membranes, and proteins. Beyond that, manganese is also a cofactor for glycosyltransferases involved in proteoglycan synthesis, the structural molecules required for the formation of cartilage and the connective tissue matrix of bone, and for arginase, the enzyme that converts arginine to ornithine in the urea cycle.

Eggs

Eggs are one of the most nutritionally complete foods available. The yolk contains all of the fat-soluble vitamins (A, D, E, K) and the majority of the micronutrient content, while the white provides high-quality protein with the highest net protein utilization of any whole food.

A pasture-raised egg contains:

• Choline: As covered in the liver section, choline is required for phosphatidylcholine synthesis in cell membranes, acetylcholine synthesis in cholinergic neurons, liver fat metabolism via VLDL export, and methylation through its conversion to betaine. Egg yolk is the single richest dietary source of choline per calorie. Two eggs provide approximately 300mg in a form that is significantly more bioavailable than most choline supplements, which are commonly sold as choline bitartrate or alpha-GPC at a substantially higher cost.

• Vitamin A (retinol): As covered in the liver section, egg yolks provide preformed retinol in a naturally fat-soluble matrix that supports absorption. Pasture-raised eggs contain approximately 1.5 times more vitamin A than conventional eggs, from the carotenoid-rich grasses and plants in the hen’s diet.

• Vitamin D: Egg yolks are one of the few naturally occurring food sources of vitamin D3. Pasture-raised eggs contain 3 to 4 times more vitamin D than conventionally produced indoor eggs, due to the hen’s direct sunlight exposure. Hens synthesize vitamin D3 in their skin through UVB radiation (the same mechanism as humans) and deposit it directly into the yolk. Indoor hens cannot do this regardless of their diet. The vitamin D in egg yolk is in the cholecalciferol (D3) form and is delivered in a fat matrix that supports its absorption.

• Vitamin E: Pasture-raised eggs contain up to 3.5 times more vitamin E than conventional eggs, from access to green vegetation and insects. Vitamin E is a fat-soluble antioxidant that integrates into cell membranes and protects them from lipid peroxidation. It is a cofactor for immune function and is required for the maintenance of membrane integrity in neurological tissue.

• Vitamin K2 (MK-4): As covered in the liver section, K2 is required for the carboxylation of osteocalcin and matrix Gla protein—the proteins responsible for directing calcium to bone and preventing its deposition in soft tissue and arteries. Pasture-raised eggs contain meaningfully more MK-4 than conventional eggs, as K2 is synthesized from the green plant material the hen consumes and deposited into the yolk.

• Selenium: As covered in the liver and oyster sections, selenium is required for glutathione peroxidase activity in the thyroid and for the conversion of T4 to active T3. One egg provides approximately 15–20mcg, which is roughly 25–35% of the daily value.

• Iodine: As covered in the oyster section, iodine is a structural component of both T3 and T4. One egg provides approximately 25mcg—around 17% of the daily value—and is one of the more reliable non-seafood dietary sources of iodine.

• Lutein and zeaxanthin: Egg yolks contain approximately 250mcg of combined lutein and zeaxanthin per egg, and pasture-raised eggs contain significantly more. These xanthophyll carotenoids accumulate selectively in the macula of the retina, where they function as blue-light filters and antioxidants. They are the only carotenoids found in the human lens and retina, and their concentration in the macula is directly correlated with dietary intake.

• Riboflavin (B2): As covered in the liver section, riboflavin is the precursor to FAD and FMN—the coenzymes required by complex I and complex II of the mitochondrial electron transport chain and by the acyl-CoA dehydrogenases that drive fatty acid beta-oxidation. One egg provides approximately 15% of the daily value.

• Vitamin B12: As covered in the liver and oyster sections, B12 is required for DNA synthesis, myelin integrity, neurological function, and red blood cell production. One egg provides approximately 0.6mcg, which is around 25% of the daily value.

Goat Milk

Goat milk is consumed by more people globally than cow milk. It is not dramatically different in nutrient content, but its minerals are more bioavailable, its fat digests more easily, and its protein structure is less allergenic than commercial cow milk.

A cup of full-fat goat milk provides:

• Calcium: Approximately 330mg per cup, which is around 33% of the daily value, and approximately 13% more than cow milk per serving. Calcium is the primary mineral in bone matrix, required for hydroxyapatite crystal formation, and is also involved in muscle contraction, neurotransmitter release, intracellular signalling, and blood clotting. The bioavailability of calcium from goat milk is higher than from cow milk, attributed to the smaller fat globule size and different protein structure, which produce a softer, more open curd in the stomach and allow faster enzymatic action.

• Magnesium: Goat milk contains more magnesium than cow milk, with higher bioavailability. Magnesium is involved in over 3,000 enzymatic processes including ATP synthesis, DNA replication, calcium regulation, insulin signalling, and HPA axis regulation. It is the body's primary defence against intracellular calcium excess. When magnesium is depleted, calcium accumulates in cells, driving inflammation, mitochondrial dysfunction, and neuronal overactivation. Most people are chronically depleted, and goat milk's higher bioavailability makes it a more effective dietary source than cow milk for addressing this.

• Potassium: Goat milk contains more potassium than cow milk at approximately 500mg per cup, around 11% of the daily value. Potassium is the primary intracellular cation and is required for membrane potential, nerve conduction, muscle contraction, and fluid balance. Potassium also plays a direct role in insulin secretion—the pancreatic beta cells that release insulin in response to rising blood glucose depend on potassium channel activity to regulate that release. Chronic low potassium impairs this mechanism and is independently associated with increased risk of type 2 diabetes. It is also required for glycogen synthesis in muscle and liver tissue, meaning that potassium status directly affects the body's capacity to store carbohydrate as usable fuel rather than converting it to fat.

• Vitamin A (retinol): As covered in the liver and egg sections, vitamin A is required for vision, immune function, thyroid health, and skin cell turnover. Goat milk contains meaningfully more vitamin A than cow milk.

• Riboflavin (B2): As covered in the liver section, riboflavin is the precursor to FAD and FMN, the coenzymes required by the mitochondrial electron transport chain and fatty acid beta-oxidation. Goat milk is a good source, providing approximately 20% of the daily value per cup.

• Medium-chain fatty acids and digestibility: Goat milk fat contains a higher proportion of short- and medium-chain fatty acids—including caprylic acid (C8) and capric acid (C10)—than cow milk. These fatty acids are absorbed directly via the portal vein to the liver rather than requiring chylomicron packaging and lymphatic transport, making them more rapidly available for energy production. The fat globules in goat milk are also smaller than those in cow milk, providing a greater surface area for lipase activity and significantly faster fat digestion. Additionally, goat milk does not contain the protein agglutinin, which promotes clustering of fat globules in cow milk and slows digestion. The result is that goat milk fat is digested faster, more completely, and with less gastrointestinal burden than cow milk fat.

• Lower allergenicity: Goat milk contains significantly less alpha-s1 casein than cow milk, which is the specific casein fraction most frequently implicated in cow milk allergy and digestive sensitivity. This is the primary reason goat milk is tolerated by many people who react to cow milk.

Beef Heart

Beef heart is considered an organ meat, but its taste and texture are more similar to a steak. It is the most concentrated food source of CoQ10 and contains substantial amounts of B vitamins, heme iron, zinc, and selenium. For people who find liver difficult to eat, beef heart is a more practical place to start. Depending on where you source it, it is also insanely cheap.

A 100g serving of beef heart provides:

• CoQ10: Approximately 11–13mg per 100g. The heart requires a constant and exceptionally high supply of energy to pump blood continuously without rest, which is why it concentrates CoQ10 to a greater degree than any other tissue. CoQ10 is a fat-soluble molecule embedded in the inner mitochondrial membrane that functions as a mobile electron carrier between complex I and complex II and complex III of the electron transport chain. It shuttles electrons from NADH and FADH2 to cytochrome c, enabling the proton gradient that drives ATP synthase. Without adequate CoQ10, this transfer stalls and ATP production falls. Beyond its role in energy metabolism, CoQ10 is the only lipid-soluble antioxidant that cells synthesize de novo. It protects the mitochondrial membrane from lipid peroxidation by reactive oxygen species generated during normal respiration and maintains the proton gradient across lysosomal membranes that facilitates cellular waste clearance.

• Vitamin B12: As covered in the liver and oyster sections, B12 is required for DNA synthesis, myelin integrity, neurological function, and red blood cell production. Beef heart provides approximately 360% of the daily value per 100g serving—one of the most concentrated sources outside of liver and oysters.

• Riboflavin (B2): As covered in the liver section, riboflavin is the precursor to FAD and FMN, the coenzymes required by the mitochondrial electron transport chain and fatty acid beta-oxidation. Beef heart provides approximately 90% of the daily value per 100g serving.

• Iron: As covered in the liver and oyster sections, heme iron is absorbed at 15–35% compared to 2–20% for non-heme iron from plant foods and supplements. Beef heart provides approximately 30% of the daily value.

• Zinc: As covered in the liver section, zinc is a cofactor in over 300 enzymatic reactions including DNA synthesis, immune cell development, and testosterone production. Beef heart provides approximately 20% of the daily value.

• Selenium: As covered in the liver and oyster sections, selenium is required for glutathione peroxidase activity in the thyroid and for the conversion of T4 to active T3. Beef heart provides approximately 45% of the daily value.

• Coenzyme A precursors and carnitine: Heart muscle tissue is rich in carnitine, which is the compound responsible for transporting long-chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Carnitine is widely sold as a supplement for energy metabolism and fat oxidation. Beef heart is one of the richest dietary sources available, alongside other muscle meats.

Orange Juice

Orange juice’s reputation as “a good source of vitamin C” undermines what it actually contains. Freshly squeezed orange juice provides a meaningful dose of vitamin C along with folate, potassium, and a set of citrus-specific flavanones (e.g. hesperidin and naringenin) that have documented effects on aromatase enzyme activity, inflammation, endothelial function, and gut serotonin.

A 240ml serving provides:

• Vitamin C: Approximately 100–125mg per 240ml serving, which exceeds the daily value of 90mg. Vitamin C is required for collagen synthesis, immune function, neurotransmitter production, and adrenal hormone synthesis. It is the primary water-soluble antioxidant in plasma and intracellular fluid, and it regenerates oxidized vitamin E back to its active form. Deficiency produces scurvy, which is a collagen failure. Subclinical deficiency, which is more common, impairs immune response, slows wound healing, and reduces noradrenaline synthesis. The adrenal glands contain the highest concentration of vitamin C of any tissue and deplete it rapidly under physiological stress, which is one reason requirements rise during illness, surgery, and chronic stress.

• Hesperidin and naringenin: Freshly squeezed orange juice is one of the richest dietary sources of citrus flavanones. Hesperidin and naringenin inhibit aromatase—the enzyme responsible for converting androgens to estrogen—and have been shown to reduce estrogen receptor activity. They also reduce the production of prostaglandins and inflammatory cytokines by inhibiting COX-2 and suppressing NF-κB signalling. Naringenin specifically inhibits the release of serotonin from enterochromaffin cells in the gut. These flavanones have also been shown to reduce diastolic blood pressure, improve endothelial function, and reduce circulating inflammatory markers.

• Folate: Approximately 15–20% of the daily value per serving, in its natural food form. As covered in the liver section, natural dietary folate does not carry the conversion issues associated with synthetic folic acid, which requires the MTHFR enzyme to reach its active form. Orange juice is one of the more reliable non-animal sources of folate.

• Potassium: Approximately 450–500mg per serving, which is around 10% of the daily value. As covered in the goat milk section, potassium is required for membrane potential, nerve conduction, muscle contraction, and fluid balance.

Sample Full Day of Eating

This day is built around the foods covered in this article, supplemented with white potato, coconut oil, and ripe fruit. Quantities reflect moderate to high activity at approximately 2,765 calories.

The Cronometer breakdown below shows the actual micronutrient output.

A few things worth noting:

The purpose of this Cronometer breakdown is to show the combined nutrient density of these foods, not to suggest they should all be eaten on the same day. Liver and oysters in particular are sufficient at one to two times per week.

Vitamin K appears low because Cronometer tracks K primarily as K1, which comes from leafy greens. K2 from liver, eggs, and butter is present in this day but is not fully captured in standard food databases.

Vitamin E requirements scale directly with PUFA intake, so the 39% figure is not a meaningful target on a diet built around saturated fat. Most food sources of vitamin E (e.g. nuts, seeds, and vegetable oils) come with a substantial amount of PUFAs, which defeats the purpose of obtaining vitamin E from them.

Safe Supplements

On a nutritional basis, there are a couple of supplements I view as worth taking to either cover genuine gaps in the diet, protect against deficiency, or because they have documented benefits at doses the diet cannot reliably reach.

Vitamin D3

Most people living at northern latitudes, working indoors, or spending limited time in direct sun do not synthesize sufficient D3 regardless of the quality of their diet. Lark Supply produces a D3 in extra-virgin olive oil with no fillers or excipients. Every product comes with a certificate of analysis before purchase, which is not standard practice in the supplement industry. I have no affiliation with them, I’m simply an avid user of their products.

Vitamin K2 (MK-4)

Liver and pasture-raised eggs provide MK-4, but the amounts are modest and food database tracking of K2 is unreliable. Most people are not getting enough from diet alone. Lark Supply produces a K2 MK-4 in extra-virgin olive oil to the same standard as their D3: no fillers or excipients, with a certificate of analysis published before purchase. Once again, I have no affiliation with them.

Vitamin E

Vitamin E has documented benefits at doses the diet cannot reliably reach without simultaneously increasing polyunsaturated fat intake. The majority of commercial supplements use synthetic dl-alpha tocopherol in a seed oil carrier. SkinFood produces a full-spectrum vitamin E containing all four tocopherol fractions in their natural ratios with no seed oils, which makes it one of the few products on the market that is both compositionally complete and free of the compounds that counteract its purpose. No affiliation.

You can’t out-supplement a bad diet, but you can build one that makes most supplements unnecessary.

The foods covered in this article are not hard to find or overly expensive. Liver, oysters, eggs, goat milk, beef heart, and orange juice are not difficult to source and, if eaten regularly, cover the full spectrum of essential nutrients without having to supplement with a B vitamin complex, vitamin A, zinc, copper, selenium, iodine, iron, choline, folate, CoQ10, carnitine, taurine, vitamin C, or the majority of minerals.

The goal is not to eliminate supplementation entirely, but to ensure that every supplement is taken for a reason.

This assessment is based on what collagen lacks rather than what it contains, and it ignores a body of research on the biological activity of its primary amino acid…

Glycine

Glycine makes up approximately 25–30% of collagen by weight.

It has documented anabolic, anti-catabolic, and anti-inflammatory properties—some of which operate through muscle protein synthesis directly, and others through independent mechanisms.

The research below covers several areas where collagen peptides and glycine have demonstrated meaningful effects relevant to training and body composition.

Collagen peptides improve body composition and strength in resistance training

A randomized, double-blind, placebo-controlled trial of 53 elderly sarcopenic men found that 15g of collagen peptides per day combined with 12 weeks of resistance training produced significantly greater improvements in fat-free mass and muscle strength than placebo. Both groups followed an identical training program. The collagen group gained 4.2kg of fat-free mass compared to 2.9kg in the placebo group. [1]

Glycine is anti-catabolic under inflammatory conditions

An animal study found that glycine supplementation in tumor-bearing mice—a model for severe muscle wasting—attenuated the loss of fat and muscle mass, reduced markers of inflammation including IL-6, reduced atrophic signaling, and tended to preserve muscle function and reduce oxidative stress. The protective effect was compared against isonitrogenous doses of alanine and citrulline and found to be specific to glycine. [2]

3g of glycine before bed improves sleep quality and next-day performance

A double-blind, placebo-controlled study in sleep-restricted healthy volunteers found that 3g of glycine taken before bedtime significantly reduced fatigue, improved daytime sleepiness, and produced significant improvements in psychomotor vigilance the following day. Sleep was restricted to 25% below normal for three consecutive nights. [3]

The mechanism appears to involve peripheral vasodilation and a reduction in core body temperature rather than sedation or melatonin modulation. Given that sleep quality directly affects muscle protein synthesis, hormonal output, and training performance, this is a relevant finding for anyone training under conditions of sleep restriction.

Collagen peptides reduce muscle soreness and fatigue after exercise

A randomized, double-blind crossover trial in 20 healthy middle-aged men found that 10g of collagen peptides per day for 33 days significantly reduced muscle soreness and fatigue immediately after a standardized exercise bout compared to placebo. The collagen group also maintained greater knee extension force in the days following exercise. [4]

Reduced post-exercise soreness and faster force recovery support a higher training frequency, which is a primary determinant of long-term strength and hypertrophy adaptations.

Glycine activates mTORC1 and directly inhibits muscle protein degradation

A cell study found that glycine enhanced muscle cell growth by activating the mTORC1 pathway—the same signaling pathway activated by leucine and resistance exercise—while simultaneously inhibiting the expression of MuRF1 and atrogin-1, the two primary genes responsible for muscle protein breakdown. Protein synthesis increased by 20–80% and protein degradation decreased by 15–30% in a concentration-dependent manner. [5]

Glycine restores the anabolic response to leucine under inflammatory conditions

A mouse study found that inflammation induced by LPS completely blunted the normal anabolic response to leucine. Pre-treatment with glycine restored leucine-stimulated muscle protein synthesis by 51%, accompanied by higher phosphorylation of mTOR, S6, and 4E-BP1. [6]

This is directly relevant to training. Intense exercise produces an acute inflammatory response. Glycine has been shown to restore anabolic sensitivity under inflammatory conditions in animal models, suggesting a meaningful role in post-exercise recovery independent of its direct anti-catabolic effects.

Collagen peptide supplementation supports connective tissue synthesis

A systematic review of 15 randomized controlled trials found that collagen peptide supplementation combined with exercise supported extracellular matrix biosynthesis in tendons, ligaments, and intramuscular connective tissue, reduced joint pain, and accelerated recovery from connective tissue injuries. [7]

This is the aspect of collagen supplementation that has the most consistent support across studies and is the most directly applicable to athletes. Connective tissue is the limiting factor in training volume for most experienced lifters, and it responds to nutrition differently from muscle tissue.

Collagen peptides are not a replacement for complete protein sources.

The case for including them is that glycine—their primary amino acid—actively regulates muscle protein turnover, supports anabolic signaling under inflammatory conditions, improves sleep quality and next-day performance, and reduces post-exercise soreness and fatigue. Collagen also provides the structural precursors for connective tissue synthesis that complete proteins do not.

The most practical way to get enough glycine is through a combination of food sources and supplementation.

Food sources of collagen and glycine include:

• Bone broth

• Oxtail

• Osso buco

• Chicharrones

• Ground beef

• Skin-on cuts of meat

• Whole fish

• Organ meats

• Eggs

For supplementation, I use the following:

Glycine: I source mine from LifeBlud. Use code MALACHY for 10% off at checkout.

Collagen peptides: Great Lakes Wellness collagen peptides are my preferred source.

Gelatin: Great Lakes Wellness also has a good gelatin, which is simply collagen in its unhydrolyzed form. The amino acid profile and glycine content are identical.

[1] Zdzieblik et al. (2015), Collagen peptide supplementation in combination with resistance training improves body composition and increases muscle strength in elderly sarcopenic men

[2] Ham et al. (2013), Glycine administration attenuates skeletal muscle wasting in a mouse model of cancer cachexia

[3] Bannai et al. (2012), The effects of glycine on subjective daytime performance in partially sleep-restricted healthy volunteers

[4] Kuwaba et al. (2023), Dietary collagen peptides alleviate exercise-induced muscle soreness in healthy middle-aged males: a randomized double-blinded crossover clinical trial

[5] Sun et al. (2016), Glycine Regulates Protein Turnover by Activating Protein Kinase B/Mammalian Target of Rapamycin and by Inhibiting MuRF1 and Atrogin-1 Gene Expression in C2C12 Myoblasts

[6] Ham et al. (2016), Glycine restores the anabolic response to leucine in a mouse model of acute inflammation

[7] Khatri et al. (2021), The effects of collagen peptide supplementation on body composition, collagen synthesis, and recovery from joint injury and exercise: a systematic review

I tried everything that I saw online: benzoyl peroxide, salicylic acid, topical retinoids & antibiotics, a strict carnivore diet, and more than a thousand dollars in skincare products across different brands and formulations.

I was also seeing a dermatologist throughout this period, which turned out to be both a waste of time and money.

When I asked the lead dermatologist whether eating certain foods like pizza could cause breakouts, he told me that food had no effect on acne whatsoever, and that the only way pizza would ever cause a breakout is if I picked it up and rubbed it directly on my face.

I eventually went on Accutane, which cleared my skin after about seven months of use, but the first couple of months involved a purging phase where my acne was more than twice as bad as it had ever been.

The side effects throughout the course were significant:

• Hair loss

• Skyrocketed cholesterol

• No libido

• Joint pain

• Persistent facial puffiness

• Depression

Each time I raised one of these with the clinic, I was told they would improve over time, which was not the case.

Accutane is a synthetic retinoid (a derivative of vitamin A) that works by reducing sebum production, shrinking the sebaceous glands, and slowing the turnover of cells lining the follicle.

While it is effective, it carries significant risk that a large number of people online describe as having seriously damaged their health in ways that outlasted the course itself.

In many cases the effects appear to be persistent in a way that is comparable to post-finasteride syndrome, where a subset of users report lasting hormonal, neurological, and sexual dysfunction long after discontinuing the drug.

My acne also returned a few months after stopping the drug, which made it clear that Accutane had not addressed whatever was actually causing it.

Working out what that was, and addressing it directly, is what eventually resolved the problem, and this article covers what I found along the way.

What Causes Acne

The standard explanation for acne is that it is an androgenic condition.

Excess testosterone and DHT stimulate the sebaceous glands, producing excess sebum, clogged follicles, bacterial colonization, and inflammation. This framing has driven most conventional acne treatments for decades, and is probably wrong, or at least significantly incomplete.

Acne is better understood as an inflammatory condition driven primarily by gut dysfunction and the hormonal dysregulation that follows.

The gut is the body’s primary line of defense against bacterial toxins.

Gram-negative bacteria, which make up a large portion of the gut’s microbial population, release a compound called endotoxin when they die. Under normal conditions, the intestinal barrier prevents this from entering circulation, but in a large number of people this barrier is not functioning as it should.

Small intestinal bacterial overgrowth (SIBO) is part of the reason why.

When bacterial populations accumulate in the small intestine, which should contain very little bacteria, the endotoxin produced passes directly into circulation rather than being contained and cleared.

SIBO increases intestinal permeability and allows endotoxin to translocate into the bloodstream. [1]

Several things contribute to this:

• Low stomach acid, which is the primary mechanism keeping bacteria confined to the colon

• A poorly functioning ileocecal valve, which normally prevents colonic bacteria from migrating back into the small intestine

• A gut barrier that has been progressively weakened by chronic exposure to endotoxin, serotonin, and nitric oxide

Circulating endotoxin places a significant burden on the liver, which is responsible for the clearance and detoxification of gut-derived endotoxin.

Chronic endotoxin load impairs this process, allowing toxic levels to develop in liver tissue and enter systemic circulation. [2]

The liver is also the primary site of estrogen detoxification through glucuronidation and sulfation. When it is overburdened by endotoxin, estrogen clearance is compromised and estrogen accumulates.

At the same time, endotoxin directly activates the adrenal gland, raising cortisol and increasing estrogen synthesis further.

Elevated estrogen is a direct contributor to acne.

Estrogen receptors are expressed in the sebaceous glands, and excess estrogen keeps the adrenal glands chronically overactive. Estrogen also sensitizes hepatic Kupffer cells to endotoxin, amplifying the inflammatory response and compounding the burden on the liver. [3]

The skin is one of the earliest and most visible indicators of the state of the gut.

Inflammatory lesions tend to appear first on the face and neck, and spread to the back, chest, and torso as the underlying condition becomes more severe. This pattern maps directly onto the severity of the endotoxin load, and is not consistent with a purely androgenic explanation.

This is where the androgen theory loses its validity.

Tetracycline antibiotics (e.g. doxycycline, minocycline) are routinely prescribed for hormonal acne, and they are known to lower estrogen while simultaneously raising DHT levels. If androgens were the primary driver, these drugs would worsen acne, but they do not. I have also applied DHT topically to my face without any breakouts, and if anything my skin appeared clearer during that period.

Published research supports this.

A study of 90 women with acne found no correlation between androgen levels and acne severity. [4]

A separate study concluded that the role of androgens in acne is permissive rather than causative, and that plasma androgen measurements have no place in its clinical management. [5]

For a more detailed treatment of this subject, the article that was most important in shaping my understanding of it can be found here:

Skin Breakouts Broken Down With Georgi Dinkov

I am not a doctor. None of this is medical device. It reflects my personal experience and research. Do your own research and due diligence before trying anything discussed here.

Diet and Food-Based Interventions

Daily Insoluble Fiber

Insoluble fiber—which is found in raw carrots, bamboo shoots, and white button mushrooms—passes through the digestive tract largely undigested, sweeping the intestinal walls and reducing bacterial load and endotoxin accumulation.

Raw carrots are particularly useful.

They contain a unique combination of insoluble fiber and natural antibacterial compounds, including falcarinol, that discourage bacterial overgrowth in the small intestine. The fiber also binds to excess estrogen and endotoxin in the digestive tract, carrying them out before they can be reabsorbed.

A daily raw carrot—grated lengthwise, with a small amount of olive oil and vinegar—is an effective intervention for acne. White button mushrooms prepared the same way serve a similar purpose and can be rotated in or used alongside it.

As covered in my recent article (A Non-Exhaustive List of My Favorite Biohacks), white button mushrooms show the strongest dose-dependent inhibition of aromatase among all vegetables tested, which directly addresses estrogen excess.

Olive oil increases the antibacterial effect and improves absorption of fat-soluble compounds. Vinegar contributes additional antimicrobial activity.

Weekly Oysters

Acne patients consistently show lower serum zinc levels than healthy controls, and zinc supplementation has been shown to reduce both inflammatory and non-inflammatory acne lesions. [6]

Zinc has a bacteriostatic effect on Cutibacterium acnes, inhibits chemotaxis, and reduces the production of inflammatory cytokines. [7]

It is also required for the synthesis of retinol-binding protein—the carrier that delivers vitamin A to the skin. Acne patients have been shown to have lower retinol-binding protein levels than those with mild acne or healthy controls. [8]

Without sufficient zinc, vitamin A cannot reach the tissue that needs it regardless of dietary intake.

Oysters are the single richest food source of zinc, containing ~74mg per serving.

Eating a can of oysters in olive oil once or twice per week is enough to meaningfully support zinc status without relying on supplementation. They are also a good source of selenium, copper, and vitamin B12.

Sufficient Vitamin C

Vitamin C is an essential cofactor for collagen synthesis, directly activating the transcription factors involved in collagen production and stabilizing procollagen mRNA. [9]

In the context of acne, this matters for two reasons.

Active lesions involve tissue damage that requires collagen for repair, and the post-inflammatory scarring that follows is determined in large part by how efficiently that repair occurs.

Vitamin C also functions as a primary antioxidant in the skin, reducing oxidative damage from UV radiation and environmental stress.

Dietary sources including oranges, guava, and kiwi are preferable to supplementation where possible, as whole food sources come with synergistic cofactors.

Replace A1 Dairy w/A2 or Eggshell Calcium

Most commercial dairy comes from cows that produce A1 beta-casein.

When digested, A1 beta-casein releases a peptide called beta-casomorphin-7 (BCM-7), which has been shown to induce pro-inflammatory immune activation and increase gut dysfunction.

A2 beta-casein does not generate this fragment. [10]

A systematic review found that consumption of milk containing A1 beta-casein was associated with increased gastrointestinal inflammation and delayed transit compared to milk containing only A2 beta-casein. [10]

A meta-analysis of over 78,000 children, adolescents, and young adults found that dairy consumption was associated with a significantly increased risk of acne across all forms (e.g. milk, cheese, yogurt) with the association strongest for low-fat and skim milk. [11]

Switching to A2 dairy where available, or removing dairy entirely and replacing calcium intake through eggshell calcium, removes this source of gut irritation without sacrificing nutrient density.

High-Dose Vitamin A or Beef Liver

Vitamin A is directly involved in the regulation of sebum production and the differentiation of the epithelial cells lining the follicle.

Deficiency leads to keratinization disorders, follicular plugging, and impaired skin cell turnover—all of which contribute directly to acne pathogenesis. [12]

Accutane itself is a synthetic retinoid that works by flooding this system at a pharmacological dose.

Before isotretinoin was approved in 1982, high-dose vitamin A was the standard treatment for severe acne.

A review of eight clinical trials conducted between the 1940s and 1980s found that acne improved in all but one, with 100,000 IU per day being the most commonly used and successful dose. Mean time to clinical improvement ranged from seven weeks to four months, which is comparable to isotretinoin. [13]

Getting sufficient dietary vitamin A through liver, egg yolks, and full-fat dairy addresses the same pathway at a physiological level. High-dose vitamin A is not without side effects, but the risk profile is much more favorable than Accutane.

Supplements

High-Dose Pantothenic Acid (Vitamin B5)

Pantothenic acid is a component of coenzyme A (CoA), which plays a central role in fatty acid metabolism.

The proposed mechanism for its effect on acne is that insufficient CoA availability causes the body to prioritize hormone production over fatty acid metabolism in the sebaceous glands, resulting in excess sebum accumulation and acne.

High-dose supplementation provides enough pantothenic acid to support both processes simultaneously. [14]

A randomized, double-blind, placebo-controlled trial of 41 adults with mild to moderate acne found that pantothenic acid supplementation significantly reduced total lesion count, inflammatory lesion count, and quality-of-life scores at 12 weeks compared to placebo. The supplement was well tolerated with no significant adverse effects. [15]

The doses used in clinical research range from 2.2g to 10g per day.

Starting low and titrating up is advisable. High doses can cause loose stools, which is a reliable indicator that the upper limit has been reached. It is also worth noting that pantothenic acid and biotin share the same intestinal transporter—the sodium-dependent multivitamin transporter (SMVT)—meaning that high doses of either can competitively inhibit the absorption of the other. [16]

Keep this in mind when supplementing with high doses of pantothenic acid over an extended period of time.

Daily Low-Dose Aspirin

Aspirin is useful in this context for two reasons.

The first is its anti-estrogenic effect. Aspirin inhibits COX-2, which suppresses aromatase activity—the enzyme responsible for converting androgens into estrogen.

A double-blind, placebo-controlled trial found that 100 mg of aspirin daily for six weeks produced a significant 23% reduction in estradiol levels. [17]

The second is its antimicrobial effect on the small intestine. Aspirin is absorbed primarily in the stomach and small intestine, which makes it an effective agent against SIBO before it reaches the colon.

A dose of 81 to 325 mg taken with food is sufficient. Since aspirin inhibits platelet aggregation, pairing it with vitamin K2 helps maintain normal clotting function and reduces the risk of excess bleeding.

CamphoSal + Activated Charcoal + Coconut Oil

This combination targets the colon directly, which aspirin can not reach on its own.

Camphor and phenyl salicylate (CamphoSal) work similarly to rifaximin—a non-absorbable antibiotic used for SIBO—in that they are not absorbed in the upper digestive tract and reach the colon intact where they exert an antimicrobial effect.

Activated charcoal binds endotoxin and other bacterial metabolites, preventing their absorption into circulation.

Coconut oil contributes additional antibacterial activity and, when combined with charcoal, is carried further down the digestive tract than it would be if taken alone.

Together they address the colonic bacterial load and endotoxin accumulation that drive the hormonal cascade described earlier. This combination does not need to be used daily. Two to three times per week is sufficient for most people.

Topical Treatments

Vitamin E Spot Treatment

Vitamin E applied topically to an active lesion reduces inflammation through several direct mechanisms.

Alpha-tocopherol inhibits COX-2 expression and iNOS in skin cells, which decreases prostaglandin E2 synthesis and nitric oxide production—two primary mediators of the redness and swelling associated with an acne breakout. [18, 19]

It also decreases the release of pro-inflammatory cytokines including IL-1β, IL-6, and TNF-α. [20]

As a fat-soluble antioxidant, it integrates into cell membranes and protects them from the lipid peroxidation that drives oxidative damage during the inflammatory phase.

Acne patients consistently show lower vitamin E levels in both serum and sebum than healthy controls, which means the tissue most affected by active lesions is also the most depleted of the compound that would normally protect it. [21]

For post-inflammatory hyperpigmentation, beta, gamma, and delta tocopherols have been shown to directly inhibit tyrosinase and reduce melanin production in cell models—reducing the dark marks that follow a breakout. [22]

I apply it directly to acne lesions before bed and consistently notice it looking less inflamed by morning.

For this purpose, a mixed tocopherol product—containing alpha, beta, gamma, and delta forms—is more effective than pure alpha-tocopherol alone, as the other forms contribute more directly to both COX-2 inhibition and tyrosinase suppression.

SkinFood’s vitamin E product (E Complete) is my preferred source.

TocoVit from IdeaLabs is another good option.

Baking Soda Face Wash

This one is based primarily on personal experience.

Rubbing a small amount of baking soda on the face and washing it off has consistently made my skin look less red and less inflamed.

There is some research basis for the antimicrobial properties of sodium bicarbonate.

It has demonstrated inhibitory activity against bacterial and fungal species responsible for skin infections in vitro, and a dermatology review concluded it may be an effective and safe dermatological agent in several capacities. [23]

However, a randomized controlled study on topical sodium bicarbonate in psoriasis found no reduction in erythema, and no human studies have examined its use specifically for acne. [24]

Regardless, I have had only positive experiences with it.

Avoid Commercial Skincare Products

Most commercial skincare products, including those marketed specifically for acne, contain preservatives and stabilizers with documented endocrine-disrupting properties.

Parabens, the most common preservatives in liquid skincare products, are readily absorbed through the skin and have been shown to mimic estrogen in tissue. [25]

Phthalates, found in fragrances and plasticizers, have been linked to altered testosterone and reproductive hormone changes in human studies. [26]

Chemical UV filters such as oxybenzone have shown estrogenic activity in laboratory studies and measurable skin absorption in humans. [27]

The simplest approach to circumvent this problem is to reduce product count to the minimum necessary. Water, a gentle cleanser, targeted spot treatments, and clean lotions are more than enough.

Light & Peptide Therapy

Red Light Therapy

Red light therapy, or photobiomodulation, uses low-level light in the 620 to 850 nm range to alter biological processes in skin cells without generating heat. In the context of acne, it works through two primary mechanisms.

The first is anti-inflammatory.

Red light penetrates deep enough to reach the sebaceous glands, where it reduces lipid production, modulates cytokine release from macrophages, and downregulates the inflammatory signaling that drives active lesions. [28]

A review of visible light in acne treatment confirmed that red light in the 620 to 750 nm range has well-documented anti-inflammatory effects with good skin penetration, including to the level of the sebaceous gland. [29]

The second is tissue repair.

Red light stimulates fibroblast activity and collagen synthesis, which directly supports the resolution of post-inflammatory lesions and reduces the likelihood of scar formation.

This makes it useful both during an active breakout and in the recovery phase.

A clinical study involving 35 participants found that daily red and blue LED therapy for four weeks reduced inflammatory acne lesions by 77% and non-inflammatory lesions by 54%, with pathological results confirming reduced sebaceous secretion, reduced inflammatory cell infiltration, and decreased sebaceous gland size. [30]

Ten to twenty minutes per day, three to five times per week, is the range used in most clinical protocols.

GHK-Cu Copper Peptide

GHK-Cu (glycyl-L-histidyl-L-lysine-copper) is a naturally occurring tripeptide found in human plasma, saliva, and urine.

Levels are around 200 ng/ml at age 20 and decline to roughly 80 ng/ml by age 60. This decline coincides with a measurable reduction in tissue regenerative capacity. [31]

In the context of acne, its relevance is primarily post-inflammatory.

Active lesions cause tissue damage that requires collagen synthesis, fibroblast migration, angiogenesis, and extracellular matrix remodeling for proper repair.

GHK-Cu has been shown to stimulate all of these processes. [31, 32]

It also reduces TNF-alpha induced secretion of the pro-inflammatory cytokine IL-6 in normal human dermal fibroblasts, an effect significant enough that the authors of one study proposed it as a topical alternative to corticosteroids in inflammatory skin conditions. [32]

Applied topically to active lesions or areas of post-inflammatory hyperpigmentation, it accelerates tissue repair and reduces the inflammatory environment that prolongs healing.

The research on it is largely preclinical and in vitro, with limited human RCTs, but the mechanistic basis is well established and the safety profile is favorable. [33]

Antibiotics

Minocycline / Doxycycline / Penicillin

When the gut bacterial burden is significant enough that diet and other interventions are not moving the needle, antibiotics become worth considering.

The conventional explanation for why antibiotics work is that they reduce C. acnes on the skin. The more probable explanation is that they reduce bacterial load and endotoxin in the gut, which is where the hormonal dysregulation driving the acne originates.

Reducing that load lowers the burden on the liver, reduces circulating endotoxin, and gives the body the conditions it needs to regulate estrogen properly.

Tetracycline antibiotics, particularly minocycline and doxycycline, are the most studied in this context.

Beyond their antimicrobial activity, both have well-documented immunomodulatory properties that operate independently of bacterial killing.

Minocycline inhibits pro-inflammatory enzymes including iNOS, MMPs, and COX-2, suppresses inflammatory cytokines including IL-1β, IL-6, IL-8, and TNF-α, and restores epithelial barrier integrity in colitis models. [34, 35]

It has also been shown to reduce intestinal bacterial load and modulate gut microbiota composition, which directly addresses the SIBO-driven endotoxin accumulation at the root of hormonal acne. [36]

The estrogen-lowering effect of tetracyclines is a separate and clinically relevant mechanism.

Tetracyclines reduce enterohepatic recirculation of estrogen by altering the gut bacteria responsible for deconjugating estrogen metabolites in the bile, reducing the reabsorption of free estrogen back into circulation and lowering systemic estrogen levels. [37]

This is why tetracyclines are known to reduce the efficacy of estrogen-based oral contraceptives, and it is also part of why they work for hormonal acne.

Minocycline has a favorable safety profile at doses up to 200 mg per day, with common side effects limited to light-headedness, vestibular symptoms, and nausea at standard doses. Most are dose-dependent and resolve quickly on discontinuation. [38]

Penicillin is worth mentioning separately.

Unlike broad-spectrum tetracyclines, penicillin acts primarily on gram-positive bacteria and has a narrower disruption profile on the overall gut microbiome.

In the context of acne, this makes it a useful option for targeting specific bacterial populations without the broader microbiome disruption that comes with long-term tetracycline use.

Antibiotics should not be approached carelessly.

There is enough anecdotal data and scientific evidence to take the side effect profile seriously, particularly with extended use. Starting at the smallest measurable dose and titrating up slowly is essential. Supplementing with a generous amount of vitamin K2 throughout any course is something I consider non-negotiable, as is closely monitoring symptoms and adjusting accordingly.

Conclusion

The interventions on this list are not a substitute for addressing the root cause. Cleaning up the diet, fixing digestion, and reducing endotoxin load will do more for persistent acne than any supplement or topical treatment.

If you have done all of that and are still struggling, the interventions covered here can meaningfully accelerate the process. None of them are quick fixes, but they address real mechanisms rather than masking symptoms.

References

[1] Losurdo et al. (2020), The Influence of Small Intestinal Bacterial Overgrowth in Digestive and Extra-Intestinal Disorders

[2] Nolan (1975), The role of endotoxin in liver injury

[3] Ikejima et al. (1998), Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin

[4] Cibula et al. (2000), The role of androgens in determining acne severity in adult women

[5] Levell et al. (1989), Acne is not associated with abnormal plasma androgens

[6] Yee et al. (2020), Serum zinc levels and efficacy of zinc treatment in acne vulgaris: A systematic review and meta-analysis

[7] Cervantes et al. (2018), The Role of Zinc in the Treatment of Acne: A Review of the Literature

[8] Michaëlsson, Vahlquist & Juhlin (1977), Serum zinc and retinol-binding protein in acne

[9] Pullar, Carr & Vissers (2017), The Roles of Vitamin C in Skin Health

[10] Brooke-Taylor et al. (2017), Systematic Review of the Gastrointestinal Effects of A1 Compared with A2 β-Casein

[11] Juhl et al. (2018), Dairy Intake and Acne Vulgaris: A Systematic Review and Meta-Analysis of 78,529 Children, Adolescents, and Young Adults

[12] Everts (2012), Endogenous retinoids in the hair follicle and sebaceous gland

[13] Cook et al. (2022), Oral vitamin A for acne management: a possible substitute for isotretinoin

[14] Leung (1995), Pantothenic acid deficiency as the pathogenesis of acne vulgaris

[15] Yang et al. (2014), A Randomized, Double-Blind, Placebo-Controlled Study of a Novel Pantothenic Acid-Based Dietary Supplement in Subjects with Mild to Moderate Facial Acne

[16] Said (2009), Cell and molecular aspects of human intestinal biotin absorption

[17] Mohamadi et al. (2022), Aspirin versus placebo on estrogen levels in postmenopausal women: a double-blind randomized controlled clinical trial

[18] Yoshida et al. (2006), Topical application of a novel, hydrophilic gamma-tocopherol derivative reduces photo-inflammation in mice skin

[19] Wu et al. (2008), IL-8 production and AP-1 transactivation induced by UVA in human keratinocytes: roles of D-alpha-tocopherol

[20] Singh & Jialal (2004), Anti-inflammatory effects of alpha-tocopherol

[21] Ozuguz et al. (2014), Evaluation of serum vitamins A and E and zinc levels according to the severity of acne vulgaris

[22] Kamei et al. (2009), Comparison of the inhibitory effects of vitamin E analogues on melanogenesis in mouse B16 melanoma cells

[23] Rosenberg et al. (2024), Baking Soda and the Skin: A Review of Baking Soda in Dermatology

[24] Mazzarello et al. (2019), Efficacy of a Topical Formulation of Sodium Bicarbonate in Mild to Moderate Stable Plaque Psoriasis: a Randomized, Blinded, Intrapatient, Controlled Study

[25] Darbre & Harvey (2008), Paraben esters: review of recent studies of endocrine toxicity, absorption, esterase and human exposure

[26] Jurewicz & Hanke (2011), Exposure to phthalates: reproductive outcome and children health

[27] Matta et al. (2019), Effect of Sunscreen Application Under Maximal Use Conditions on Plasma Concentration of Sunscreen Active Ingredients

[28] Guo et al. (2025), The Application of Light Emitting Diode (LED) in Cosmetic Dermatology

[29] Akuffo-Addo et al. (2024), Visible Light in the Treatment of Acne Vulgaris

[30] Kwon et al. (2013), The clinical and histological effect of home-use, combination blue-red LED phototherapy for mild-to-moderate acne vulgaris in Korean patients: a double-blind, randomized controlled trial

[31] Pickart (2008), The human tri-peptide GHK and tissue remodeling

[32] Pickart et al. (2015), GHK Peptide as a Natural Modulator of Multiple Cellular Pathways in Skin Regeneration

[33] Wojcieszuk et al. (2025), BPC-157 and GHK-Cu in Wound Healing and Tissue Repair: A Review of Clinical Efficacy and Safety

[34] Garrido-Mesa, Zarzuelo & Gálvez (2013), Minocycline: far beyond an antibiotic

[35] Garrido-Mesa et al. (2011), The intestinal anti-inflammatory effect of minocycline in experimental colitis involves both its immunomodulatory and antimicrobial properties

[36] Vezza et al. (2022), Minocycline Prevents the Development of Key Features of Inflammation and Pain in DSS-induced Colitis in Mice

[37] Kwa et al. (2016), The Intestinal Microbiome and Estrogen Receptor–Positive Female Breast Cancer

[38] Gump et al. (1977), Side effects of minocycline: different dosage regimens

Here is what the list covers:

1. 3g of Taurine Per Day

2. Bromantane / Tyrosine / Phenylalanine

3. Walking After Meals

4. Thiamine (TTFD) + Methylene Blue

5. Baking Soda “Milkshakes”

6. K2 and MgCl Scrotal Application

7. High-Dose Vitamin K2

8. Magnesium Sips Throughout Day

9. White Button Mushrooms + EVOO

10. Breakfast in the Sun

11. Low-Dose Minocycline

12. Nicotine Patches for Focus

1) 3g of Taurine Per Day

Taurine (2-aminoethanesulfonic acid) is a sulfur-containing amino acid found abundantly in the brain, heart, muscles, and retina.

It’s produced endogenously from cysteine through a three-step process:

Cysteine → Cysteine sulfinic acid
Cysteine sulfinic acid → Hypotaurine
Hypotaurine → Taurine

Production declines with age and most people do not synthesize enough to meet their physiological needs.

This is usually the result of one or more of the following:

• Diets lacking in taurine precursors and certain nutrients (e.g. cysteine, B6, methionine)

• Reduced activity of the enzymes that convert cysteine to taurine (e.g. cysteine dioxygenase, cysteine sulfinic acid decarboxylase)

• Increased physiological demand in conditions such as diabetes, illness, and high oxidative stress

Supplementation addresses this directly.

A 2023 study in Science identified taurine deficiency as a driver of aging, finding that taurine levels drop significantly over time and that supplementation improved both healthspan and lifespan in animal models. [1]

A separate study found it increases thyroid hormone and testosterone by attenuating hypothalamic-pituitary-gonadal axis dysfunction. [2]

It has also been shown to increase the bioavailability of fat-soluble vitamins A, D, E, K, and F by forming water-soluble complexes that improve their transport and absorption. [3]

A systematic review and meta-analysis of randomized controlled trials found that taurine supplementation significantly reduced HbA1c, fasting blood sugar, and insulin resistance in diabetic patients. [4]

It also prevents free fatty acid-induced hepatic insulin resistance by inhibiting JNK1 activation, and increases liver glycogen through its insulin-like effects. [5]

A systematic review found that 1g of taurine before or after exercise reduces lactate levels, and that low-dose taurine decreases muscular fatigue and increases enzymatic antioxidants. [6]

It also modulates circadian rhythms disrupted by a high-fat diet, which has downstream effects on body composition and glucose tolerance. [7]

Taurine has also been studied for fatty liver disease, bone formation, memory, neurodegeneration, and cancer. [8, 9, 10, 11]

3 grams/day is the dose I use to cover most of my bases.

My preferred source of taurine: Toro from LifeBlud.

You can use code MALACHY at checkout for 10% off.

[1] Singh et al. (2023), Taurine deficiency as a driver of aging

[2] Mohamed & Abdel Gawad (2017), Taurine dietary supplementation attenuates brain, thyroid, testicular disturbances and oxidative stress in streptozotocin-induced diabetes mellitus in male rats

[3] Petrosian & Haroutounian (2000), Taurine as a universal carrier of lipid soluble vitamins: a hypothesis

[4] Tao et al. (2022), The effects of taurine supplementation on diabetes mellitus in humans: A systematic review and meta-analysis

[5] Wu et al. (2010), Taurine prevents free fatty acid-induced hepatic insulin resistance in association with inhibiting JNK1 activation and improving insulin signaling in vivo

[6] Chen et al. (2021), The Dose Response of Taurine on Aerobic and Strength Exercises: A Systematic Review

[7] Figueroa et al. (2017), Taurine Treatment Modulates Circadian Rhythms in Mice Fed A High Fat Diet

[8] Song et al. (2020), The beneficial effects of taurine in alleviating fatty liver disease

[9] Gupta & Kim, Taurine, Analogues and Bone: A Growing Relationship

[10] Huf et al. (2023), Neuroprotection elicited by taurine in sporadic Alzheimer-like disease: benefits on memory and control of neuroinflammation in the hippocampus of rats

[11] Ma et al. (2022), Taurine and Its Anticancer Functions: In Vivo and In Vitro Study

2) Bromantane / Tyrosine / Phenylalanine

Bromantane is a synthetic adaptogen developed in the Soviet Union that is classified as an actoprotector, which is a compound that improves physical and mental performance under stress without increasing oxygen consumption or depleting the body’s energy reserves. [1]

Unlike conventional stimulants, it does not flood the brain with dopamine or block its reuptake. Instead, it upregulates the enzymes responsible for producing it (e.g. tyrosine hydroxylase), which leads to a sustained increase in dopamine synthesis. [2]

This is where tyrosine and phenylalanine become important.

Tyrosine hydroxylase upregulation requires an adequate supply of substrate. Phenylalanine converts to tyrosine, and tyrosine is the direct precursor to L-DOPA and dopamine. Without them, the upregulated enzymes have no substrate to use.

Here’s what the research shows:

A large multicenter trial of 728 patients given 50 to 100 mg of bromantane daily for 28 days found that 90.8% showed improvement in asthenic symptoms (e.g. fatigue, low energy, sleep disturbance, anxiety) with effects persisting for a full month after discontinuation. [3]

A separate placebo-controlled trial confirmed it outperformed placebo in reducing asthenic symptoms and found no withdrawal syndrome on discontinuation. [4]

Animal studies found that bromantane’s effect on physical work capacity exceeded that of phenamine at optimal doses by 1.3 to 1.6 times, lasted at least 24 hours, and protected mitochondria in cardiac and skeletal muscle cells under repeated extreme loads. [5]

Animal research also found positive effects on memory, attention, motivation, and planning. [6]

It was approved in Russia under the brand name Ladasten for the treatment of neurasthenia, and was banned by WADA following the 1996 Olympics after several Russian athletes tested positive for it.

The combination of stimulant and anxiolytic effects in a single compound is unique. Most stimulants (e.g. Adderall, modafinil, methylphenidate) increase anxiety and lead to dopamine receptor downregulation with repeated use.

Bromantane increases the brain's capacity to produce dopamine rather than forcing release. Tyrosine and phenylalanine provide the substrate the pathway needs to do so.

I take 50 mg of bromantane, 500–1000 mg of tyrosine, and 500–1000 mg of phenylalanine irregularly on days where I have mentally taxing and unenjoyable work to complete. Since bromantane is highly lipophilic and insoluble in water, it requires fat for adequate absorption.

My preferred source of tyrosine and phenylalanine: Tyrophen from LifeBlud

Once again, you can use code MALACHY for 10% off your order.

[1] Morozov & Ivanova (2013), The Pharmacology of Actoprotectors: Practical Application for Improvement of Mental and Physical Performance

[2] Morozov et al. (2001), Actoprotector and adaptogen properties of adamantane derivatives

[3] Ivanova et al. (2010), Treatment of asthenic disorders in patients with psychoautonomic syndrome: results of a multicenter study on efficacy and safety of ladasten

[4] Neznamov et al. (2009), Ladasten, the new drug with psychostimulant and anxiolytic actions in treatment of neurasthenia

[5] Morozov & Kleĭmenova (1998), The effect of bromantane on the physical work capacity of laboratory animals

[6] Alyautdin et al. (1999), The characteristics of the neuropsychotropic activity of bromantane in laboratory animals

3) Walking After Meals

This is a pretty simple one.

When you eat, blood glucose rises as carbohydrates are broken down and absorbed into the bloodstream. Walking immediately after a meal uses your muscles as a sink for that glucose, blunting the postprandial spike.

At the same time, the rhythmic movement of walking stimulates peristalsis, the wave-like contractions of the stomach and intestines that move food through the digestive tract, which speeds gastric emptying and reduces bloating.

A randomized crossover study of 41 adults with type 2 diabetes found that 10 minutes of walking after each meal was significantly more effective at lowering postprandial blood glucose than a single 30-minute walk at any other point in the day. [1]

A separate study found that even slow postmeal walking reduced the blood glucose response to a carbohydrate-rich meal, with the effect scaling with duration. [2]

Brisk postprandial walking has also been shown to substantially reduce the glucose peak across meals with different carbohydrate content and macronutrient composition. [3]

A 2022 systematic review and meta-analysis found that walking as little as 2 to 5 minutes after a meal reduced both blood glucose and insulin levels. Additionally, light walking throughout the day reduced glucose by 17% compared to prolonged sitting. [4]

10 minutes is more than enough.

[1] Henson et al. (2016), Advice to walk after meals is more effective for lowering postprandial glycaemia in type 2 diabetes mellitus than advice that does not specify timing

[2] Høstmark et al. (2009), Slow postmeal walking reduces postprandial glycemia in middle-aged women

[3] Bellini et al. (2022), The Effects of Postprandial Walking on the Glucose Response after Meals with Different Characteristics

[4] Buffey et al. (2022), A Systematic Review with Meta-analysis on the Effect of Breaking Up Prolonged Sitting with Light-Intensity Walking on Cardiometabolic Health Outcomes

4) Thiamine (TTFD) + Methylene Blue

TTFD is a fat-soluble derivative of thiamine (vitamin B1) with significantly higher bioavailability than the standard forms more commonly sold.

Unlike regular thiamine, it does not need a transport system to enter cells. Instead, it passes through the cell membrane directly.

As a result, more thiamine reaches the cell, where it is converted into thiamine pyrophosphate (TPP), which is an essential coenzyme for pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase—the enzymes that drive ATP production in the mitochondria. [1]

In more practical terms, this means more efficient energy production.

Studies show that TTFD improves endurance, increases grip strength, reduces lactate production, and elevates liver and muscle glycogen after exercise. [2]

A separate study found it attenuates the decrease in ATP content in skeletal muscle during physical fatigue, which is not seen with standard thiamine. [3]

Research also found it promotes voluntary physical activity through dopaminergic activation in the prefrontal cortex. [4]

An open trial in 44 patients with nutritional polyneuropathy found that TTFD produced significant improvement in motor function, with no side effects observed during treatment. [5]

Methylene blue is a synthetic compound originally developed as a textile dye in the 1870s and later the first fully synthetic drug used in humans.

At low doses (1–15 mg), it acts as a redox mediator in the mitochondrial electron transport chain, bypassing dysfunctional segments to sustain ATP production and reduce reactive oxygen species. [6]

It crosses the blood-brain barrier readily and has been shown to enhance memory, improve mitochondrial respiration, and reduce neuroinflammation in models of Alzheimer's, Parkinson's, stroke, and traumatic brain injury. [7]

In healthy humans, low-dose methylene blue improved fMRI activity in brain regions responsible for sustained attention and memory. [8]

A 2025 animal study found that methylene blue provided neuroprotection against exhaustive exercise-induced neurological deficits by enhancing mitochondrial function and rescuing behavioral performance. [9]

Both compounds act on ATP production in the mitochondria, but at different points.

TTFD increases substrate availability and supports the enzymes involved in energy metabolism, and methylene blue improves the efficiency of the electron transport chain—the process responsible for the majority of ATP synthesis.

I use 100 mg of TTFD and between 0.5 and 5 mg of methylene blue before cognitively demanding work or intense exercise.

My preferred source of TTFD: Thiamax from Objective Nutrients

My preferred source of methylene blue: Meraki Blu from Meraki Medicinal

[1] Lonsdale (2004), Thiamine tetrahydrofurfuryl disulfide: a little known therapeutic agent

[2] Liao et al. (2018), The Effects of Thiamine Tetrahydrofurfuryl Disulfide on Physiological Adaptation and Exercise Performance Improvement

[3] Nozaki et al. (2009), Thiamine tetrahydrofurfuryl disulfide improves energy metabolism and physical performance during physical-fatigue loading in rats

[4] Naito et al. (2018), Thiamine tetrahydrofurfuryl disulfide promotes voluntary activity through dopaminergic activation in the medial prefrontal cortex

[5] Djoenaidi et al. (1990), Thiamine tetrahydrofurfuryl disulfide in nutritional polyneuropathy

[6] Rojas et al. (2012), Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

[7] Bhurtel et al. (2017), From Mitochondrial Function to Neuroprotection — An Emerging Role for Methylene Blue

[8] Gonzalez-Lima & Barksdale (2014), Mitochondrial respiration as a target for neuroprotection and cognitive enhancement

[9] Zhang et al. (2025), Intranasal methylene blue administration confers neuroprotection in rats subjected to exhaustive exercise training

5) Baking Soda “Milkshakes”

The name comes from horse racing.

Starting in the late 1980s, trainers began tubing concentrated sodium bicarbonate solutions directly into horses’ stomachs before races to reduce lactic acid and increase muscular endurance.

The practice became widespread enough that Racing Australia and most other racing authorities banned it within 24 hours of race time, with career-ending penalties for trainers caught using it. [1]

Here’s how it works:

During high-intensity exercise, muscles produce hydrogen ions as a byproduct of anaerobic metabolism. The accumulation of these ions drops intramuscular pH, impairing muscle contraction and accelerating fatigue.

Sodium bicarbonate is alkaline and ingesting it before exercise raises blood bicarbonate concentration, which increases the body’s capacity to buffer those hydrogen ions and delays the onset of acidosis. [2]

The research supports this in humans as well.

A systematic review found performance improvements of up to 3% in swimming and cycling, with the strongest effects in events involving repeated bouts of intense effort. [3]

The International Society of Sports Nutrition concluded in its position stand that sodium bicarbonate consistently improves performance in high-intensity exercise, with the strongest evidence for repeated sprint and intermittent efforts. [4]

A separate systematic review and meta-analysis found significant improvements in muscular endurance specifically. [5]

In my experience, 1 teaspoon of baking soda before cardio noticeably reduces the burning sensation and allows me to maintain full intensity throughout the session.

[1] Denham et al. (2020), A Systematic Review and Meta-analysis on Sodium Bicarbonate Administration and Equine Running Performance

[2] Calvo et al. (2021), Effect of sodium bicarbonate contribution on energy metabolism during exercise: a systematic review and meta-analysis

[3] Siegler et al. (2016), Mechanistic Insights into the Efficacy of Sodium Bicarbonate Supplementation to Improve Athletic Performance

[4] Grgic et al. (2021), International Society of Sports Nutrition Position Stand: Sodium Bicarbonate and Exercise Performance

[5] Grgic et al. (2020), Effects of Sodium Bicarbonate Supplementation on Muscular Strength and Endurance: A Systematic Review and Meta-analysis

6) K2 and MgCl Scrotal Application

The testicles are the primary site of testosterone production in men. Leydig cells within the testes convert cholesterol into testosterone through steroidogenesis.

Both magnesium and vitamin K2 (MK-4) play direct roles in this process, and applying them topically to the scrotal area allows for local absorption at the site of production. Scrotal skin is more permeable than skin elsewhere on the body, which makes it a well-established route for transdermal delivery of hormonal compounds.

Vitamin K2 (MK-4) has been shown to stimulate testosterone production directly in Leydig cells by activating the cAMP/PKA signaling pathway and upregulating CYP11A, the rate-limiting enzyme in steroidogenesis.

Rats fed an MK-4 supplemented diet for five weeks showed significantly higher testosterone levels in both plasma and testicular tissue. [1]

Magnesium supports testosterone through a different mechanism.

It competes with SHBG (sex hormone-binding globulin) for testosterone binding, which increases the proportion of free and bioavailable testosterone in circulation. [2]

A study in Biological Trace Element Research found that magnesium supplementation increased both free and total testosterone in active and sedentary men after four weeks, with a greater effect in those who exercised. [3]

A separate study in 399 men over 65 found that serum magnesium was strongly and independently associated with total testosterone levels after adjusting for age, BMI, and other confounders. [4]

Applied topically to the scrotal area, both compounds reach the tissue where testosterone is produced directly. The anecdotal reports are consistent with what the research shows.

[1] Ikai et al. (2011), Menaquinone-4 enhances testosterone production in rats and testis-derived tumor cells

[2] Excoffon et al. (2009), Magnesium effect on testosterone-SHBG association studied by a novel molecular chromatography approach

[3] Cinar et al. (2011), Effects of magnesium supplementation on testosterone levels of athletes and sedentary subjects at rest and after exhaustion

[4] Maggio et al. (2011), Magnesium and anabolic hormones in older men

7) High-Dose Vitamin K2

Vitamin K2 exists in several forms. MK-4 is the form most concentrated in animal tissues and the one with the most direct research behind it for therapeutic use.

Its primary role is as a cofactor for the carboxylation of vitamin K-dependent proteins, which is a process that activates them and allows them to function.

Two of the most important are osteocalcin, which binds calcium to bone matrix, and matrix Gla protein (MGP), the most potent known inhibitor of arterial calcification.

When K2 is insufficient, these proteins remain undercarboxylated and inactive, causing calcium to end up in soft tissue and arteries rather than bone. [1]

MK-4 has been approved in Japan as a prescription treatment for osteoporosis since 1995, under the brand name Glakay, at a dose of 45 mg/day.

A systematic review of Japanese randomized controlled trials found that supplementation with MK-4 at this dose was associated with reduced fracture incidence and maintained bone mineral density. [2]

A separate dose-finding study found that 5 mg per day reduced undercarboxylated osteocalcin to levels typical of healthy premenopausal women. [3]

Beyond bone, MK-4 has been studied for its effects on testosterone production, cardiovascular health, and cancer.

On the cardiovascular side, MGP carboxylation by K2 actively prevents calcium from depositing in arterial walls, a mechanism with direct implications for cardiovascular disease risk. [1]

There is also emerging research on its role in inhibiting hepatocellular carcinoma and other forms of cancer. [4]

Vitamin K2 has also been shown to decrease intracellular estradiol levels by binding to 17beta-hydroxysteroid dehydrogenase 4, an enzyme involved in estrogen metabolism, which reduces estrogen receptor activity at the DNA level. [5]

At 45 mg, I notice a profound calming effect and generally feel healthier. During a period where I was relying on nicotine heavily for focus, a single dose made me forget to apply my patch before sitting down to study. I also noticed that my sleep onset and quality improved significantly.

It’s quite expensive at this dose, but I use it when I can.

This is what I use: Vitamin K2 MK-4 in EVOOO from Lark Supply

[1] Schwalfenberg (2017), Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health

[2] Cockayne et al. (2006), Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials

[3] Burckhardt et al. (2019), Maximal dose-response of vitamin K2 (MK-4) on undercarboxylated osteocalcin in women with osteoporosis

[4] Mizuta & Ozaki (2008), Hepatocellular carcinoma and vitamin K

[5] Otsuka et al. (2005), Vitamin K2 binds 17beta-hydroxysteroid dehydrogenase 4 and modulates estrogen metabolism

8) Magnesium Sips Throughout Day

Magnesium is the fourth most abundant mineral in the body.

A 2012 study identified 3,174 magnesium-dependent processes in the human body, including virtually every reaction that involves ATP. [1]

It forms the Mg-ATP complex, which is the true substrate for most ATP-dependent reactions in the body. Without sufficient magnesium, cells cannot effectively produce or transfer energy. [2]

One of its most important roles is regulating intracellular calcium.

Excess calcium is implicated in nearly every major inflammatory pathway, and magnesium is the body’s primary defense against it. When magnesium is depleted, calcium accumulates, driving inflammation, mitochondrial dysfunction, and neuronal overactivation. [3, 4]

Part of this involves NMDA receptor blockade.

Under normal conditions, magnesium sits in the NMDA receptor channel and limits calcium influx into neurons. When magnesium levels drop, this block weakens, causing excess calcium to enter the cell, which increases the risk of excitotoxicity, neurodegeneration, anxiety, and seizures. [5]

Beyond this, magnesium is required for:

• Active vitamin D synthesis

• DNA replication and repair

• Glutathione production

• Insulin signaling

• Testosterone synthesis in Leydig cells

• Conversion of T4 to active T3

• HPA axis regulation (blunts cortisol output)

This last point is important because chronic stress depletes magnesium, and low magnesium increases stress sensitivity, which creates a cycle that is difficult to break without consistent repletion. [2]

Most people are chronically depleted.

Soil depletion has reduced the magnesium content of food over decades, and physical output, psychological stress, and environmental toxins accelerate loss daily.

The most practical way to maintain consistent levels throughout the day is to dissolve magnesium chloride in a water bottle and sip it steadily. Large single oral doses tend to cause digestive issues, so spreading intake across the day circumvents this and keeps levels more stable.

Not all forms are equally useful. Here is a brief breakdown:

Magnesium glycinate

• Magnesium bound to glycine. Well absorbed, inexpensive, and well tolerated.

• Best starting point for most people. Good for sleep, stress reduction, and general repletion.

Magnesium chloride

• The most versatile form. Can be taken orally or applied topically.

• Best for muscle recovery, general repletion, and people with digestive issues who struggle to absorb other forms.

Magnesium threonate

• One of the only forms shown to meaningfully raise magnesium levels in the brain, as it crosses the blood-brain barrier. [6]

• Best suited for cognitive applications (e.g. memory, focus, neuroprotection).

Magnesium malate

• Magnesium paired with malic acid, which supports the Krebs cycle and has mild utility for heavy metal chelation, particularly aluminum.

• Best for muscle recovery, energy metabolism, and general detox support.

Magnesium N-acetyl taurate

• Combines magnesium with N-acetyl taurine, enhancing both magnesium and taurine delivery to the brain and cardiovascular tissue.

• Best for anxiety, high blood pressure, and cardiovascular health.

Magnesium taurate

• Combines magnesium with taurine, with documented benefits for cardiovascular and neurological function.

• Best for heart health and neurological support, though N-acetyl taurate is the more bioavailable option for these applications.

Magnesium oxide

• Poorly absorbed and produces pro-oxidant compounds. Not worth using.

On dosing:

The largest dose is best taken before bed, as most detox and repair processes occur during sleep. Daytime doses should be smaller and spread across meals.

Using two or more forms across different routes of administration, such as oral and topical, gives better overall tissue saturation than relying on a single form.

[1] Piovesan et al. (2012), The human “magnesome”: detecting magnesium binding sites on human proteins

[2] Rosanoff et al. (2012), Suboptimal magnesium status in the United States: are the health consequences underestimated?

[3] Rossol et al. (2012), Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors

[4] Brookes et al. (2004), Calcium, ATP, and ROS: a mitochondrial love-hate triangle

[5] Paoletti et al. (2013), NMDA receptor subunit diversity: impact on receptor properties, synaptic plasticity and disease

[6] Slutsky et al. (2010), Enhancement of learning and memory by elevating brain magnesium

9) White Button Mushrooms + EVOO

White button mushrooms have more research behind them than most people assume.

One important note before getting into the benefits:

White button mushrooms should not be eaten raw. They contain agaritine, a hydrazine compound with potential mutagenic and carcinogenic properties. Cooking reduces agaritine levels significantly. Boiling for at least 10 minutes and discarding the water removes most of it, and cooking for 1 to 3 hours removes virtually all of it. Microwaving is also effective and reduces agaritine levels substantially in a fraction of the time. The water should always be discarded when boiling, as agaritine is water-soluble and transfers into it. [1]

Now, onto the benefits.

Among all vegetables tested, white button mushrooms showed the strongest dose-dependent inhibition of aromatase, which is the enzyme responsible for converting androgens into estrogen. [2]

White button mushrooms also reduce gut inflammation. Research found that white button mushroom powder reduced intestinal permeability and lowered inflammatory markers including IL-1β. [3]

Their polysaccharides have also been shown to stimulate macrophage activity and inhibit the growth of breast cancer cells in vitro.

In animal models, white button mushroom extract reduced tumor weight and suppressed myeloid-derived suppressor cells (immune cells that tumors exploit to evade detection) while activating T cells and NK cells. This effect has also been observed in prostate cancer patients in a Phase II clinical trial. [4, 5]

EVOO has a separate but complementary set of effects. The polyphenols in extra virgin olive oil (e.g. oleuropein, hydroxytyrosol) selectively suppress pathogenic bacteria and reduce gut inflammation. [6]

Unlike antibiotics, they act selectively, targeting harmful organisms without broadly disrupting the gut environment. [7]

Beyond the gut, EVOO polyphenols improve endothelial function, reduce LDL oxidation, improve HDL function, and lower inflammatory markers such as CRP and IL-6. [8]

I blend well-cooked white button mushrooms with a splash of vinegar and a teaspoon of EVOO. It has had a noticeable effect on digestion and bowel movements, and it tastes very good.

Highly recommend.

[1] Claeys et al. (2020), Warning on false or true morels and button mushrooms with potential toxicity linked to hydrazinic toxins

[2] Grube et al. (2001), White button mushroom phytochemicals inhibit aromatase activity and breast cancer cell proliferation

[3] Dempsey et al. (2025), Protective properties of the white button mushroom in a mouse model of colitis

[4] Adams et al. (2008), Macrophage immunomodulating and antitumor activities of polysaccharides isolated from Agaricus bisporus white button mushrooms

[5] Twardowski et al. (2024), Reduction of myeloid-derived suppressor cells in prostate cancer murine models and patients following white button mushroom treatment

[6] Prieto et al. (2023), Evidence supporting the involvement of the minority compounds of extra virgin olive oil through gut microbiota modulation

[7] Cicerale et al. (2010), Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil

[8] Gorzynik-Debicka et al. (2025), Exploring the cardiovascular benefits of extra virgin olive oil: insights into mechanisms and therapeutic potential

10) Breakfast in the Sun

Sunlight includes a spectrum of wavelengths, each with distinct biological effects, and the composition of that spectrum changes throughout the day.

In the morning, the sun sits low on the horizon. At this angle, the atmosphere filters out most of the higher-energy UV wavelengths, leaving a spectrum rich in red and near-infrared light (roughly 630–850 nm).

These wavelengths penetrate the skin and interact directly with cytochrome c oxidase—an enzyme in the mitochondrial electron transport chain—stimulating ATP production, reducing oxidative stress, and supporting cellular repair. [1]

Red and near-infrared light also displaces nitric oxide from cytochrome c oxidase, where it would otherwise compete with oxygen and impair energy production. [1]

As the sun rises higher, UVB becomes available. UVB triggers vitamin D synthesis in the skin, which is a cofactor in the enzymatic conversion of dopamine precursors into active dopamine.

It also stimulates the release of beta-endorphins. More are released when vitamin D levels are low, creating a dose-dependent feedback loop that regulates sun-seeking behavior. [2]

Beyond the wavelength-specific effects, morning light exposure sets the cortisol awakening response.

Bright light in the first hour after waking enhances the natural morning cortisol rise by 20–40%, which drives alertness, energy, and readiness for the day. [3]

This also suppresses residual melatonin, sets the circadian rhythm to the solar day, and sets the timing for melatonin release later that night—improving sleep onset and quality downstream. [4]

Eating breakfast outside combines the metabolic benefits of the morning light spectrum with the circadian signal that food has arrived, which reinforces the body’s internal clock and improves how efficiently that food is used for energy throughout the day.

[1] Powner et al. (2024), Light stimulation of mitochondria reduces blood glucose levels

[2] Kemeny et al. (2021), Vitamin D deficiency exacerbates UV/endorphin and opioid addiction

[3] Scheer & Buijs (1999), Light affects morning salivary cortisol in humans

[4] Czeisler et al. (1995), Suppression of melatonin secretion in some blind patients by exposure to bright light

11) Low-Dose Minocycline

Antibiotics are often regarded as a necessary evil, used only in situations of dire need. However, I think this is a viewpoint worth reconsidering.

Minocycline is a semi-synthetic tetracycline antibiotic that has been in clinical use for decades, primarily for acne and bacterial infections.

What makes it interesting beyond its antibiotic activity is the wide range of conditions it has been studied for…

• Cancer

• Long COVID

• Osteoporosis

• Autism

• Rheumatoid arthritis

• Traumatic brain injury

• Neuropathic pain

• Parkinson’s disease

• Huntington’s disease

• Alzheimer’s disease

• Multiple sclerosis

• Spinal cord injury

• IBD

• Diabetes

And more. [1]

The common denominator in nearly all of these is inflammation.

The mechanisms behind this are well documented.

Minocycline inhibits pro-inflammatory enzymes including iNOS, matrix metalloproteinases (MMPs), and COX-2. It suppresses microglial activation—the primary driver of neuroinflammation—and reduces the release of IL-1β, IL-6, and TNF-α. It also chelates metals, regulates calcium, and directly suppresses reactive oxygen and reactive nitrogen species through antioxidant activity comparable to vitamin E in some models. [2, 3]

Importantly, it crosses the blood-brain barrier readily due to its high lipophilicity, which distinguishes it from most antibiotics and explains its documented neuroprotective effects. [1]

Minocycline has a favorable safety profile at doses up to 200mg per day, with common side effects at standard doses limited to light-headedness, vestibular symptoms, and nausea. Most are dose-dependent and resolve quickly on discontinuation. [4]

I have experienced the most benefit at lower doses, well below the standard clinical range. This is consistent with the observation that its anti-inflammatory effects operate independently of its antibiotic activity and do not require high plasma concentrations to be meaningful.

With that being said, minocycline should not be approached carelessly. There is enough anecdotal data and scientific evidence to take the side effect profile seriously, particularly with extended use.

Starting at the smallest measurable dose and titrating up slowly is essential.

Supplementing with a generous amount of vitamin K2 throughout any course of minocycline is something I consider non-negotiable, as is closely monitoring symptoms and adjusting accordingly.

[1] Garrido-Mesa, Zarzuelo & Gálvez (2013), Minocycline: far beyond an antibiotic

[2] Shultz & Zhong (2017), Minocycline targets multiple secondary injury mechanisms in traumatic spinal cord injury

[3] Noble, Garwood & Hanger (2009), Minocycline as a potential therapeutic agent in neurodegenerative disorders characterised by protein misfolding

[4] Gump et al. (1977), Side effects of minocycline: different dosage regimens

12) Nicotine Patches for Focus

Nicotine is a compound with a broad range of documented biological effects that are largely obscured by its association with tobacco smoking.

Nicotine works by binding to nicotinic acetylcholine receptors (nAChRs) in the brain, particularly the α4β2 and α7 subtypes. Activation of these receptors facilitates the release of acetylcholine, dopamine, serotonin, and glutamate, which are neurotransmitters central to attention, working memory, and motivation. [1]

The prefrontal cortex, which governs executive function and sustained attention, is particularly sensitive to nicotinic stimulation. The cognitive effects are most pronounced on tasks requiring focused attention, especially under conditions of difficulty or distraction. [1]

A meta-analysis of over 40 double-blind placebo-controlled studies found that nicotine reliably improves focused and sustained attention, recognition memory, and motor responding. [2]

Transdermal nicotine has also been shown to improve attention and episodic memory in patients with mild cognitive impairment, and chronic patch use improved cognitive function in Alzheimer’s patients across multiple trials. [3]

At the cellular level, nicotine modulates long-term potentiation (LTP)—the synaptic mechanism underlying learning and memory formation—in the hippocampus and prefrontal cortex. It does this by reducing GABAergic inhibition of pyramidal cells, which lowers the threshold for LTP induction and increases the signal-to-noise ratio for synaptic input. [4]

Chronic nicotine administration has been shown to significantly enhance object recognition memory through nAChR-dependent changes in synaptic plasticity in the medial prefrontal cortex. [5]

It also rescues LTP in conditions where it is impaired, including sleep deprivation, Alzheimer’s disease, chronic stress, and hypothyroidism, primarily through desensitization of α7 nAChRs. [6]

Nicotine also improves memory function through chromatin modification, inhibiting histone deacetylases and producing transcriptional changes in memory-related genes. [6]

It activates the PI3K/AKT pro-survival pathway, which increases LTP and protects against the memory dysfunction associated with Alzheimer’s disease. [6]

The patch is the most practical delivery method for cognitive use. I have one on as I’m typing this out.

It provides steady plasma nicotine levels and avoids the acute spike of other delivery methods such as smoking, vaping, or Zyn-ing. I use a low-dose patch on days where sustained focus is required and remove it in the afternoon.

[1] Levin et al. (2017), Cognitive effects of nicotine: recent progress

[2] Heishman et al. (2010), Meta-analysis of the acute effects of nicotine and smoking on human performance

[3] Newhouse et al. (2012), Nicotine treatment of mild cognitive impairment: a 6-month double-blind pilot clinical trial

[4] Fujii et al. (2000), Nicotine reverses GABAergic inhibition of long-term potentiation induction in the hippocampal CA1 region

[5] Goto et al. (2025), Chronic nicotine enhances object recognition memory via inducing long-term potentiation in the medial prefrontal cortex in mice

[6] Bhatt et al. (2021), Molecular insights into the benefits of nicotine on memory and cognition

If you made it this far, thank you so much for reading!

None of this is medical advice.

These are compounds and habits I have found useful through personal experimentation and research. What works for me may not work for you. Make sure to do your own research, start low with anything new, and pay attention to how your body responds.

Despite consistently high smoking rates among Japanese men over the past 30 years, lung cancer incidence and mortality in Japan have remained lower than in Western countries. This is a phenomenon researchers call the Japanese smoking paradox. [3]

Ikaria, a small Greek island in the Aegean Sea, follows a similar trend.

It is one of the world's five designated Blue Zones, which are locations where people live measurably longer than average. One in three Ikarians lives into their nineties and rates of cancer, heart disease, and dementia are significantly lower than in the West. [4]

Ikaria is also a population with a long history of high smoking prevalence. Studies of Ikarian elders found that nearly 50% had been smokers at some point in their lives. [5]

The same pattern also holds in Sardinia, another Blue Zone, where 48% of elders aged 89 to 101 also reported being smokers in the past. [5]

These are not isolated coincidences.

Nicotine, the primary active compound in tobacco, has a well-documented set of biological effects that mainstream public health messaging has largely ignored.

Here is what the research shows:

Nicotine raises resting metabolic rate by roughly 6-10%, which translates to an additional 200 calories burned per day without any change in diet. [6, 7]

It inhibits aromatase—the enzyme that converts testosterone to estrogen—by more than 50% in some studies. [8]

Chronic use lowers prolactin, TSH, LH, FSH, and growth hormone, all of which are associated with aging and metabolic dysfunction. [9]

"Serum prolactin levels are significantly lower in both male and female chronic smokers who smoke more than 10 cigarettes per day.”

"Chronic nicotine consumption may also lead to lower responses of other stress hormones (ACTH, prolactin, growth hormone) to a variety of stimuli.”

"Nicotine activates the sympathoadrenal system and increases the synthesis and release of noradrenaline and adrenaline into circulation, and also alters the bioavailability of dopamine."

It increases dopamine synthesis, reduces serotonin, and raises neurosteroid levels of pregnenolone and progesterone. [10, 11, 12]

Cotinine, nicotine's primary metabolite, has been shown to reduce amyloid-beta deposition in Alzheimer's models and improve working memory. [13]

There is also evidence for neuroprotection against Parkinson's disease, anti-epileptic effects, and increased osteoblast activity—which has a protective effect against osteoporosis. [14, 15, 16]

Nicotine has also demonstrated reliable improvements in attention, working memory, and fine motor skills in both smokers and healthy non-smokers. [17]

And controlled clinical trials have shown that transdermal nicotine produces meaningful improvement in active ulcerative colitis. [18]

“At 4 weeks, 12 of 31 patients (39%) who received nicotine showed clinical improvement compared with 3 of 33 patients (9%) who received placebo (P = 0.007).”

Chronic exposure to nicotine has been shown to enhance insulin sensitivity through activation of the α7 nicotinic acetylcholine receptor, independent of weight loss. [19]

Transdermal nicotine has shown meaningful clinical improvement in non-smokers with late-life depression, improving both mood and cognitive performance. [20]

“Nicotine may be a promising therapy for depressed mood and cognitive performance in LLD.”

And nicotine has demonstrated broad anti-inflammatory effects across more than 20 disease models, with particularly strong evidence in ulcerative colitis, arthritis, and sepsis. [21]

Now, if you have more than 2 brain cells you’ll realize there’s a major caveats to what I’m arguing.

I don’t actually believe that smoking a pack a day is good for you.

I do believe, however, that nicotine has a large number of health-promoting effects, contrary to what the general public believes. Whether cigarettes fall into that category depends on their quality, additives, and how they are made.

I personally notice that when I smoke a couple of Marlboro Golds on a night out, my lungs feel like they’ve been coated with a thick layer of tar.

When I roll my own cigarettes with an additive-free tobacco (such as Manitou) and good filters and papers, I feel little to none of the negatives.

Do with this information what you will.

References:

[1] United Nations Department of Economic and Social Affairs (2024), World Population Prospects 2024

[2] World Health Organization (2023), WHO Report on the Global Tobacco Epidemic: Japan Country Profile

[3] Nakaji et al. (2003), Explanations for the Smoking Paradox in Japan

[4] Buettner, D. (2011), National Geographic, Ikaría at Dusk

[5] Kreouzi et al. (2024), Lessons Learned from Blue Zones, Lifestyle Medicine Pillars and Beyond

[6] Perkins et al. (1989), Acute Effects of Nicotine on Resting Metabolic Rate in Cigarette Smokers

[7] Hofstetter et al. (1986), Increased 24-Hour Energy Expenditure in Cigarette Smokers

[8] Biegon et al. (2010), Nicotine Blocks Brain Estrogen Synthase (Aromatase): In Vivo Positron Emission Tomography Studies in Female Baboons

[9] Tziomalos et al. (2004), Endocrine Effects of Tobacco Smoking

[10] Porcu et al. (2003), Nicotine-Induced Changes in Cerebrocortical Neuroactive Steroids and Plasma Corticosterone Concentrations in the Rat

[11] Hiremagalur & Sabban (1993), Nicotine Increases Expression of Tyrosine Hydroxylase

[12] Yoshida et al. (2002), Alcohol and Nicotine Administration Inhibits Serotonin Synthesis and Tryptophan Hydroxylase Expression in Dorsal and Median Raphe of Young Rats

[13] Echeverria et al. (2011), Cotinine Reduces Amyloid-β Aggregation and Improves Memory in Alzheimer’s Disease Mice

[14] Quik et al. (2012), Nicotine as a Potential Neuroprotective Agent for Parkinson’s Disease, Movement Disorders

[15] Willoughby et al. (2003), Nicotine as an Antiepileptic Agent in ADNFLE: An N-of-One Study

[16] Daffner et al. (2013), Nicotine Increases Osteoblast Activity of Induced Bone Marrow Stromal Cells in a Dose-Dependent Manner

[17] Heishman et al. (2010), Meta-Analysis of the Acute Effects of Nicotine and Smoking on Human Performance

[18] Sandborn et al. (1997), Transdermal Nicotine for Mildly to Moderately Active Ulcerative Colitis: A Randomized, Double-Blind, Placebo-Controlled Trial

[19] Xu et al. (2012), Chronic Exposure to Nicotine Enhances Insulin Sensitivity through α7 Nicotinic Acetylcholine Receptor-STAT3 Pathway

[20] Gandelman et al. (2018), Transdermal Nicotine for the Treatment of Mood and Cognitive Symptoms in Non-Smokers with Late-Life Depression

[21] Su et al. (2022), Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects