I have found that my energy levels are one of the most important conditions in my life. Whenever my energy levels are good, everything is much easier. Furthermore, whenever my energy levels are high my mood is much better – partly because of a shared underlying neurobiology between energy & mood, partly because in times of high energy I get more stuff done, and partly because having high energy simply feels good.
Unfortunately, many people struggle with low energy levels. In fact, “I am tired all the time” (fatigue) is one of the most frequent complaints at the doctor’s office. According to one study, 40 percent of adults experience daytime tiredness severe enough to interfere with their daily activities. They are always tired or even exhausted, which makes life hard and unenjoyable.
Even more unfortunately, in my experience, the vast majority of doctors are spectacularly incompetent at doing anything about it.
On the one hand, there are the evidence-based medicine worshippers, incapable of non-dogmatic thought, who will test for a pathetically small set of laboratory parameters all of which come back “normal” most of the time, eventually telling people to eat better, sleep more, and exercise. Thanks. Sometimes they give out stimulants and antidepressants or send their patients to a psychotherapist.
Then there are the cowboys doing whatever the hell they want. For example, a friend complaining of fatigue went to a specialist and was told to have all her dental fillings removed and replaced because they were “very likely” the cause of her fatigue. Another friend was prescribed an expensive lymphocyte subtype profiling on his first visit. Then there are the acupuncturists.
Fed up with doctors, many people embark on their own and go down the supplement rabbit hole. Unfortunately, in the vast majority of cases, no amount of carnitine, CoQ10, NMN, or exotic herb XY, will make much of a non-placebo difference (other than to people’s wallet and the wallet of the sellers). Sure, people may feel somewhat better (even in a non-placebo way) but rarely does it solve the underlying problem unless a deficiency was causing the problem in the first place.
In this article, I will line out 13 common and often overlooked causes of fatigue and low energy levels, some of them obvious, others not so much. They are listed in no particular order.
#1 Poor sleep quality
Wakefulness is sort of “low-level brain damage” and sleep is necessary to reset the brain because there are a large number of cellular processes that can only be carried out during sleep. These include clearing out metabolic detritus, reregulating the expression of a large number of neuronal genes, executing hundreds of cellular housekeeping tasks, and synaptic regulation.
Without sufficient sleep, the nervous system is dysregulated. One of the most common symptoms is the homeostatic drive to get the organism to sleep through sleepiness and fatigue.
Interventions
- Realigning the Circadian rhythm with melatonin and morning bright light exposure
- Reducing caffeine intake (or cutting out caffeine completely)
- Using earplugs
- Installing blackout curtains
- Using cooling devices such as cooling blankets, Chili Pad, or Easy Sleep mattresses
- Supplements: magnesium, glycine, taurine
- If all else fails, (temporary) use of hypnotic agents
I discuss my sleep optimization protocol in more detail here.
Sleep apnea
Sleep apnea is worth mentioning separately because it is quite common and usually undiagnosed. Sleep apnea, even light sleep apnea, can wreck energy levels.
Interventions
- Sleep laboratory
- CPAP device
- Losing weight (particularly body fat)
#2 Low blood pressure
In medicine, all the talk is about hypertension, while hypotension is usually disregarded. Low blood pressure can sometimes not only cause dizziness when standing up but can also cause fatigue.
Low blood pressure can be “idiopathic” (no cause can be found), due to anemia, due to a diet low in sodium, or due to hormone deficiencies. In fact, low levels of cortisol, thyroid hormones, or leptin can all cause low blood pressure.
In my early twenties, I sometimes used to have low blood pressure after heavy cardio workouts. It took a while for me to realize that this kind of exercise-related “fatigue” was not true fatigue but just hypotension.
Interventions
- Measuring blood pressure correctly
- Getting hormones properly checked out
- Eating more sodium
- Midodrine, a selective a1-receptor agonist
- Fludrocortisone, a synthetic aldosterone with a long half-life
#3 Hormone deficiencies
Many of these hormones have a major say in central nervous system neurotransmission in one way or another.
Among other things, receptors for these hormones are found in many neural structures associated with energy and alertness, such as the locus coeruleus in the brain stem (the major source of brain noradrenaline), and the tuberomammillary nucleus in the hypothalamus (the major source of brain histamine).
If one of the major hormones (IGF-1, testosterone, estradiol, T3, leptin, cortisol) is deficient, this is often accompanied by fatigue. While many of the fatigue symptoms are unspecific, such as low energy levels, each hormone deficiency is associated with a distinct kind of fatigue.
I will now discuss how fatigue for a major hormone deficiency typically “feels” like.
Thyroid hormones
Thyroid hormones regulate the speed of cellular metabolism and when they are low, everything happens more slowly. In a way, thyroid hormones set the idle for the system. Low thyroid hormones are associated with fatigue at rest (during “idle” states).
For example, when my thyroid hormones were low, I often got sleepy while I was reading something and I also needed a long time to get going in the morning. Whenever I was mentally or physically stimulated, the fatigue improved markedly, presumably because the stress hormones cortisol and adrenaline took over.
Cortisol
Even though the symptoms of cortisol and thyroid hormone deficiency tend to overlap, the fatigue associated with these feels somewhat different. With low levels of cortisol, I felt “like crap” in the morning, whereas with low levels of thyroid hormones, I just felt groggy and sleepy. With low levels of thyroid hormones I got lethargic and sleepy at rest, whereas with low levels of cortisol, I felt best when resting.
If thyroid hormones set the idle state, cortisol is the gas pedal. Cortisol prepares the body and mind for action, and gives energy, clarity, and “punch”. As my cortisol was low, being active took a lot of effort and I often wanted to not do anything that required physical activity.
Mentally I was drowsy and brain-foggy and found it hard to concentrate. Physically, I felt “weak” and my limbs felt quite “heavy”. I was also exhausted at night as if somebody had pulled my batteries.
As I supplemented with even low doses of cortisone acetate, all these symptoms went away. In fact, out of all the hormones I have experimented with, low cortisol caused me to feel the most miserable (short of low leptin levels) but also produced the quickest and most drastic improvement with replacement.
Sex hormones
Many males experience fatigue if their testosterone is low. Both testosterone and estradiol regulate the sympathetic nervous system and a deficiency in either can cause people to feel tired. Furthermore, many report a state of low mood and little zest for life. Testosterone is a major regulator of dopamine levels and thus motivation.
The decrease in sympathetic nervous system output in combination with low dopaminergic neurotransmission, causes a distinct kind of “background exhaustion”.
Growth hormone/IGF-1
Growth hormone/IGF-1 deficiency causes quite unspecific symptoms of tiredness, exhaustion, and poor recovery. Growth hormone deficiency is also associated with little vigor, reduced well-being, and sometimes depression.
I discuss my experience with GH in a little more detail here.
Leptin
The fatigue associated with low leptin levels is twofold. Firstly, leptin is a master regulator of hypothalamic and pituitary hormone output and if leptin levels are low, so are levels of many of the other major hormones.
Secondly, hypoleptinemia itself causes a distinct kind of “restless” fatigue even if other hormones are replaced. Leptin receptors are widely distributed in the central nervous system and the fatigue is in part due to leptin regulating neurogenesis, noradrenaline, and histamine levels whereas the restlessness is due to an increase in dopamine levels (which presumably serves the purpose of increasing foraging behaviors in starved animals).
A note on hormone replacement
Even people who are not hormone deficient usually experience an increase in energy levels if one of the hormones mentioned above is exogenously introduced. This is one of the reasons why I supplemented with a low dose of thyroid hormones for a long time even though my thyroid hormones were technically “normal”. (I recently stopped but I may return to thyroid hormones at some point in the future).
Some doctors (sometimes) check for one of these hormones. More often than not, lab tests come back “normal” – though the “normal” reference range often spans a factor of three or more. Somebody with three times as much hormone X will surely feel and function much differently compared to someone with only one-third as much – despite both being considered “normal”.
Interventions
- Hormones are a huge topic, and I discuss some of them, including diagnostics & interventions, in more detail here.
#4 Depression
What many people fail to understand is that, from a neurobiological perspective, depression has little to do with “suffering all the time”. Depression means nothing more than “a downward deviation from baseline” ultimately caused by changes in gene expression in the central nervous system leading to, for example, reduced monoaminergic signaling (dopamine, noradrenaline, histamine, serotonin) and a drop in neuroplasticity, manifesting as a decline in energy, mood, or motivation.
A common form of slight depression that occurs in almost everyone is the seasonal dip in energy and mood during the winter months. Full-blown seasonal affective disorder is only the most extreme version.
Latent depression often goes unrecognized and not until people do something about it, do they realize that they had been depressed (which, as mentioned, does not necessarily mean that they are “suffering”). The opposite of depression is not happiness but rather vitality.
Interventions
- Depression is a huge topic. I discuss how I personally would go about treating it in more detail here.
#5 Being on the wrong diet
Some people feel much better if they reduce carbohydrate intake, particularly overweight and sedentary individuals, while others feel much worse. Some people feel much better if they do intermittent fasting, while others feel much worse. Similar things hold true for the ketogenic diet. We are all different and different people react differently to the same intervention.
However, I would like to clear up one of the misconceptions that “insulin is bad”. Insulin per se is not bad at all and it has many great effects on multiple body and brain systems. “High insulin all the time” is bad.
Interventions
- I share many thoughts on diet and related topics here.
#6 Allergies & food insensitivities
Many people have allergies or food insensitivities that rob them of vitality without them being aware. Frequent culprits are eggs, dairy, cashews, and grains.
Interventions
- Strategic elimination diets
- Blood test: eosinophils, IgE levels
- Antihistamines: While antihistamines can combat some of the fatigue associated with allergies, antihistamines also cause some tiredness by themselves as hypothalamic histamine levels are one of the key regulators of alertness. Second-generation antihistamines are much better than the first-generation but some blood-brain-barrier penetration is still present. Furthermore, some parts of the hypothalamus have no or a naturally “leaky” blood-brain barrier (circumventricular organs), which 2nd-gen antihistamines can reach.
#7 Low levels of iron or vitamin B12
Both iron and B12 are necessary for countless things and low levels of both iron or vitamin B12 are associated with fatigue.
Other nutrient deficiencies that frequently cause fatigue are sodium, magnesium, or zink.
Interventions
- B12 injections: I inject 3mg of vitamin B12 three to four times per year
- Iron supplementation: OTC supplements have a terrible cost-benefit ratio because of the low iron content. Prescription iron is much more cost-effective.
- I discuss other supplements in more detail here.
#8 Stimulant abuse (current or past)
I discuss the downsides of stimulant abuse in more detail here.
Similar to how starvation can “imprint” on the nervous system, so can substance abuse. Withdrawal from stimulants (including prescription stimulants) can sometimes last a long time, presumably due to stubborn changes in gene expression and long-term depression (LTD) in certain neural networks associated with alertness and attention.
Furthermore, harsh stimulants such as amphetamine are potentially neurotoxic.
Interventions
- Tapering & patience
- Switching from a harsher stimulant to a less harsh one (e.g., from amphetamines to bupropion)
#9 Gut issues
A good friend of mine has gut issues and whenever he eats something “bad” (he has a whole list of foods he does not tolerate well) his energy and mood go through the floor. As a result, he meticulously plans out his diet but after years of doctor-shopping, expensive microbiome tests, experiments with various kinds of prebiotics and probiotics, “microbiome reset protocols” with rifaximin, etc. he still has not found the exact cause. He only knows that he has few to no bifidobacteria.
Gut health is a huge topic and is not solely limited to the microbiome. Gut issues include leaky gut, small intestinal bacterial overgrowth, food sensitivities (e.g., gluten, eggs, dairy), NSAID overuse, candida overgrowth, H. pylori infection, ENS overactivity, and irritable and inflammatory bowel disorders.
I discuss gut health, and some strategies to improve it, in more detail here.
Interventions
- Avoiding gut-irritating stuff such as carrageenan, NSAIDs, and alcohol.
- Going on a cumbersome elimination diet and reintroducing potential trigger foods one by one. Insensitivity tests, such as Cyrex, can sometimes be helpful.
- Experimenting with various probiotics and prebiotics. However, probiotics can oftentimes make things worse.
- Performing a gut flora “reset” with rifaximin (a gut-targeted antibiotic).
- Stopping metformin.
- Experimenting with eating more (or less) fiber – and also experimenting with different kinds of fiber.
- Supplementing with psyllium husk (a mostly insoluble fiber) to increase bulk, promote bowel movements, and “coat” the gut lining protecting it from mechanical irritation.
- Supplementing with low doses of inulin (a prebiotic soluble fiber) to help with increasing “good” gut bacteria (e.g., certain species of lactobacilli and bifidobacterial), to decrease intestinal permeability, and to promote the microbial secretion of short-chain fatty acids (SCFA), the latter of which are linked to an improvement in intestinal barrier function (e.g., LPS translocation), metabolic health, and gastrointestinal immune function. Acacia fiber is basically “slow-release inulin” with reduced side effects (e.g., indigestion, bloating, flatulence) and supplementing with it can be particularly helpful to adapt to inulin supplementation.
- Getting thyroid hormones checked out.
- Eating small amounts of fermented foods every day. However, people with a histamine intolerance can react badly to fermented foods.
#10 Low caloric intake
I may be biased because of my personal experience, but in my opinion, a low caloric intake is a very common cause of low energy levels. This one is one of the simplest things to fix on this list (but far from the easiest – because many people are obsessed with “fitness” relying on TDEE calculators).
In the past, I was eating 2000-2500 calories for a long time and I always felt like crap. In a stepwise fashion, I increased my caloric intake to about 4000 calories over the course of about half a year (disclaimer: I do about 1h of intense exercise per day and I naturally do have a fast metabolism). Lo and behold, my energy levels and mood went way up and my body fat levels stayed essentially the same (verified by two DEXA scans taken 6 months apart).
Increasing my caloric intake was one of the most powerful interventions I ever did. Without being aware, I had been undereating for a long time, and because I can’t beat physics (i.e., my body can just give out what I put in) my body adapted to the low caloric intake, which presumably goes far beyond hormonal changes.
There are a plethora of mechanisms for how caloric intake is signaled to the nervous system, including short-acting gi-peptides (e.g., GLP1, CCK, insulin), direct vagal nerve endings, receptors for nutrients at the level of the hypothalamus, and leptin levels. These will ultimately co-determine energy expenditure.
One of the most misunderstood concepts is that caloric intake should not be judged by whether someone is losing or gaining weight because of the large arsenal of adaptive feedback mechanisms that increase or decrease energy expenditure, including sympathetic nervous system activity, “tiny” activity levels (NEAT), and hormonal systems.
Depending on one’s genetics, energy expenditure may increase quickly (as it did with me) or it may take a long time.
I discuss this in more detail here: Why Weight Loss is Not About Calories In Vs. Calories Out
Interventions
- Reverse dieting (e.g., increasing calories by about 100kcal per week)
#11 Past crash diet
Related to the point above, crash diets can potentially “imprint” on the nervous system and individuals may suffer for a long time to come.
For example, subjects of the TV show The Biggest Loser burned about 500kcal less than before (despite weight regain) six years after the fact.
Similarly, patients who are recovered from anorexia nervosa still show much reduced brain noradrenaline levels four years after recovery. The importance of noradrenaline is discussed here. The changes presumably extend to much more than just noradrenaline levels.
It is possible, and in my opinion probable, that many people may never fully recover from a severe enough crash diet.
Interventions
- Avoiding crash diets & starvation states
- GLP-1 agonists such as semaglutide can potentially speed up recovery if caloric intake is maintained or increased at the same time and/or weight does not decline. However, GLP-1 agonists are probably far from sufficient because they act on measly G-protein coupled receptors.
- Starvation is almost single-handedly induced by a stepwise drop in plasma leptin levels. Similarly, metreleptin has been shown to reverse the adaptations to weight loss (if caloric intake is sufficient). In my opinion, pharmacological leptin manipulations may be the most promising, and perhaps only intervention (as the intervention is causal) to fully reverse starvation-induced stubborn adaptations in the central nervous system without having to gain a bunch of weight.
#12 Latent inflammation
Inflammation, more specifically cytokines (inflammatory mediators), acts on many brain sites and puts the brain into “sickness mode”, including a drop in monoaminergic signaling (dopamine, noradrenaline, serotonin, histamine) and neurogenesis, ultimately resulting in poor energy levels and mood. I discuss sickness behavior in more detail here.
Latent inflammation can have many causes, ranging from obesity, and autoimmune diseases, to undetected pathogens.
Interventions
- Getting properly checked out by a rheumatologist.
- Blood test: CRP (which is an indicator of systemic inflammation)
- Taking a short course of doxycycline (e.g., 100mg/d for 14 days): Doxycycline is an interesting antibiotic with a great ability to kill lots of intracellular exotic microorganisms such as borrelia bacteria, the pathogens causing Lyme disease. Doxycycline is also effective against certain protist species (which are not bacteria but rather eucaryotes).
- Some people benefit from taking a short course of itraconazole, an azole antimycotic agent that kills off unwanted fungal co-residents. Itraconazole has a better blood-brain-barrier penetration than other antimycotics.
- Everolimus and rapamycin make some people feel immediately better, potentially because of their ability to reduce neuroinflammation. Of note, everolimus has a greater ability to penetrate the blood brain barrier and is therefore presumably more effective than rapamycin for this purpose. Rapamycin is discussed in more detail here.
#13 Recent (or sometimes not so recent) viral infection
Long COVID wrecked the life of one of my best friends. For months he slept 12-15 hours per day, had post-exertional malaise (energy crashes after increased activity), and a host of psychiatric symptoms he never had before. We tried many things and what helped him were everolimus and low-dose naltrexone, though he is still far from cured.
Another friend was literally taken out for 1 year after an infection with EBV and it took him a long time to make the connection.
At the extreme end, viral infections can cause ME/CFS and at the less extreme end, they can cause tiredness for many months to come. Long COVID is somewhere in the middle. How exactly viral infections bring about lingering fatigue is poorly understood but it may ultimately have to do with neuroinflammation and stubborn gene expression in the central nervous system.
I discuss my Long-COVID prevention protocol in more detail here.
Unfortunately, there is no definite treatment but there are a couple of things that may help.
Interventions
- Patience & pacing: Things often get better on their own – though sometimes it takes a long time. Anecdotally, things seem to get better faster if people pace themselves, meaning they avoid any exertion whatsoever. Also anecdotally, people who do not pace themselves are made worse, sometimes permanently, by the ensuing crashes.
- Some people report benefits by taking a low dose of naltrexone.
- NSAIDs, such as dexibuprofen, help reduce sickness behavior
- Ketamine administration can temporarily (1-2 weeks) counteract the neuroinflammation-induced drop in neuroplasticity, which is associated with tiredness, among other things.
- mTOR inhibitors such as rapamycin or everolimus (discussed below).
- Some people report benefits from taking minocycline, which through a poorly understood mechanism inhibits microglia (macrophages that are resident in the central nervous system)
- Adopting a ketogenic diet
- Supplements rarely make a meaningful difference though some people report very small improvements from n-acetyl cysteine (NAC), alpha-lipoic acid (ALA), and coenzyme Q10. Supplements are discussed in more detail here.
- Last in line is rituximab, a CD20-targeting antibody that depletes B lymphocytes. It is hypothesized that, in some people, symptoms may be due to cross-reacting antibodies (e.g., autoantibodies targeting muscarinic or beta-adrenergic receptors).
- Related to rituximab, it may be the case that, in some people, there is something in the blood plasma (perhaps autoantibodies, perhaps something else) that is co-responsible for the symptoms. Anecdotally, removing that via plasmapheresis helps some. In fact, in Germany, whole businesses are being built around this.
Bonus – Genetics: Some people are just born lucky
Even if all of the above are “fixed”, some people will still have low energy levels due to their genetics…and there is little one can do about it.
Conversely, some people just seem to have great energy levels despite a “terrible” lifestyle in the same way that some people make it past 100 years despite smoking & drinking for decades. Similar to longevity or the capacity to build a great physique, energy levels have strong genetic underpinnings.
Until the many different genetic underpinnings of vitality have been elucidated and gene therapies become more widely available, we are stuck with biohacking, which though is pathetically inferior to genetic factors. I discuss this in more detail here: Biohacking Can’t Beat Genetics
Disclaimer
The content available on this website is based on the author’s individual research, opinions, and personal experiences. It is intended solely for informational and entertainment purposes and does not constitute medical advice. The author does not endorse the use of supplements, pharmaceutical drugs, or hormones without the direct oversight of a qualified physician. People should never disregard professional medical advice or delay in seeking it because of something they have read on the internet.