canucklifter
New Member
My notes on fat loss. Includes DNP/T3/Clen etc so felt like it belonged here
Fat Loss Notes
-== This is not medical advice. I have zero medical background, I'm a software engineer. ==-
-== Over the years, I've obsessively researched various topics in the general banner of fat loss. I've read everything from anecdotes from individuals or coaches on blog posts, forums and podcasts to reading many, many research papers on PubMed, and most recently subscribing to several research reviews to make sure I knew how to interpret the results of the research correctly. It's not an exaggeration to say I've spent thousands of hours and read thousands of viewpoints on this topic. I'm not going to cite sources here, because I don't have the time. But finding the research that backs claims I make should not be that hard with a few minutes and a google search. ==-
-== After doing all of this research I found there was a large gap in between claims ('yohimbine burns stubborn fat') and the actual mechanisms underpinning them. You can find thousands of anecdotal recommendations on forums, but no one bothers to explain WHY their recommendation is correct. Often times, the recommendations are unfounded. I wanted to try to tie common practices back into their scientific underpinnings. ==-
-== None of this is advice. Some of the compounds mentioned in the 'chemical interventions' section I have used myself, and many I have not. The ones I've decided not to use, I generally researched thoroughly before making the decision not to use them. I'm not an expert in their use at all, and this isn't meant as an expert guide. It's an overview and intro.
-== Consider this article to be for entertainment purposes only. Never begin any dietary, supplement or pharmacological intervention without consulting a doctor first. ==-
-== Introduction ==-
For the majority of people, the energy balance model is sufficient for fat loss. Excellent results can be achieved by calorie input and energy output manipulations.
Intermediate level fat loss involves understanding the major hormones underlying fat storage and loss. This usually leads to strategies such as fasted LISS cardio, insulin control mechanisms, targeted intake of food around non-insulin mediated glucose uptake, or using extended periods of ketosis. While these are all more advanced strategies than simple energy balance, the majority of them have been shown in multiple studies to have a very minor effect on overall body composition.
Advanced fat loss is where supplements and OTC stimulants come into play. These are usually used without knowledge of their underlying biological interactions, which frequently causes them to be used incorrectly.
Finally, extreme fat loss involves pharmacological interventions; often with the goal of disrupting the bodies counter regulatory mechanisms to fat loss. Certain medications act on the same systems as the supplements in advanced fat loss but to a more advanced degree, or with higher side effects.
This article is organized from the bottom up, beginning with the basics of energy balance, then delving into cellular energy metabolism, continuing on to hormones involved in regulating metabolism and finally on to compounds that selectively increase fat burning. It wraps up with an overview of common chemical/pharmacological interventions and ties their mechanisms back into learnings from earlier sections.
1 - Energy Balance
2 - Energy metabolism, storage
3 - Primary metabolic hormones
4 - Catecholamines and adrenergic receptors
5 - Chemical interventions
-== Energy Balance ==-
Everything flows from energy balance, and only in extreme circumstances will fat loss not be directly tied to energy balance. Energy balance is a model in which food is viewed as an energy input to the system (the human body), and activity (including everything from sitting at rest to hard exercise) is energy output. In this context, 'food' and 'energy' are used almost interchangeably.
The basis of energy balance is rooted in the intersection of the first law of thermodynamics - energy can never be created or destroyed - and the simple fact that animal life requires energy to perform its functions, which it receives in the form of food. If you do not eat food, you will die, because every process in your body from cell division to brain function requires energy to perform. This first law has far-reaching implications. This ranges from the simple: you cannot gain fat from drinking water, to the less-obvious: things that have little to no caloric content cannot cause you to gain weight.
People tend to understand the simple cases without issue - water does not cause you to gain fat. They become less clear about topics such as artificial sweeteners, because of mixed messaging in the media that artificial sweeteners may cause fat gain, by doing things like 'messing with hormones'. However, as asserted earlier, the key principle that you cannot generate energy from things without energy, and artificial sweeteners do not contain energy, proves these arguments incorrect. As a thought experiment, it's quite clear that no matter your hormonal status, water will not provide energy. Chemically, neither do the compounds used in artificial sweeteners. Your body cannot convert them to useable energy; just as it can't convert glass into energy (try living off of marbles for a week). So, while these chemicals may end up affecting your metabolism in subtle ways, they cannot directly cause you to gain fat.
The other side of the energy balance equation is easier to grasp - activity requires energy. The more vigorous the activity, the more energy is required. The body requires energy simply to survive, even if placed in a coma, as bodily functions such as cellular division (which is constantly occurring in your body, not just when you're growing), brain function (the brain is a primary consumer of energy), even breathing. Energy metabolism is complex, and there are many systems in the body that affect its efficiency, so the energy consumed by activity (in other words, calories burned during exercise), is not fixed. It varies from person to person and over time for a given person.
When the body is in equilibrium, energy taken in equal to energy expended, no weight change is generally noted. This is known as 'homeostasis', and a diet of this type is called 'isocaloric'. A diet where more energy is taken in than is expended is called 'hypercaloric' and generally results in weight gain, a diet where less energy is taken in than is expended is called 'hypocaloric'. Now, various systems in the body affect exactly where the lines between these live, and these vary over time. But following on the above, if you eat less energy than you require, you will lose weight (conversely, gain weight).
There's a fallacy that some people cannot lose weight, even though they are eating a hypocaloric diet. While the observed effect is accurate, the presumed cause is not. In prolonged hypocaloric periods, the body will do several things: increase the efficiency of its use of energy, conversely decreasing the energy used to power activity. Thus, energy conservation and the energy balance model are preserved. Taken to the extreme, the body cannot counter regulate enough to survive long periods of outright starvation. No one can live without food. The food needed to support basic bodily functions may become extremely low, however.
Now that we have a basic understanding of energy balance, the follow-on question for someone seeking to lose weight is: 'So, how much should I eat/exercise?'. We need to delve into the 'energy output' side of the equation further to answer this.
As mentioned, the body requires some amount of energy simply to survive, without exercise. This is known as the 'Basal Metabolic Rate'. This varies between populations, and many studies have produced different ways of estimating it. The simplest one is fairly accurate - bodyweight in pounds multiplied by 10-12 (with metabolism, a range is always provided to recognize inter-individual differences).
The next step is to estimate the effect size of several contributors to actual energy expenditure. Broadly, these are non-exercise daily activity (a cubicle worker vs. a construction worker), daily exercise activity, and the ability of food to alter metabolic rate.
Non-exercise activity, broadly, is any daily activity not generally considered formal 'exercise'. It varies based on a person's job and lifestyle, and also based things like how fidgety a person is, or how frequently they get up from the couch for any reason. A term 'Non-Exercise Activity Thermogenesis' is used in this context, where Thermogenesis (literally, creation of heat) is a proxy for energy used by the body (energy use generally releases heat as a byproduct). NEAT can vary wildly between people, to the degree of many hundreds or more calories a day.
Formal activity is fairly well understood. Running for an hour will burn calories. As with estimation of BMR, studies have been conducted to determine an average level of calories burned per minute of exercise based on bodyweight. These numbers are guesses, it's not fixed that running for one hour will burn 400 calories, so be aware that these numbers may vary significantly from person to person.
13
Finally, digestion of food does require energy. Protein is the most metabolically intensive to digest, carbohydrates and fats less so. Again, averages are presented based on macronutrient type although the exact type of food may cause changes here - it's less energy-consuming to digest pure dextrose (sugar) than it is to consume a whole wheat bread.
Generally the way people model this is to combine a 'total non-exercise metabolic rate' estimate, plus estimates of exercise on any given day. The total non-exercise metabolic rate can be estimated times bodyweight in pounds. Add any energy expenditure from exercise on top of that to determine a rough guideline of energy use for a given day.
Now that we have a target energy output, we can begin to alter body composition by intentionally under- or over- eating. If our total energy expenditure is 3000, we would eat less than that to lose weight. The final piece of the equation is to determine how much more/less than the energy expenditure to eat. The ideal starting point is around a 10% deficit/surplus. 20% is aggressive, and 30% is the highest that anyone can achieve without significant counter regulatory mechanisms kicking in.
Note that nowhere in this discussion is a rule given for how much body weight, in pounds, can be given or lost in a given time frame. There's a rough rule that 3500 calories = one pound of fat, but that's quite loose. For one thing, when beginning a new diet, there's often a large fluctuation in weight in the first two weeks. This isn't actually due to fat loss, simply water content changes in the body. Food in the body - especially carbohydrate - is stored along with some amount of water. So, changing the amount of food intake affects the amount of water you're storing. This can easily cause a 5% weight swing in a matter of days. Once on a diet plan for over two weeks, week to week changes are more indicative of actual body weight changes. For example, if your energy expenditure is 3000, and you begin a diet at 2500 calories, you may notice a 5 pound weight drop in the first week, 1 pound in the second week, nothing in the third week and 1 pound in the third week. In actuality, you're likely using about one pound a week, but your water balance is changing as your body adapts to the new caloric intake - first by reducing water stores, then a counter regulatory system kicks in in the third week to attempt to counter the water loss by storing more water. In week four things have stabilized and a pound of weight loss is observed. The week after you might see 3 pounds of drop. The takeaway is to not over index on body weight. If the scale is moving in the right direct on a biweekly basis, the diet is working.
In closing, remember that these numbers for energy expenditure are estimates. One should stick to a given caloric intake for two weeks to determine its effect. If after two weeks, no weight change or body composition change (don't fully rely on the scale) is noticed, an adjustment up or down should be made.
The vast majorities of people do not need or want to delve into this topic further than understanding energy balance. The effects of the following chapters are miniscule compared to the effect of energy balance. However, some will want to understand at a more fundamental level how these systems function. The following chapters cover this.
-== Energy Metabolism ==-
Energy expenditure/'calorie burn' is usually taken for granted, without understanding the underlying mechanisms. This chapter gives an overview of the primary systems here: basic cellular metabolism, primary energy stores (glycogen), and secondary energy stores (adipose tissue).
Let's start at the bottom: cellular metabolism. A cell's primary energy source is Adenosine Triphosphate, ATP. This molecule releases energy in the form of a phosphate when used, degrading into Adenosine Diphosphate, ADP. Thus, a cell's energy must come from processes that convert ADP into ATP. There are three primary processes here: Glycolysis, the Citric Acid Cycle, and Beta-oxidation. Feel free to read up more on these, but their differences are simply in their substrates. Glycolysis uses glycogen or glycerol (body stores of glucose), Beta oxidation uses fatty acids, and the Krebs cycle is fed by the outputs of these two. The key takeaway here is that the energy in a cell, in the form of ATP, can be replenished either via glycogen/glycerol, or fatty acids. The next step in understanding here is to guess where glycogen/glycerol and fatty acids come from.
Flipping back up to the top, we start with the macronutrients protein, carbohydrate and fat. The digested versions of these are amino acids (protein), glucose (carbohydrates), and triglycerides (sometimes in di- or mono-glyceride, or free fatty acid + glycerol formation) (fat). Some degree of conversion between these is possible. Both amino acids and triglycerides can be converted into glucose via gluconeogenesis. However, this process only functions at significant levels when the body is deprived of a direct source of glucose (carbohydrate). Specifically, glucagon is secreted by the pancreas in reaction to low blood sugars, which regulates gluconeogenesis. In short, low blood sugar can trigger protein and fat conversion to glucose for use as energy within the cell.
Amino acids may also be stored in various muscle tissues. There is no long-term store in the body for amino acids, so if you overconsume protein one day, and your muscles have already uptaken their 'fill', the amino group is stripped and ultimately converted into urea to be urinated out, and 'alpha-keto acid' to be converted into energy or stored. However, this process is very inefficient. As such, 1 calorie of protein and 1 calorie of carbohydrate do not result in the same net energy to be burned or stored.
Glucose may be used directly as an energy source, stored as glycogen in the liver or skeletal muscle, or converted into fat via fatty acid synthesis in the cell (technically, the acetyl-CoA produced by glycolysis is converted into fat).
Fat can be converted into glucose via gluconeogenesis, or stored as fat.
Now, just because all of these substrates can be converted to fat doesn't mean they convert at the same rates. I don't know of any studies that compare the rates directly, but it's fairly well known that eating a calorically equivalent amount of protein, fat or carb will not result in the same net fat storage. Carbohydrates and fat convert readily into adipose tissue, but protein requires a very energy intensive conversion process. Studies have demonstrated repeatedly that increasing if eating an isocaloric diet, increasing protein amounts does not contribute to fat gain as readily as the same energy increase from carbohydrates or fats.
As mentioned above, the body has no long-term amino acids store. It does, however, have long-term glucose and fatty acids stores. There are three primary storage sites at play: skeletal muscle glycogen, liver glycogen, and adipose tissue. They differ in their potential size, preferential usage and turnover.
Liver glycogen is used by the body to control stable blood sugar levels. If depleted, it is the first site that will be replenished by excess blood glucose. However, it only stores around 100-120g of glycogen. The brain alone can use 120g of glucose a day, so on a restrictive diet this store may deplete rapidly, and keep in mind 120g of glucose is not very much.
Skeletal muscle glycogen is more interesting. While the body will store into the liver preferentially, it's not as simple as deciding that it will store in skeletal muscle next. While it is true that a depleted muscle glycogen store will be filled, if there is excess blood glucose and the liver is already full, the rate of skeletal muscle glucose uptake is dependent on several pathways that are rate limited. One primary mechanism for glucose uptake in both skeletal muscle and adipose tissue is the Glucose Transporter Type 4 (GLUT-4). This is activated by both exercise (technically, skeletal muscle contraction, so it's a localized effect) and via insulin. We'll go more into insulin later, but for now it's sufficient to know that it's released by the liver in response to high blood glucose. A side note here is since GLUT4 is present on both skeletal muscle and adipose tissue; increased insulin levels cause higher storage rates in both sites. However, non-insulin mediated GLUT-4 translocation (AKA, exercise induced translocation) is limited to skeletal muscle. This allows you to preferentially store glucose in skeletal muscle over adipose tissue.
A last point on the two glycogen stores: liver glycogen can and is released into the blood stream to maintain stable blood sugar levels. Muscle glycogen is not readily released into the blood stream, and can primarily be used only to provide energy to muscle cells.
Adipose tissue is the largest store of energy in the body, of theoretically unlimited size. Although it goes through various intermediate forms, they are eventually stored as triglycerides (a combination of fatty acid and glycerol). Triglycerides are readily stored as adipose tissue, as no conversion is required for their storage. However, the overall metabolic environment determines their storage. If blood sugar is low, such as in a hypocaloric environment, triglycerides are released from adipose tissue to undergo gluconeogenesis. If blood sugar is high (such as in a hypercaloric environment), insulin is increased which causes triglyceride storage. If the hypercaloric environment is driven by an excess of fat, insulin will not be elevated, but excess fat is still stored as adipose tissue, although the mechanisms here are not well understood. Acyclation stimulating protein is a possibility, but the research there is lacking. It may be that excess triglyceride levels in a low insulin environment cause an upregulation of gluconeogenesis, and the subsequent insulin release triggers storage of other triglycerides.
It's also important to note that triglycerides are a precursor to steroid hormones, and the integrity of cell walls. Severely restricting fats is extremely unhealthy, although the amount required for health function is not likely that high (25-30% of bodyweight in pounds, in grams may be the lowest healthy range).
-== Primary metabolic hormones ==-
Insulin has been detailed above as a storage hormone released by the liver in response to high blood glucose. This is true, although a bit simplistic. Protein, and likely to some degree fat, stimulates insulin release. Insulin is viewed as a 'storage hormone', as it signals muscle and fat cells to increase their uptake rates of energy (both triglycerides and glucose). This serves to regulate blood sugar - since insulin is released in response to high blood sugar, and it signals cells to store the glucose present in the blood, the effect is a lower circulating blood glucose.
Insulin is paired with a similar but opposite hormone, glucagon, which is released in response to low blood sugar. Glucagon causes the liver to release glycogen and promotes lipolysis in adipose tissue (although this lipolytic effect may be minimal in humans).
Insulin manipulation strategies, such as eating a diet that promotes ketosis, have been theorized to increase the rate of fat burning. The underlying theory is that since insulin causes fat cells to store circulating triglycerides (and glucose after conversion to triglycerides), maintaing lower levels of insulin would lower the rates of energy storage in adipose tissue. However, this theory has been thoroughly debunked. This goes back to the learning in chapter one, that energy balance is the primary driver of body composition changes. Consider that a diet with insulinogenic foods may cause a rise in blood sugar, triggering insulin release and energy storage in adipose tissue. At this point, blood sugar has been lowered. The lowered blood sugar will trigger lipolysis, so the energy that was stored in adipose tissue is now released. This has been demonstrated in many extremely well controlled studies.
Of course, eating a diet that prevents chronically elevated blood glucose levels is both healthy and promotes lower body fat levels. But the cause of fat storage with chronically elevated blood glucose (even in diabetics) is NOT the presence of insulin itself, it's the present of an excess of calories triggering prolonged insulin release. If you remove the root cause of elevated blood glucose, the issue resolves itself. If you suppress insulin release or insulin's efficiency without removing the issue of excess calories, you'll die of blood glucose toxicity. The issue isn't the insulin; it's the elevated blood glucose.
All of this adds up to an extremely adaptive system, with multiple regulatory stages. Individual cells may store energy locally in the form of ATP, and have multiple systems to regenerate that ATP from varying sources. There are multiple transport methods that a cell may use to intake energy from the blood, activated in response to different metabolic conditions. Blood energy levels (glucose, triglycerides, and free fatty acids) have multiple regulatory systems to ensure that the ideal level of energy is present in both hypo- and hyper- caloric conditions. The effects of insulin and glucagon, while powerful, are often misrepresented. Some foods stimulate their release to higher degrees than other, but even when insulin and glucagon levels are stable (either due to dietary choices or medical intervention); net energy intake still drives the accumulation or dissipation of the body’s energy stores. Much of this adaptability comes from the body's ability to convert various energy sources into the fuel it needs to function. Amino acids may be converted to triglycerides or glucose, glucose may be converted to triglycerides and triglycerides may be converted to glucose. Due to this adaptability, dietary manipulations while holding total energy (and micronutrient levels) stable often have very minor effects on overall body composition.
Finally, a quick note on ketone metabolism. In the presence of chronically depressed blood sugar, the body needs to find a way to provide energy to the brain, which is generally fueled by glucose. As the conversion of fat to glucose is inherently rate-limited, there is a parallel system that can provide fuel to the brain (and other cells) - ketones. Thus, when gluconeogenesis is not producing sufficient blood glucose levels, the body will ramp up ketosis, a process in which fatty acids are converted to ketone bodies which cells in the body, especially the brain, my use as a fuel source. This has combined with the insulin hypothesis to promote diets that result in ketosis as an ideal fat loss technique. While the insulin hypothesis, and thus the effectiveness of a ketosis diet over any other hypocaloric diet has been debunked, ketosis diets are still in favor by many people. A hypocaloric diet that includes carbohydrates will cause blood sugar fluctuations during the day, often leading to periods of 'brain fog'. However, a state of ketosis provides a more stable energy level and thus may provide better overall feeling while in a dieting state. However, ketones are not an effective source of energy for skeletal muscle, and so performance of anaerobic activities will suffer on ketosis diet. As such, an athlete will need to decide if periods of brain fog are more or less important than maintaining performance. As a final note on ketosis diets, protein has a marked effect in insulin secretion, and as such a high protein diet may impair ketosis. A true ketosis diet is high fat, low to moderate protein and very low carbohydrate. This style of diet may line up well with the general population's needs, but has proven suboptimal for athletes.
It's also worth briefly discussing the thyroid hormones triiodothyronine (T3) and thyroxine (T4). In a normally functioning thyroid, the release of these hormones is scaled based on energy input to scale overall metabolism. T3 directly increases cardiac output, hear rate, ventilation rate, basal metabolic rate, potentiates catecholamines (next chapter) effect, and increases catabolism of proteins and carbohydrates. T4 is a precursor to T3, and does not exert direct effects. In a prolonged hypocaloric period a decrease in T3 will be observed, and vice versa in prolonged hypercaloric periods. The release of these hormones is dependent on long-term energy increases; their release is not directly tied to any given meal as with insulin. Their use as a chemical intervention will be discussed later.
-== Catecholamine effects on metabolism ==-
Before delving into advanced and extreme fat loss interventions, we need to briefly discuss the role of two catecholamines: epinephrine and norepinephrine, as the systems they regulate are often the targets of chemical weight loss intervention. Epinephrine (adrenalin) and norepinephrine (noradrenalin) activate various receptors ('adrenergic receptors') on various cells. The proliferation of these receptors varies based on cell type, and the specific receptor target is present in higher concentrations in different cells.
At a high level, both epinephrine and norepinephrine activate the adrenergic receptors, although at varying rates. There are two types of receptors: alpha and beta, which are further broken down into alpha-1, alpha-2, beta-1, beta-2 and beta-3. Certain receptors have a stronger binding affinity to epinephrine, and others to norepinephrine, but in general these catecholamines assert their affects through these receptors. The effects of these are widespread, but the primary ones to be aware of for affecting energy metabolism are discussed below. Key terms are 'adrenergic agonist' - a compound that directly activates an adrenergic receptor - and 'adrenergic antagonist' - a compound that blocks the effects of a receptor from being activated.
Alpha-2 receptor activation suppresses norepinephrine release, causes vasoconstriction and venoconstriction, and inhibits lipolysis. All of these suppress fat loss mechanisms, and as such, alpha-2 receptor antagonists (compounds that block its effects) are used to promote fat loss.
Beta-2 receptors cause smooth muscle relaxation in the bronchi, and as such many of the agonists for this receptor were developed to treat asthma patients. As a target of norepinephrine, it aids in vasodilation to increase systemic blood flow and increases mass and constriction speed of striated muscle, important as norepinephrine is key in the fight-or-flight response. Its activation also interferes with motor nerves, and may cause tremors. Beta-2 activation also stimulates glycogenolysis (glucose release from glycogen) and gluconeogenesis directly. Finally, beta-2 activation forms cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A, which causes lipolysis in adipose tissue and hepatic gluconeogenesis, while increasing skeletal muscle glycolysis and simultaneously inhibiting it in the liver. Note that it also inhibits glycogenesis, and so while activated it may be more difficult to replenish glycogen stores. After all, its purpose is to make as much glucose available as possible to the system. All in all, this produces a hefty punch when it comes to body recomposition.
Beta-3 receptors are located primarily in adipose tissue, and on activation enhance lipolysis. It also increases thermogenesis in skeletal muscle. As thermogenesis is nothing more than the body releasing free energy in the form of heat, and increase in thermogenesis implies an increase in energy output.
Through a combination of these receptors, the overall effect of epinephrine and norepinephrine are to increase heart rate and cardiac output, increase the production of free energy (glucose release via glycolysis and fatty acid release via lipolysis), and prime the nervous system for action. While certain chemical interventions have selective effects on the adrenergic receptors, epinephrine and norepinephrine themselves are slightly blunter.
-== 4: Chemical interventions ==-
Now that we have a reasonable theoretical basis for metabolism and various systems that act on it, we can begin to try to find ways to 'game' the system. Some have already been touched on, like ketosis diets based on the insulin hypothesis. In general, there are many dietary structures that attempt to alter body composition by exerting targeted effects on various metabolic regulatory pathways. Most of these fall short, as the body is extremely good at maintaining homeostasis. At least, in the absence of exogenous chemicals.
These chemicals range from the common (caffeine) to the extreme (2,4 Dinitrophenol). These will be outline below, tying them into previous section's notes on metabolism.
Again, this is not medical advice. It's not advice at all, it's simply information. The use, or abuse, of these compounds can cause serious health effects, and their effects pale in comparison to overall energy balance. In other words, you could take extreme doses of the harshest of these chemicals and cause serious, permanent damage to your body without losing any fat if your caloric intake is too high.
Caffeine. Caffeine is the most widely consumed psychoactive drug, acting as a central nervous system stimulant. Its primary action is to inhibit the adenosine receptor, which is a regulatory receptor in the nervous system that increases drowsiness. Caffeine ingestion increases plasma epinephrine and norepinephrine levels, thus acting as an adrenergic agonist. This increase in catecholamines is varied, and appears to be moderated by repeated use. Its direct impact on the adenosine receptor also causes downstream lipolysis directly, separately from the increase in catecholamines. Due to the downregulation of its effects on catecholamine production, cycling caffeine may be useful. Also, the side effects of caffeine may become pronounced in high doses, and become self-defeating. High doses of caffeine can directly impair sleep, and either via that effect or via chronically depressed adenosine activation can lead to increases in cortisol (anecdotally). As cortisol is bluntly catabolic, it directly contributes to muscle wasting. As such, caffeine in moderation (especially with cycling) can provide noted increases in lipolysis, but its abuse is more likely to cause systemic issues such as extreme fatigue, muscle wasting and general depression. Finally, caffeine is useful as an appetite suppressant and I find that 150-300mg a day is the ideal dose, often I prefer to stay near 150mg a day and combine it with other stimulants so that the side effects of any one stimulant are minimized. Effects are felt around 20-30 minutes after intake, and half-life is 5-6 hours.
Nicotine. Nicotine has a lot of societal baggage due to its association with tobacco products, but when isolated from tobacco (gum, lozenges or patches) it can be used as a stimulant and nootropic. Nicotine activates the release of epinephrine and norepinephrine, apparently in a dose-dependent manner. It may also directly promote lipolysis, although there appears to be counter regulatory effects as well. Either through its production of catecholamines or other mechanisms it acts as an appetite suppressant. Finally, it also appears to stimulate the release of endogenous opioids, causing a feeling of general wellbeing, calm or euphoria. Of course, even when removed from tobacco nicotine is highly addictive. Some liken using nicotine for fat loss to using methamphetamines for fat loss. As mentioned above, this guide is not a list of recommendations. It's up to each individual to weigh the risk/rewards. The downsides of nicotine are clear: addiction. The benefits may include stimulating fat loss via catecholamine release, possible direct lypolytic effects, appetite suppression and feelings of general wellbeing. Tolerance varies wildly from person to person, if new to nicotine a low dose should be used. I started with 2mg of nicotine gum once a day, I now find two 4mg pieces a day to give a great effect on appetite suppression, energy levels, focus and generally feeling good - one upon waking, one at the afternoon slump. Overuse can be extremely uncomfortable (a general feeling of 'something is wrong') and so buildup of dose should be gradual. Make sure to space doses out no more frequently than one piece of gum every two hours. I prefer to only use nicotine as needed, and never for longer than two weeks at a time, in an attempt to avoid tolerance, dependence, or addiction. Nicotine gum's effect can be noticed minutes after beginning to chew a piece, and the half-life is 1-2 hours.
Yohimbine HCL. Yohimbine HCL acts as an alpha-2 antagonist. As the alpha-2 receptor is counter regulatory to norepinephrine, this causes a systemic increase in norepinephrine and fat loss via secondary activation of adrenergic receptors. As alpha-2 also inhibits lipolysis, its antagonism effectively increases lipolysis in target tissues. There's anecdotal evidence that alpha-2 receptors are more prolific in 'stubborn/trouble fat areas'. It makes sense that 'stubborn' fat might be so at least in part due to a proliferation of a receptor that dulls fat loss. As such, yohimbine may help selectively reduce these 'stubborn' fat deposits. Note that Yohimbine's effects are strongly blunted by insulin, and it acts mainly to release fatty acids (not to stimulate their ultimate use as energy), so it is only really effective when fasting. Yohimbine is usually dosed at a maximum of .2mg/kg of bodyweight. I usually use about half that dose, as higher amounts can cause uncomfortable jitters, racing heart rate, and general feelings of unease. I find 10mg (at a bodyweight of 230lb) before fasted cardio brings a great energy and focus, the time just flies by. It's unclear if Yohimbine's effects are blunted over time, but most tend to use it for no longer than 4-6 weeks. It should be taken around 30 minutes before activity, and half-life is around 1.5 hours. Make sure to get Yohimbine HCL (the isolated chemical) - not Yohimbe (the tree bark the chemical is derived from), as Yohimbe carries many negative side effects and is less effective at fat burning.
Clenbuterol (and to a lesser extent, albuterol). Clenbuterol and albuterol are both selective beta-2 agonists. As outlined in the chapter about catecholamines and adrenergic receptors, beta-2 activation has a multitude of body recomposition effects. In general, clenbuterol directly increases lipolysis (fat release from adipose tissue), fat conversion to usable energy (gluconeogenesis), and overall metabolic rate and thermogenesis. This is often noted by a measurable increase in body temperature around one hour after clenbuterol use, which is sustained. Side effects can be pronounced at the dosages used for fat loss, including a noted increase in body heat and sweating, and hand tremors. Dehydration is a risk due to the thermogenic effects. Further, clebuterol tends to deplete the body's taurine stores greatly, which can cause extreme cramping and benign fasiculations. As such, 2.5-5g of Taurine (split doses are effective) should be used. Effects are generally noticeable around one hour after ingestion, and the half-life is 28-36 hours. Even with the long half-life, there's a noticeable peak after ingestion, and as such many choose to split larger dosages into multiple daily doses. Common dosing protocols begin at 20mcg and pyramid up at varying rates. Some recommend a two weeks on / two weeks off protocol as the beta-2 receptor is sensitive to downregulation. That might look like 20mcg starting dose, increasing by 20mcg every 4 days to a highest dose of 80mcg. Others will start clenbuterol 6 weeks out from a contest and increase the dosage weekly: /100/120. 120mcg daily should never be exceeded or there is a high risk of permanent heart damage. Also, be careful with higher doses combined with high intensity activity, as the combination may lead to heart attack. Some people use the antihistamine ketotifen to attempt to prevent the beta cell downregulation, although there isn't a strong scientific underpinning to support that this has the desired effect, and anecdotes on its effectiveness are mixed.
Ephedrine. Ephedrine directly stimulates the beta adrenergic cells, while having little effect on the alpha cells. As with all beta adrenergic agonists, this causes lipolysis, gluconeogenesis, and thermogenesis. It's often used similarly to clenbuterol; although the side effects may be less (it's unclear if this is due to lower dosages, its shorter half-life, or other reasons). It's generally cycled two on / two off to avoid receptor downregulation (as with clenbuterol). Dosages when stacked with other stimulants (caffeine and ephedrine are often combined) is generally 20-25mg three times a day. Extreme doses of 150mg are not well tolerated by most.
T3/T4. T3 is used to increase basal metabolic rate, either to supraphysiologic levels or simply to maintain baseline levels when dieting. However, its use needs to be very carefully controlled as there are many negative effects. First, T3 increases metabolism in all cells, vs. promoting lipolysis as with catecholamine manipulations. This creates noticeable muscle wasting in a dose-response manner. As such, high doses are rarely seen due to the high muscle wasting they cause. High level bodybuilders will only risk this with high anabolic usage to offset the muscle wasting. T3 can cause muscles to flatten out, as the rate of glucose use may increase past the ability of the cell to uptake it, which both makes the person look and feel weaker. Finally, unlike catecholamine manipulations which don't tend to cause long-term damage to the underlying systems when used in moderation, exogenous T3 use will suppress the body's natural thyroid function. If this is done for extended periods of time (greater than 6-8 weeks), the body may take months or years to return to baseline function (and may never achieve it). As such, usage is normally only for the final weeks of competition prep. 25mcg is thought to be the exogenous equivalent of normal endogenous levels, and as such may be sufficient to maintain normal metabolic rate when dieting. Any greater dose will increase metabolic rate past basal levels, at which time muscle wasting and glucose uptake issues become noticeable. 50mcg is the most common dosage most coaches recommend. Some extreme users will go as high as 100mcg for short periods of time.
Injectable L-Carnitine. L-Carnitine's oral bioavailability is poor, so for a true fat burning effect an injectable form must be used. In fact, it's been proven very poor as a fat burner when taken orally (except in those deficient in it). L-Carnitine is generally good for cellular and mitochondrial health, and may help prevent certain negative effects of aging such as neurological decline and has beneficial effects on cognitive function. It's used to increase beta-oxidation rates (and thus fat burning), as such shifting the cell's metabolism more in favor of burning fat directly. It's absorption by the cell is rate-limited, and absorption is boosted by high insulin levels. As a simple compound (vs. pharmacological compound), it doesn't have any appreciable serum half-life, and so dosages are best taken pre-workout. There is a loading phase until peak intracellular L-Carnitine levels are reached, at which point the maximum benefit is realized. Dosing protocols for fat loss generally combine it with highly insulinogenic carbohydrates (simple sugars), to attempt to increase intracellular levels to supraphysiologic levels by combining high serum levels (due to injection) plus increasing absorption rates by stimulating insulin release. Astute readers may recognize other ways to increase serum insulin levels exogenously, but that's out of scope for this article. As beta-oxidation inside the cell is limited by more than just L-Carnitine, there is a limited usefulness here instead of a dose-response relationship. Because this maximum benefit is far below levels that cause side-effects, and L-Carnitine is a substrate of beta-oxidation itself (instead of a compound that stimulates beta-oxidation), it can be used quite safely for extended periods of time. Often it is used through an entire competition prep cycle of 8-12 weeks at moderate dosages. Note: if a competitor must drop carbohydrates to very low levels to lose fat, they may not be able to maintain the recommendation of combining the L-Carnitine injection with insulinogenic carbohydrates. However, this is only needed during the loading phase. It may be maintained later to keep levels as high as possible, but is primarily critical during loading.
2,4 Dinitrophenol (DNP). DNP is widely considered the most dangerous fat burner, namely because its lethal dose is very close to its normally used dose, and that misuse of the drug is irrecoverably fatal. Consider that the lethal dose (LD50) of caffeine is about 150-200mg/kg of bodyweight, and the normal dose followed is around 1.5mg/kg. The LD50 of DNP can scale from 400-2500mg (scales with the temperature of the user's environment, this range is from 60F-110F), and common usage is around 400-600mg a day. Further, its long half-life (36 hours) makes overdose especially hard to manage. DNP is also used as a dye, and as a fertilizer.
The way that DNP works is by decoupling oxidative phosphorylation. Oxidative phosphorylation is part of the citric acid (Krebs) cycle, where energy in the form of electrons is transferred across the mitochondrial boundary, fueled by protons generated by the citric acid cycle. This is used to generated ATP - energy from outside the mitochondria is 'pumped' inside due to the electron differential created by the citric acid cycle. Those electrons are then used to create ATP. DNP diffuses the electron gradient - in layman’s terms, it severely impairs the pump - so the cell has to work extra hard to generate ATP. The energy that would have been used to generate ATP is instead burned off as heat.
This has many downstream effects. The most important is a rise in body temperature due to the electrons being 'wasted' as heat. This is uncomfortable at low doses and nearly unmanageable at moderate doses and of course downright deadly at higher doses. There is no antidote to DNP, once it's in the system it will be cleared only at its half-life rate. As such, an overdose will quite literally cook the person from the inside out. The only way to lower the extreme body temperature is an ice bath, and past a certain DNP level that will not be sufficient to cool the person down. It's worth mentioning that DNP has been used historically to keep Russian soldiers alive in harsh winters.
A second effect is extreme dehydration and electrolyte imbalance. Water consumption must ramp up; many users cite consuming 1.5-2 gallons a day. Electrolyte supplementation is important, but as DNP does not deplete the electrolytes at the same rate, must be done cautiously. There are anecdotal reports of issues with potassium retention, and thus excessive supplementation may cause toxicity. However, the electrolyte depletion can be to such a high amount in general that organ failure becomes a strong concern, especially as the extreme heat may cause a loss of electrolytes that the digestive system cannot match. As such, electrolyte supplementation is essential. But the exact breakdown of electrolytes used must be researched.
The third noticeable effect is just an extrapolation from its mechanism of action - extreme fatigue. As DNP makes it difficult for a cell to generate the energy it needs to fuel itself, every action (even simply lying down) is made more difficult. Put another way, if DNP makes you burn 30% more calories, it does so by making every action you take 30% more difficult. The rest of your body's systems may be functioning fine, but if there isn't energy at the cellular level, you can't function.
Finally, DNP causes both muscle flatness and water retention. The first's cause is clear, as the cell fights to generate energy it will preferentially use stored glycogen. Thus, glycogen is rapidly depleted. The causes for holding water are less clear / studied, but are not surprising given the combination of a need to sweat excessively and electrolyte balance issues.
This effect is less noticeable but critical: over-revving the Krebs cycle causes significant oxidation in the cell (it is driven by many oxidative reactions). This causes the generation of a high level of oxidative stress, a process which does direct harm to the cell and its ability to proliferate. DNP has been noted as a cancer treatment, it may be due to this reason. Nothing can be done to limit this issue, as it's driven by the primary mechanism of the drug. Many users will take high dosages of antioxidants (berry extract, Vitamins C and E, Alpha-Lipoic Acid), but it's unclear if these actually have any effect.
Combined, this makes DNP an extremely dangerous drug that most will not use. Those that do use it generally stick between 200 and 400mg a week for a maximum of 2 weeks. Many will limit that to 10 days. It's also critical to take significant time off between usage, at minimum twice as long as the period of use (10 days on, 20 days off) as it will take that long to both fully clear the drug from the system, and then allow the body to restore proper water and electrolyte balances and recover from the oxidative stress. Some people have tried two on / two off, and find either that runs after the first are not as effective or that the side effects are magnified (likely because of long clearance times of the drug).
Stacks, stack support supplementation and general discussion. Many of the above may be combined synergistically, especially when their mechanisms of action are well understood. For example, combining clenbuterol - a beta-2 agonist, with ephedrine, a general beta-agonist, is not ideal as they compete for receptors sites to bind to. However, ephedrine and caffeine are commonly stacked, perhaps because even though caffeine does indirectly stimulate beta cells, that's not its primary mechanism of action. By combining the two, a lower dose of each can be used, thus keeping clear of each separate system's counter regulatory properties. However, clenbuterol and caffeine are rarely stacked, as clenbuterol already causes a marked increase in heart and respiratory rates, and adding caffeine onto that can result in overstimulation.
Another common stack is to add T3 to the use of the above. This is generally not because any two are synergistic, but because these advanced/extreme fat burners are generally employed when a competitor is already extremely lean, and thus already has a suppressed metabolic rate. The T3 allows them to use chemicals to artificially enhance their fat loss, while maintaining a higher basal metabolic rate. In this case, T3 is not used at high doses as its primary goal is maintaining the metabolism, not boosting it. This allows for compounds that directly metabolize fat (especially problem areas) to ramp the metabolism, instead of using high dose T3 and risking muscle wasting. Any fat burners may be used in combination with T3, as T3 is not a primary CNS stimulant. Using T3 when more than 2-3% above a competition body fat percentage is likely a waste, as the thyroid is fairly resilient to dieting when the dieter is at higher body fat levels.
Injectable L-Carnitine may be combined with any of the other compounds mentioned. It is not a stimulant, and serves to enhance natural fat burning pathways instead of 'revving them up'.
Electrolyte supplementation and a concurrent increase in water intake are a must with all stimulant fat burners. Quite simply, they all increase thermogenesis to some degree, causing the body to need to sweat to cool itself down. This must be replenished. If using any of these in high dosages or for extended periods of time, a blood panel should be drawn to check for issues.
Personally, I like a combination of caffeine and nicotine at a dose of 150mg / 4mg. I find this avoids any jitters or overstimulation, instead providing a clear mind and focus levels. Adding in 10mg of Yohimbine increases the stimulatory effect, but not to unmanageable levels. However, as all three stimulate the nervous system, it's a fine line between a clear, focused stimulation and feeling very uncomfortable.
I find that clenbuterol, while undeniably effective, provides an extreme fatigue at higher dosages. This is likely due to its persistent activation of the nervous system causing a general fatigue of that system. As such, shorter cycles (two on/two off) at moderate dosages (the system doesn't downregulate much in two weeks’ time) are preferred. I do not combine other stimulants with clenbuterol, as I find the heart rate increases it brings on its own when doing heavy weight training are already quite high.
Finally, a reasonable question to ask is: 'How much fat will these burn'? That's a very tough and very individual question. You'll see people cite things like '3% increase in metabolic rate', 'extra 100 calories a day', but these aren't based on anything. Realistically, I view the real usage of these compounds more simply. Stimulant-type fat burners are great to keep energy levels up when in a caloric deficit. This allows you to train harder, maintain normal activity levels, and power through cardio. This effect can be worth their use alone. Alpha-adrenergic antagonists and beta-adrenergic agonists have an added effect of helping reduce 'stubborn fat'. It's tough to quantify this in terms of calories or weight lost, but the evidence in the mirror of their use is noticeable when at low body fat levels. T3, DNP, and L-Carnitine are far more difficult to gauge. T3 really shouldn't be used to increase metabolic rate much, more to maintain baseline levels when extremely lean. L-Carnitine may increase fat use, but you can't really quantify its effects. You'd just need to try it. DNP increases fat burn greatly, but at the risk of death.
-== Conclusion ==-
In this article we've built from the simple concept of energy balance to advanced chemical usage. Depending on the person's goals, different levels of intervention may be used. Most of the chemical compounds have notable major side effects, and are only useful when used for short periods of time. As such, if someone is overweight and beginning a fat loss journey, chemical interventions are neither necessary, nor advisable. When the body has high fat levels, it's quite simple (although not always easy) to drop significant amounts of body fat. Eating in a caloric deficit with high body fat stores does not cause the significant metabolic slowdown seen in lean individuals, which inherently makes sense. Why would the body need to slow it's metabolism down if it has tons of stored energy to use?
At the intermediate level (lean body fat levels), dieting can become more difficult. OTC supplements like caffeine may be used here to maintain energy levels during the day when dieting.
At the advanced level (early competition prep, very lean body fat levels) you start considering chemical interventions. Injectable L-Carnitine, clenbuterol, ephedrine and yohimbine often come into the picture here. T3 is often used when hitting competition body fat levels to maintain basal metabolic rate, but generally only in combination with anabolics to offset muscle wasting.
DNP is rarely used by anyone due to its extreme danger. It also, quite frankly, isn't needed by anyone. All the other chemicals mentioned are sufficient to hit competition shape.
In closing, it's important to remember that the foundation, and most critical level of body recomposition, is energy balance. You can easily out-eat any of the chemicals mentioned, and they're effects are generally small enough that the side effects are not worth it unless you're already at a very lean body fat level. While there may be no silver bullet, fat loss is remarkably simple. All it takes is time.
Fat Loss Notes
-== This is not medical advice. I have zero medical background, I'm a software engineer. ==-
-== Over the years, I've obsessively researched various topics in the general banner of fat loss. I've read everything from anecdotes from individuals or coaches on blog posts, forums and podcasts to reading many, many research papers on PubMed, and most recently subscribing to several research reviews to make sure I knew how to interpret the results of the research correctly. It's not an exaggeration to say I've spent thousands of hours and read thousands of viewpoints on this topic. I'm not going to cite sources here, because I don't have the time. But finding the research that backs claims I make should not be that hard with a few minutes and a google search. ==-
-== After doing all of this research I found there was a large gap in between claims ('yohimbine burns stubborn fat') and the actual mechanisms underpinning them. You can find thousands of anecdotal recommendations on forums, but no one bothers to explain WHY their recommendation is correct. Often times, the recommendations are unfounded. I wanted to try to tie common practices back into their scientific underpinnings. ==-
-== None of this is advice. Some of the compounds mentioned in the 'chemical interventions' section I have used myself, and many I have not. The ones I've decided not to use, I generally researched thoroughly before making the decision not to use them. I'm not an expert in their use at all, and this isn't meant as an expert guide. It's an overview and intro.
-== Consider this article to be for entertainment purposes only. Never begin any dietary, supplement or pharmacological intervention without consulting a doctor first. ==-
-== Introduction ==-
For the majority of people, the energy balance model is sufficient for fat loss. Excellent results can be achieved by calorie input and energy output manipulations.
Intermediate level fat loss involves understanding the major hormones underlying fat storage and loss. This usually leads to strategies such as fasted LISS cardio, insulin control mechanisms, targeted intake of food around non-insulin mediated glucose uptake, or using extended periods of ketosis. While these are all more advanced strategies than simple energy balance, the majority of them have been shown in multiple studies to have a very minor effect on overall body composition.
Advanced fat loss is where supplements and OTC stimulants come into play. These are usually used without knowledge of their underlying biological interactions, which frequently causes them to be used incorrectly.
Finally, extreme fat loss involves pharmacological interventions; often with the goal of disrupting the bodies counter regulatory mechanisms to fat loss. Certain medications act on the same systems as the supplements in advanced fat loss but to a more advanced degree, or with higher side effects.
This article is organized from the bottom up, beginning with the basics of energy balance, then delving into cellular energy metabolism, continuing on to hormones involved in regulating metabolism and finally on to compounds that selectively increase fat burning. It wraps up with an overview of common chemical/pharmacological interventions and ties their mechanisms back into learnings from earlier sections.
1 - Energy Balance
2 - Energy metabolism, storage
3 - Primary metabolic hormones
4 - Catecholamines and adrenergic receptors
5 - Chemical interventions
-== Energy Balance ==-
Everything flows from energy balance, and only in extreme circumstances will fat loss not be directly tied to energy balance. Energy balance is a model in which food is viewed as an energy input to the system (the human body), and activity (including everything from sitting at rest to hard exercise) is energy output. In this context, 'food' and 'energy' are used almost interchangeably.
The basis of energy balance is rooted in the intersection of the first law of thermodynamics - energy can never be created or destroyed - and the simple fact that animal life requires energy to perform its functions, which it receives in the form of food. If you do not eat food, you will die, because every process in your body from cell division to brain function requires energy to perform. This first law has far-reaching implications. This ranges from the simple: you cannot gain fat from drinking water, to the less-obvious: things that have little to no caloric content cannot cause you to gain weight.
People tend to understand the simple cases without issue - water does not cause you to gain fat. They become less clear about topics such as artificial sweeteners, because of mixed messaging in the media that artificial sweeteners may cause fat gain, by doing things like 'messing with hormones'. However, as asserted earlier, the key principle that you cannot generate energy from things without energy, and artificial sweeteners do not contain energy, proves these arguments incorrect. As a thought experiment, it's quite clear that no matter your hormonal status, water will not provide energy. Chemically, neither do the compounds used in artificial sweeteners. Your body cannot convert them to useable energy; just as it can't convert glass into energy (try living off of marbles for a week). So, while these chemicals may end up affecting your metabolism in subtle ways, they cannot directly cause you to gain fat.
The other side of the energy balance equation is easier to grasp - activity requires energy. The more vigorous the activity, the more energy is required. The body requires energy simply to survive, even if placed in a coma, as bodily functions such as cellular division (which is constantly occurring in your body, not just when you're growing), brain function (the brain is a primary consumer of energy), even breathing. Energy metabolism is complex, and there are many systems in the body that affect its efficiency, so the energy consumed by activity (in other words, calories burned during exercise), is not fixed. It varies from person to person and over time for a given person.
When the body is in equilibrium, energy taken in equal to energy expended, no weight change is generally noted. This is known as 'homeostasis', and a diet of this type is called 'isocaloric'. A diet where more energy is taken in than is expended is called 'hypercaloric' and generally results in weight gain, a diet where less energy is taken in than is expended is called 'hypocaloric'. Now, various systems in the body affect exactly where the lines between these live, and these vary over time. But following on the above, if you eat less energy than you require, you will lose weight (conversely, gain weight).
There's a fallacy that some people cannot lose weight, even though they are eating a hypocaloric diet. While the observed effect is accurate, the presumed cause is not. In prolonged hypocaloric periods, the body will do several things: increase the efficiency of its use of energy, conversely decreasing the energy used to power activity. Thus, energy conservation and the energy balance model are preserved. Taken to the extreme, the body cannot counter regulate enough to survive long periods of outright starvation. No one can live without food. The food needed to support basic bodily functions may become extremely low, however.
Now that we have a basic understanding of energy balance, the follow-on question for someone seeking to lose weight is: 'So, how much should I eat/exercise?'. We need to delve into the 'energy output' side of the equation further to answer this.
As mentioned, the body requires some amount of energy simply to survive, without exercise. This is known as the 'Basal Metabolic Rate'. This varies between populations, and many studies have produced different ways of estimating it. The simplest one is fairly accurate - bodyweight in pounds multiplied by 10-12 (with metabolism, a range is always provided to recognize inter-individual differences).
The next step is to estimate the effect size of several contributors to actual energy expenditure. Broadly, these are non-exercise daily activity (a cubicle worker vs. a construction worker), daily exercise activity, and the ability of food to alter metabolic rate.
Non-exercise activity, broadly, is any daily activity not generally considered formal 'exercise'. It varies based on a person's job and lifestyle, and also based things like how fidgety a person is, or how frequently they get up from the couch for any reason. A term 'Non-Exercise Activity Thermogenesis' is used in this context, where Thermogenesis (literally, creation of heat) is a proxy for energy used by the body (energy use generally releases heat as a byproduct). NEAT can vary wildly between people, to the degree of many hundreds or more calories a day.
Formal activity is fairly well understood. Running for an hour will burn calories. As with estimation of BMR, studies have been conducted to determine an average level of calories burned per minute of exercise based on bodyweight. These numbers are guesses, it's not fixed that running for one hour will burn 400 calories, so be aware that these numbers may vary significantly from person to person.
13
Finally, digestion of food does require energy. Protein is the most metabolically intensive to digest, carbohydrates and fats less so. Again, averages are presented based on macronutrient type although the exact type of food may cause changes here - it's less energy-consuming to digest pure dextrose (sugar) than it is to consume a whole wheat bread.
Generally the way people model this is to combine a 'total non-exercise metabolic rate' estimate, plus estimates of exercise on any given day. The total non-exercise metabolic rate can be estimated times bodyweight in pounds. Add any energy expenditure from exercise on top of that to determine a rough guideline of energy use for a given day.
Now that we have a target energy output, we can begin to alter body composition by intentionally under- or over- eating. If our total energy expenditure is 3000, we would eat less than that to lose weight. The final piece of the equation is to determine how much more/less than the energy expenditure to eat. The ideal starting point is around a 10% deficit/surplus. 20% is aggressive, and 30% is the highest that anyone can achieve without significant counter regulatory mechanisms kicking in.
Note that nowhere in this discussion is a rule given for how much body weight, in pounds, can be given or lost in a given time frame. There's a rough rule that 3500 calories = one pound of fat, but that's quite loose. For one thing, when beginning a new diet, there's often a large fluctuation in weight in the first two weeks. This isn't actually due to fat loss, simply water content changes in the body. Food in the body - especially carbohydrate - is stored along with some amount of water. So, changing the amount of food intake affects the amount of water you're storing. This can easily cause a 5% weight swing in a matter of days. Once on a diet plan for over two weeks, week to week changes are more indicative of actual body weight changes. For example, if your energy expenditure is 3000, and you begin a diet at 2500 calories, you may notice a 5 pound weight drop in the first week, 1 pound in the second week, nothing in the third week and 1 pound in the third week. In actuality, you're likely using about one pound a week, but your water balance is changing as your body adapts to the new caloric intake - first by reducing water stores, then a counter regulatory system kicks in in the third week to attempt to counter the water loss by storing more water. In week four things have stabilized and a pound of weight loss is observed. The week after you might see 3 pounds of drop. The takeaway is to not over index on body weight. If the scale is moving in the right direct on a biweekly basis, the diet is working.
In closing, remember that these numbers for energy expenditure are estimates. One should stick to a given caloric intake for two weeks to determine its effect. If after two weeks, no weight change or body composition change (don't fully rely on the scale) is noticed, an adjustment up or down should be made.
The vast majorities of people do not need or want to delve into this topic further than understanding energy balance. The effects of the following chapters are miniscule compared to the effect of energy balance. However, some will want to understand at a more fundamental level how these systems function. The following chapters cover this.
-== Energy Metabolism ==-
Energy expenditure/'calorie burn' is usually taken for granted, without understanding the underlying mechanisms. This chapter gives an overview of the primary systems here: basic cellular metabolism, primary energy stores (glycogen), and secondary energy stores (adipose tissue).
Let's start at the bottom: cellular metabolism. A cell's primary energy source is Adenosine Triphosphate, ATP. This molecule releases energy in the form of a phosphate when used, degrading into Adenosine Diphosphate, ADP. Thus, a cell's energy must come from processes that convert ADP into ATP. There are three primary processes here: Glycolysis, the Citric Acid Cycle, and Beta-oxidation. Feel free to read up more on these, but their differences are simply in their substrates. Glycolysis uses glycogen or glycerol (body stores of glucose), Beta oxidation uses fatty acids, and the Krebs cycle is fed by the outputs of these two. The key takeaway here is that the energy in a cell, in the form of ATP, can be replenished either via glycogen/glycerol, or fatty acids. The next step in understanding here is to guess where glycogen/glycerol and fatty acids come from.
Flipping back up to the top, we start with the macronutrients protein, carbohydrate and fat. The digested versions of these are amino acids (protein), glucose (carbohydrates), and triglycerides (sometimes in di- or mono-glyceride, or free fatty acid + glycerol formation) (fat). Some degree of conversion between these is possible. Both amino acids and triglycerides can be converted into glucose via gluconeogenesis. However, this process only functions at significant levels when the body is deprived of a direct source of glucose (carbohydrate). Specifically, glucagon is secreted by the pancreas in reaction to low blood sugars, which regulates gluconeogenesis. In short, low blood sugar can trigger protein and fat conversion to glucose for use as energy within the cell.
Amino acids may also be stored in various muscle tissues. There is no long-term store in the body for amino acids, so if you overconsume protein one day, and your muscles have already uptaken their 'fill', the amino group is stripped and ultimately converted into urea to be urinated out, and 'alpha-keto acid' to be converted into energy or stored. However, this process is very inefficient. As such, 1 calorie of protein and 1 calorie of carbohydrate do not result in the same net energy to be burned or stored.
Glucose may be used directly as an energy source, stored as glycogen in the liver or skeletal muscle, or converted into fat via fatty acid synthesis in the cell (technically, the acetyl-CoA produced by glycolysis is converted into fat).
Fat can be converted into glucose via gluconeogenesis, or stored as fat.
Now, just because all of these substrates can be converted to fat doesn't mean they convert at the same rates. I don't know of any studies that compare the rates directly, but it's fairly well known that eating a calorically equivalent amount of protein, fat or carb will not result in the same net fat storage. Carbohydrates and fat convert readily into adipose tissue, but protein requires a very energy intensive conversion process. Studies have demonstrated repeatedly that increasing if eating an isocaloric diet, increasing protein amounts does not contribute to fat gain as readily as the same energy increase from carbohydrates or fats.
As mentioned above, the body has no long-term amino acids store. It does, however, have long-term glucose and fatty acids stores. There are three primary storage sites at play: skeletal muscle glycogen, liver glycogen, and adipose tissue. They differ in their potential size, preferential usage and turnover.
Liver glycogen is used by the body to control stable blood sugar levels. If depleted, it is the first site that will be replenished by excess blood glucose. However, it only stores around 100-120g of glycogen. The brain alone can use 120g of glucose a day, so on a restrictive diet this store may deplete rapidly, and keep in mind 120g of glucose is not very much.
Skeletal muscle glycogen is more interesting. While the body will store into the liver preferentially, it's not as simple as deciding that it will store in skeletal muscle next. While it is true that a depleted muscle glycogen store will be filled, if there is excess blood glucose and the liver is already full, the rate of skeletal muscle glucose uptake is dependent on several pathways that are rate limited. One primary mechanism for glucose uptake in both skeletal muscle and adipose tissue is the Glucose Transporter Type 4 (GLUT-4). This is activated by both exercise (technically, skeletal muscle contraction, so it's a localized effect) and via insulin. We'll go more into insulin later, but for now it's sufficient to know that it's released by the liver in response to high blood glucose. A side note here is since GLUT4 is present on both skeletal muscle and adipose tissue; increased insulin levels cause higher storage rates in both sites. However, non-insulin mediated GLUT-4 translocation (AKA, exercise induced translocation) is limited to skeletal muscle. This allows you to preferentially store glucose in skeletal muscle over adipose tissue.
A last point on the two glycogen stores: liver glycogen can and is released into the blood stream to maintain stable blood sugar levels. Muscle glycogen is not readily released into the blood stream, and can primarily be used only to provide energy to muscle cells.
Adipose tissue is the largest store of energy in the body, of theoretically unlimited size. Although it goes through various intermediate forms, they are eventually stored as triglycerides (a combination of fatty acid and glycerol). Triglycerides are readily stored as adipose tissue, as no conversion is required for their storage. However, the overall metabolic environment determines their storage. If blood sugar is low, such as in a hypocaloric environment, triglycerides are released from adipose tissue to undergo gluconeogenesis. If blood sugar is high (such as in a hypercaloric environment), insulin is increased which causes triglyceride storage. If the hypercaloric environment is driven by an excess of fat, insulin will not be elevated, but excess fat is still stored as adipose tissue, although the mechanisms here are not well understood. Acyclation stimulating protein is a possibility, but the research there is lacking. It may be that excess triglyceride levels in a low insulin environment cause an upregulation of gluconeogenesis, and the subsequent insulin release triggers storage of other triglycerides.
It's also important to note that triglycerides are a precursor to steroid hormones, and the integrity of cell walls. Severely restricting fats is extremely unhealthy, although the amount required for health function is not likely that high (25-30% of bodyweight in pounds, in grams may be the lowest healthy range).
-== Primary metabolic hormones ==-
Insulin has been detailed above as a storage hormone released by the liver in response to high blood glucose. This is true, although a bit simplistic. Protein, and likely to some degree fat, stimulates insulin release. Insulin is viewed as a 'storage hormone', as it signals muscle and fat cells to increase their uptake rates of energy (both triglycerides and glucose). This serves to regulate blood sugar - since insulin is released in response to high blood sugar, and it signals cells to store the glucose present in the blood, the effect is a lower circulating blood glucose.
Insulin is paired with a similar but opposite hormone, glucagon, which is released in response to low blood sugar. Glucagon causes the liver to release glycogen and promotes lipolysis in adipose tissue (although this lipolytic effect may be minimal in humans).
Insulin manipulation strategies, such as eating a diet that promotes ketosis, have been theorized to increase the rate of fat burning. The underlying theory is that since insulin causes fat cells to store circulating triglycerides (and glucose after conversion to triglycerides), maintaing lower levels of insulin would lower the rates of energy storage in adipose tissue. However, this theory has been thoroughly debunked. This goes back to the learning in chapter one, that energy balance is the primary driver of body composition changes. Consider that a diet with insulinogenic foods may cause a rise in blood sugar, triggering insulin release and energy storage in adipose tissue. At this point, blood sugar has been lowered. The lowered blood sugar will trigger lipolysis, so the energy that was stored in adipose tissue is now released. This has been demonstrated in many extremely well controlled studies.
Of course, eating a diet that prevents chronically elevated blood glucose levels is both healthy and promotes lower body fat levels. But the cause of fat storage with chronically elevated blood glucose (even in diabetics) is NOT the presence of insulin itself, it's the present of an excess of calories triggering prolonged insulin release. If you remove the root cause of elevated blood glucose, the issue resolves itself. If you suppress insulin release or insulin's efficiency without removing the issue of excess calories, you'll die of blood glucose toxicity. The issue isn't the insulin; it's the elevated blood glucose.
All of this adds up to an extremely adaptive system, with multiple regulatory stages. Individual cells may store energy locally in the form of ATP, and have multiple systems to regenerate that ATP from varying sources. There are multiple transport methods that a cell may use to intake energy from the blood, activated in response to different metabolic conditions. Blood energy levels (glucose, triglycerides, and free fatty acids) have multiple regulatory systems to ensure that the ideal level of energy is present in both hypo- and hyper- caloric conditions. The effects of insulin and glucagon, while powerful, are often misrepresented. Some foods stimulate their release to higher degrees than other, but even when insulin and glucagon levels are stable (either due to dietary choices or medical intervention); net energy intake still drives the accumulation or dissipation of the body’s energy stores. Much of this adaptability comes from the body's ability to convert various energy sources into the fuel it needs to function. Amino acids may be converted to triglycerides or glucose, glucose may be converted to triglycerides and triglycerides may be converted to glucose. Due to this adaptability, dietary manipulations while holding total energy (and micronutrient levels) stable often have very minor effects on overall body composition.
Finally, a quick note on ketone metabolism. In the presence of chronically depressed blood sugar, the body needs to find a way to provide energy to the brain, which is generally fueled by glucose. As the conversion of fat to glucose is inherently rate-limited, there is a parallel system that can provide fuel to the brain (and other cells) - ketones. Thus, when gluconeogenesis is not producing sufficient blood glucose levels, the body will ramp up ketosis, a process in which fatty acids are converted to ketone bodies which cells in the body, especially the brain, my use as a fuel source. This has combined with the insulin hypothesis to promote diets that result in ketosis as an ideal fat loss technique. While the insulin hypothesis, and thus the effectiveness of a ketosis diet over any other hypocaloric diet has been debunked, ketosis diets are still in favor by many people. A hypocaloric diet that includes carbohydrates will cause blood sugar fluctuations during the day, often leading to periods of 'brain fog'. However, a state of ketosis provides a more stable energy level and thus may provide better overall feeling while in a dieting state. However, ketones are not an effective source of energy for skeletal muscle, and so performance of anaerobic activities will suffer on ketosis diet. As such, an athlete will need to decide if periods of brain fog are more or less important than maintaining performance. As a final note on ketosis diets, protein has a marked effect in insulin secretion, and as such a high protein diet may impair ketosis. A true ketosis diet is high fat, low to moderate protein and very low carbohydrate. This style of diet may line up well with the general population's needs, but has proven suboptimal for athletes.
It's also worth briefly discussing the thyroid hormones triiodothyronine (T3) and thyroxine (T4). In a normally functioning thyroid, the release of these hormones is scaled based on energy input to scale overall metabolism. T3 directly increases cardiac output, hear rate, ventilation rate, basal metabolic rate, potentiates catecholamines (next chapter) effect, and increases catabolism of proteins and carbohydrates. T4 is a precursor to T3, and does not exert direct effects. In a prolonged hypocaloric period a decrease in T3 will be observed, and vice versa in prolonged hypercaloric periods. The release of these hormones is dependent on long-term energy increases; their release is not directly tied to any given meal as with insulin. Their use as a chemical intervention will be discussed later.
-== Catecholamine effects on metabolism ==-
Before delving into advanced and extreme fat loss interventions, we need to briefly discuss the role of two catecholamines: epinephrine and norepinephrine, as the systems they regulate are often the targets of chemical weight loss intervention. Epinephrine (adrenalin) and norepinephrine (noradrenalin) activate various receptors ('adrenergic receptors') on various cells. The proliferation of these receptors varies based on cell type, and the specific receptor target is present in higher concentrations in different cells.
At a high level, both epinephrine and norepinephrine activate the adrenergic receptors, although at varying rates. There are two types of receptors: alpha and beta, which are further broken down into alpha-1, alpha-2, beta-1, beta-2 and beta-3. Certain receptors have a stronger binding affinity to epinephrine, and others to norepinephrine, but in general these catecholamines assert their affects through these receptors. The effects of these are widespread, but the primary ones to be aware of for affecting energy metabolism are discussed below. Key terms are 'adrenergic agonist' - a compound that directly activates an adrenergic receptor - and 'adrenergic antagonist' - a compound that blocks the effects of a receptor from being activated.
Alpha-2 receptor activation suppresses norepinephrine release, causes vasoconstriction and venoconstriction, and inhibits lipolysis. All of these suppress fat loss mechanisms, and as such, alpha-2 receptor antagonists (compounds that block its effects) are used to promote fat loss.
Beta-2 receptors cause smooth muscle relaxation in the bronchi, and as such many of the agonists for this receptor were developed to treat asthma patients. As a target of norepinephrine, it aids in vasodilation to increase systemic blood flow and increases mass and constriction speed of striated muscle, important as norepinephrine is key in the fight-or-flight response. Its activation also interferes with motor nerves, and may cause tremors. Beta-2 activation also stimulates glycogenolysis (glucose release from glycogen) and gluconeogenesis directly. Finally, beta-2 activation forms cyclic adenosine monophosphate (cAMP), which in turn activates protein kinase A, which causes lipolysis in adipose tissue and hepatic gluconeogenesis, while increasing skeletal muscle glycolysis and simultaneously inhibiting it in the liver. Note that it also inhibits glycogenesis, and so while activated it may be more difficult to replenish glycogen stores. After all, its purpose is to make as much glucose available as possible to the system. All in all, this produces a hefty punch when it comes to body recomposition.
Beta-3 receptors are located primarily in adipose tissue, and on activation enhance lipolysis. It also increases thermogenesis in skeletal muscle. As thermogenesis is nothing more than the body releasing free energy in the form of heat, and increase in thermogenesis implies an increase in energy output.
Through a combination of these receptors, the overall effect of epinephrine and norepinephrine are to increase heart rate and cardiac output, increase the production of free energy (glucose release via glycolysis and fatty acid release via lipolysis), and prime the nervous system for action. While certain chemical interventions have selective effects on the adrenergic receptors, epinephrine and norepinephrine themselves are slightly blunter.
-== 4: Chemical interventions ==-
Now that we have a reasonable theoretical basis for metabolism and various systems that act on it, we can begin to try to find ways to 'game' the system. Some have already been touched on, like ketosis diets based on the insulin hypothesis. In general, there are many dietary structures that attempt to alter body composition by exerting targeted effects on various metabolic regulatory pathways. Most of these fall short, as the body is extremely good at maintaining homeostasis. At least, in the absence of exogenous chemicals.
These chemicals range from the common (caffeine) to the extreme (2,4 Dinitrophenol). These will be outline below, tying them into previous section's notes on metabolism.
Again, this is not medical advice. It's not advice at all, it's simply information. The use, or abuse, of these compounds can cause serious health effects, and their effects pale in comparison to overall energy balance. In other words, you could take extreme doses of the harshest of these chemicals and cause serious, permanent damage to your body without losing any fat if your caloric intake is too high.
Caffeine. Caffeine is the most widely consumed psychoactive drug, acting as a central nervous system stimulant. Its primary action is to inhibit the adenosine receptor, which is a regulatory receptor in the nervous system that increases drowsiness. Caffeine ingestion increases plasma epinephrine and norepinephrine levels, thus acting as an adrenergic agonist. This increase in catecholamines is varied, and appears to be moderated by repeated use. Its direct impact on the adenosine receptor also causes downstream lipolysis directly, separately from the increase in catecholamines. Due to the downregulation of its effects on catecholamine production, cycling caffeine may be useful. Also, the side effects of caffeine may become pronounced in high doses, and become self-defeating. High doses of caffeine can directly impair sleep, and either via that effect or via chronically depressed adenosine activation can lead to increases in cortisol (anecdotally). As cortisol is bluntly catabolic, it directly contributes to muscle wasting. As such, caffeine in moderation (especially with cycling) can provide noted increases in lipolysis, but its abuse is more likely to cause systemic issues such as extreme fatigue, muscle wasting and general depression. Finally, caffeine is useful as an appetite suppressant and I find that 150-300mg a day is the ideal dose, often I prefer to stay near 150mg a day and combine it with other stimulants so that the side effects of any one stimulant are minimized. Effects are felt around 20-30 minutes after intake, and half-life is 5-6 hours.
Nicotine. Nicotine has a lot of societal baggage due to its association with tobacco products, but when isolated from tobacco (gum, lozenges or patches) it can be used as a stimulant and nootropic. Nicotine activates the release of epinephrine and norepinephrine, apparently in a dose-dependent manner. It may also directly promote lipolysis, although there appears to be counter regulatory effects as well. Either through its production of catecholamines or other mechanisms it acts as an appetite suppressant. Finally, it also appears to stimulate the release of endogenous opioids, causing a feeling of general wellbeing, calm or euphoria. Of course, even when removed from tobacco nicotine is highly addictive. Some liken using nicotine for fat loss to using methamphetamines for fat loss. As mentioned above, this guide is not a list of recommendations. It's up to each individual to weigh the risk/rewards. The downsides of nicotine are clear: addiction. The benefits may include stimulating fat loss via catecholamine release, possible direct lypolytic effects, appetite suppression and feelings of general wellbeing. Tolerance varies wildly from person to person, if new to nicotine a low dose should be used. I started with 2mg of nicotine gum once a day, I now find two 4mg pieces a day to give a great effect on appetite suppression, energy levels, focus and generally feeling good - one upon waking, one at the afternoon slump. Overuse can be extremely uncomfortable (a general feeling of 'something is wrong') and so buildup of dose should be gradual. Make sure to space doses out no more frequently than one piece of gum every two hours. I prefer to only use nicotine as needed, and never for longer than two weeks at a time, in an attempt to avoid tolerance, dependence, or addiction. Nicotine gum's effect can be noticed minutes after beginning to chew a piece, and the half-life is 1-2 hours.
Yohimbine HCL. Yohimbine HCL acts as an alpha-2 antagonist. As the alpha-2 receptor is counter regulatory to norepinephrine, this causes a systemic increase in norepinephrine and fat loss via secondary activation of adrenergic receptors. As alpha-2 also inhibits lipolysis, its antagonism effectively increases lipolysis in target tissues. There's anecdotal evidence that alpha-2 receptors are more prolific in 'stubborn/trouble fat areas'. It makes sense that 'stubborn' fat might be so at least in part due to a proliferation of a receptor that dulls fat loss. As such, yohimbine may help selectively reduce these 'stubborn' fat deposits. Note that Yohimbine's effects are strongly blunted by insulin, and it acts mainly to release fatty acids (not to stimulate their ultimate use as energy), so it is only really effective when fasting. Yohimbine is usually dosed at a maximum of .2mg/kg of bodyweight. I usually use about half that dose, as higher amounts can cause uncomfortable jitters, racing heart rate, and general feelings of unease. I find 10mg (at a bodyweight of 230lb) before fasted cardio brings a great energy and focus, the time just flies by. It's unclear if Yohimbine's effects are blunted over time, but most tend to use it for no longer than 4-6 weeks. It should be taken around 30 minutes before activity, and half-life is around 1.5 hours. Make sure to get Yohimbine HCL (the isolated chemical) - not Yohimbe (the tree bark the chemical is derived from), as Yohimbe carries many negative side effects and is less effective at fat burning.
Clenbuterol (and to a lesser extent, albuterol). Clenbuterol and albuterol are both selective beta-2 agonists. As outlined in the chapter about catecholamines and adrenergic receptors, beta-2 activation has a multitude of body recomposition effects. In general, clenbuterol directly increases lipolysis (fat release from adipose tissue), fat conversion to usable energy (gluconeogenesis), and overall metabolic rate and thermogenesis. This is often noted by a measurable increase in body temperature around one hour after clenbuterol use, which is sustained. Side effects can be pronounced at the dosages used for fat loss, including a noted increase in body heat and sweating, and hand tremors. Dehydration is a risk due to the thermogenic effects. Further, clebuterol tends to deplete the body's taurine stores greatly, which can cause extreme cramping and benign fasiculations. As such, 2.5-5g of Taurine (split doses are effective) should be used. Effects are generally noticeable around one hour after ingestion, and the half-life is 28-36 hours. Even with the long half-life, there's a noticeable peak after ingestion, and as such many choose to split larger dosages into multiple daily doses. Common dosing protocols begin at 20mcg and pyramid up at varying rates. Some recommend a two weeks on / two weeks off protocol as the beta-2 receptor is sensitive to downregulation. That might look like 20mcg starting dose, increasing by 20mcg every 4 days to a highest dose of 80mcg. Others will start clenbuterol 6 weeks out from a contest and increase the dosage weekly: /100/120. 120mcg daily should never be exceeded or there is a high risk of permanent heart damage. Also, be careful with higher doses combined with high intensity activity, as the combination may lead to heart attack. Some people use the antihistamine ketotifen to attempt to prevent the beta cell downregulation, although there isn't a strong scientific underpinning to support that this has the desired effect, and anecdotes on its effectiveness are mixed.
Ephedrine. Ephedrine directly stimulates the beta adrenergic cells, while having little effect on the alpha cells. As with all beta adrenergic agonists, this causes lipolysis, gluconeogenesis, and thermogenesis. It's often used similarly to clenbuterol; although the side effects may be less (it's unclear if this is due to lower dosages, its shorter half-life, or other reasons). It's generally cycled two on / two off to avoid receptor downregulation (as with clenbuterol). Dosages when stacked with other stimulants (caffeine and ephedrine are often combined) is generally 20-25mg three times a day. Extreme doses of 150mg are not well tolerated by most.
T3/T4. T3 is used to increase basal metabolic rate, either to supraphysiologic levels or simply to maintain baseline levels when dieting. However, its use needs to be very carefully controlled as there are many negative effects. First, T3 increases metabolism in all cells, vs. promoting lipolysis as with catecholamine manipulations. This creates noticeable muscle wasting in a dose-response manner. As such, high doses are rarely seen due to the high muscle wasting they cause. High level bodybuilders will only risk this with high anabolic usage to offset the muscle wasting. T3 can cause muscles to flatten out, as the rate of glucose use may increase past the ability of the cell to uptake it, which both makes the person look and feel weaker. Finally, unlike catecholamine manipulations which don't tend to cause long-term damage to the underlying systems when used in moderation, exogenous T3 use will suppress the body's natural thyroid function. If this is done for extended periods of time (greater than 6-8 weeks), the body may take months or years to return to baseline function (and may never achieve it). As such, usage is normally only for the final weeks of competition prep. 25mcg is thought to be the exogenous equivalent of normal endogenous levels, and as such may be sufficient to maintain normal metabolic rate when dieting. Any greater dose will increase metabolic rate past basal levels, at which time muscle wasting and glucose uptake issues become noticeable. 50mcg is the most common dosage most coaches recommend. Some extreme users will go as high as 100mcg for short periods of time.
Injectable L-Carnitine. L-Carnitine's oral bioavailability is poor, so for a true fat burning effect an injectable form must be used. In fact, it's been proven very poor as a fat burner when taken orally (except in those deficient in it). L-Carnitine is generally good for cellular and mitochondrial health, and may help prevent certain negative effects of aging such as neurological decline and has beneficial effects on cognitive function. It's used to increase beta-oxidation rates (and thus fat burning), as such shifting the cell's metabolism more in favor of burning fat directly. It's absorption by the cell is rate-limited, and absorption is boosted by high insulin levels. As a simple compound (vs. pharmacological compound), it doesn't have any appreciable serum half-life, and so dosages are best taken pre-workout. There is a loading phase until peak intracellular L-Carnitine levels are reached, at which point the maximum benefit is realized. Dosing protocols for fat loss generally combine it with highly insulinogenic carbohydrates (simple sugars), to attempt to increase intracellular levels to supraphysiologic levels by combining high serum levels (due to injection) plus increasing absorption rates by stimulating insulin release. Astute readers may recognize other ways to increase serum insulin levels exogenously, but that's out of scope for this article. As beta-oxidation inside the cell is limited by more than just L-Carnitine, there is a limited usefulness here instead of a dose-response relationship. Because this maximum benefit is far below levels that cause side-effects, and L-Carnitine is a substrate of beta-oxidation itself (instead of a compound that stimulates beta-oxidation), it can be used quite safely for extended periods of time. Often it is used through an entire competition prep cycle of 8-12 weeks at moderate dosages. Note: if a competitor must drop carbohydrates to very low levels to lose fat, they may not be able to maintain the recommendation of combining the L-Carnitine injection with insulinogenic carbohydrates. However, this is only needed during the loading phase. It may be maintained later to keep levels as high as possible, but is primarily critical during loading.
2,4 Dinitrophenol (DNP). DNP is widely considered the most dangerous fat burner, namely because its lethal dose is very close to its normally used dose, and that misuse of the drug is irrecoverably fatal. Consider that the lethal dose (LD50) of caffeine is about 150-200mg/kg of bodyweight, and the normal dose followed is around 1.5mg/kg. The LD50 of DNP can scale from 400-2500mg (scales with the temperature of the user's environment, this range is from 60F-110F), and common usage is around 400-600mg a day. Further, its long half-life (36 hours) makes overdose especially hard to manage. DNP is also used as a dye, and as a fertilizer.
The way that DNP works is by decoupling oxidative phosphorylation. Oxidative phosphorylation is part of the citric acid (Krebs) cycle, where energy in the form of electrons is transferred across the mitochondrial boundary, fueled by protons generated by the citric acid cycle. This is used to generated ATP - energy from outside the mitochondria is 'pumped' inside due to the electron differential created by the citric acid cycle. Those electrons are then used to create ATP. DNP diffuses the electron gradient - in layman’s terms, it severely impairs the pump - so the cell has to work extra hard to generate ATP. The energy that would have been used to generate ATP is instead burned off as heat.
This has many downstream effects. The most important is a rise in body temperature due to the electrons being 'wasted' as heat. This is uncomfortable at low doses and nearly unmanageable at moderate doses and of course downright deadly at higher doses. There is no antidote to DNP, once it's in the system it will be cleared only at its half-life rate. As such, an overdose will quite literally cook the person from the inside out. The only way to lower the extreme body temperature is an ice bath, and past a certain DNP level that will not be sufficient to cool the person down. It's worth mentioning that DNP has been used historically to keep Russian soldiers alive in harsh winters.
A second effect is extreme dehydration and electrolyte imbalance. Water consumption must ramp up; many users cite consuming 1.5-2 gallons a day. Electrolyte supplementation is important, but as DNP does not deplete the electrolytes at the same rate, must be done cautiously. There are anecdotal reports of issues with potassium retention, and thus excessive supplementation may cause toxicity. However, the electrolyte depletion can be to such a high amount in general that organ failure becomes a strong concern, especially as the extreme heat may cause a loss of electrolytes that the digestive system cannot match. As such, electrolyte supplementation is essential. But the exact breakdown of electrolytes used must be researched.
The third noticeable effect is just an extrapolation from its mechanism of action - extreme fatigue. As DNP makes it difficult for a cell to generate the energy it needs to fuel itself, every action (even simply lying down) is made more difficult. Put another way, if DNP makes you burn 30% more calories, it does so by making every action you take 30% more difficult. The rest of your body's systems may be functioning fine, but if there isn't energy at the cellular level, you can't function.
Finally, DNP causes both muscle flatness and water retention. The first's cause is clear, as the cell fights to generate energy it will preferentially use stored glycogen. Thus, glycogen is rapidly depleted. The causes for holding water are less clear / studied, but are not surprising given the combination of a need to sweat excessively and electrolyte balance issues.
This effect is less noticeable but critical: over-revving the Krebs cycle causes significant oxidation in the cell (it is driven by many oxidative reactions). This causes the generation of a high level of oxidative stress, a process which does direct harm to the cell and its ability to proliferate. DNP has been noted as a cancer treatment, it may be due to this reason. Nothing can be done to limit this issue, as it's driven by the primary mechanism of the drug. Many users will take high dosages of antioxidants (berry extract, Vitamins C and E, Alpha-Lipoic Acid), but it's unclear if these actually have any effect.
Combined, this makes DNP an extremely dangerous drug that most will not use. Those that do use it generally stick between 200 and 400mg a week for a maximum of 2 weeks. Many will limit that to 10 days. It's also critical to take significant time off between usage, at minimum twice as long as the period of use (10 days on, 20 days off) as it will take that long to both fully clear the drug from the system, and then allow the body to restore proper water and electrolyte balances and recover from the oxidative stress. Some people have tried two on / two off, and find either that runs after the first are not as effective or that the side effects are magnified (likely because of long clearance times of the drug).
Stacks, stack support supplementation and general discussion. Many of the above may be combined synergistically, especially when their mechanisms of action are well understood. For example, combining clenbuterol - a beta-2 agonist, with ephedrine, a general beta-agonist, is not ideal as they compete for receptors sites to bind to. However, ephedrine and caffeine are commonly stacked, perhaps because even though caffeine does indirectly stimulate beta cells, that's not its primary mechanism of action. By combining the two, a lower dose of each can be used, thus keeping clear of each separate system's counter regulatory properties. However, clenbuterol and caffeine are rarely stacked, as clenbuterol already causes a marked increase in heart and respiratory rates, and adding caffeine onto that can result in overstimulation.
Another common stack is to add T3 to the use of the above. This is generally not because any two are synergistic, but because these advanced/extreme fat burners are generally employed when a competitor is already extremely lean, and thus already has a suppressed metabolic rate. The T3 allows them to use chemicals to artificially enhance their fat loss, while maintaining a higher basal metabolic rate. In this case, T3 is not used at high doses as its primary goal is maintaining the metabolism, not boosting it. This allows for compounds that directly metabolize fat (especially problem areas) to ramp the metabolism, instead of using high dose T3 and risking muscle wasting. Any fat burners may be used in combination with T3, as T3 is not a primary CNS stimulant. Using T3 when more than 2-3% above a competition body fat percentage is likely a waste, as the thyroid is fairly resilient to dieting when the dieter is at higher body fat levels.
Injectable L-Carnitine may be combined with any of the other compounds mentioned. It is not a stimulant, and serves to enhance natural fat burning pathways instead of 'revving them up'.
Electrolyte supplementation and a concurrent increase in water intake are a must with all stimulant fat burners. Quite simply, they all increase thermogenesis to some degree, causing the body to need to sweat to cool itself down. This must be replenished. If using any of these in high dosages or for extended periods of time, a blood panel should be drawn to check for issues.
Personally, I like a combination of caffeine and nicotine at a dose of 150mg / 4mg. I find this avoids any jitters or overstimulation, instead providing a clear mind and focus levels. Adding in 10mg of Yohimbine increases the stimulatory effect, but not to unmanageable levels. However, as all three stimulate the nervous system, it's a fine line between a clear, focused stimulation and feeling very uncomfortable.
I find that clenbuterol, while undeniably effective, provides an extreme fatigue at higher dosages. This is likely due to its persistent activation of the nervous system causing a general fatigue of that system. As such, shorter cycles (two on/two off) at moderate dosages (the system doesn't downregulate much in two weeks’ time) are preferred. I do not combine other stimulants with clenbuterol, as I find the heart rate increases it brings on its own when doing heavy weight training are already quite high.
Finally, a reasonable question to ask is: 'How much fat will these burn'? That's a very tough and very individual question. You'll see people cite things like '3% increase in metabolic rate', 'extra 100 calories a day', but these aren't based on anything. Realistically, I view the real usage of these compounds more simply. Stimulant-type fat burners are great to keep energy levels up when in a caloric deficit. This allows you to train harder, maintain normal activity levels, and power through cardio. This effect can be worth their use alone. Alpha-adrenergic antagonists and beta-adrenergic agonists have an added effect of helping reduce 'stubborn fat'. It's tough to quantify this in terms of calories or weight lost, but the evidence in the mirror of their use is noticeable when at low body fat levels. T3, DNP, and L-Carnitine are far more difficult to gauge. T3 really shouldn't be used to increase metabolic rate much, more to maintain baseline levels when extremely lean. L-Carnitine may increase fat use, but you can't really quantify its effects. You'd just need to try it. DNP increases fat burn greatly, but at the risk of death.
-== Conclusion ==-
In this article we've built from the simple concept of energy balance to advanced chemical usage. Depending on the person's goals, different levels of intervention may be used. Most of the chemical compounds have notable major side effects, and are only useful when used for short periods of time. As such, if someone is overweight and beginning a fat loss journey, chemical interventions are neither necessary, nor advisable. When the body has high fat levels, it's quite simple (although not always easy) to drop significant amounts of body fat. Eating in a caloric deficit with high body fat stores does not cause the significant metabolic slowdown seen in lean individuals, which inherently makes sense. Why would the body need to slow it's metabolism down if it has tons of stored energy to use?
At the intermediate level (lean body fat levels), dieting can become more difficult. OTC supplements like caffeine may be used here to maintain energy levels during the day when dieting.
At the advanced level (early competition prep, very lean body fat levels) you start considering chemical interventions. Injectable L-Carnitine, clenbuterol, ephedrine and yohimbine often come into the picture here. T3 is often used when hitting competition body fat levels to maintain basal metabolic rate, but generally only in combination with anabolics to offset muscle wasting.
DNP is rarely used by anyone due to its extreme danger. It also, quite frankly, isn't needed by anyone. All the other chemicals mentioned are sufficient to hit competition shape.
In closing, it's important to remember that the foundation, and most critical level of body recomposition, is energy balance. You can easily out-eat any of the chemicals mentioned, and they're effects are generally small enough that the side effects are not worth it unless you're already at a very lean body fat level. While there may be no silver bullet, fat loss is remarkably simple. All it takes is time.
