Drugs and Obesity: Weapons of Choice in the War on Fat by Marc Collins

Guy curling.The obesity epidemic has been recognized by the World Health Organization (WHO) as one of the top 10 global health problems. Worldwide, more than one billion adults are overweight and over 300 million are obese. So the reasons for necessary measures to correct the problem are evident. Okay, I know what you’re saying: “I’m not obese! What do I care?” Well, whether you’re a 400 pounder trying to avoid you’re third coronary or just want to shed that winter coat for a summer at the beach, the contents of this article are directly applicable to you.

So why do we need drugs to help us lose weight? They’re not natural. Diet and exercise is all you need, right? First of all, opium is natural while aspirin isn’t, so lets dismiss this whole ‘natural is good’ line of thought immediately. Second, for some, genetic predisposition and previous dietary/exercise habits might make attaining a reasonable weight extremely difficult or nearly impossible. For these individuals, losing weight relatively quickly with the help of a drug would be so beneficial to their overall health, that the potential side-effects of the drug are a moot point. And what about the guy/girl who just wants to lose a few pounds for the summer? Provided the pharmaceutical (I’m including supplements in this category since I really don’t see a difference) approach is relatively safe and they did their homework first, all the power to them. If we don’t criticize someone for slamming back a 12-pack on a Saturday night, how hypocritical would we be to criticize them for supplement use?

Now, before I start talking about supplements and ingredients I’d like to mention the problem of evaluating the safety and effectiveness of certain supplements. There is a lot of conflicting scientific literature regarding both the efficacy and safety of many of the current weightloss agents. I’d like to start off by saying that the evaluation of supplements is fraught with bias and conflict of interest. Some scientists stand to profit from the sale of a dietary supplement while others stand to lose. For example, pharmaceutical companies may view supplements as stealing market share. Physicians may see alternative medicine as a partial threat to their income or authority. The media may be looking for tomorrow’s big headline. What better than “new dietary supplement kills users?” I’m not saying we should omit all scientific literature. I’m just saying we should view what we read with an open mind and a willingness to think critically and be sceptical.

Fat-accumulation occurs when energy intake exceeds energy output. I really can’t stress this enough. People often get caught up in the science of weightloss and omit this necessary equation. Now, I know someone is going to bitch me out saying that 100 calories of protein is not the same as 100 calories of table sugar (and they’d be right), but I’ll argue that the above statement is accurate to the point that it should be the basis of any weightloss strategy. Now, let’s evaluate this a little more. Getting fat depends on two things: 1) how much energy you consume and 2) how much energy you burn. So, to lose weight, you have to target one or both of these things. Increasing the amount of energy you burn can be accomplished by increasing exercise or through the use of dietary supplements (such as thermogenics). Decreasing the amount of energy you consume is obvious. If you eat less you lose weight, right? You can even get supplements to help curb those sugar cravings. The problem is that sometimes (in decreasing your energy intake), you concurrently decrease your energy expenditure by screwing with endogenous hormone levels. This is where supplements can really be helpful to keep your body in a fat-burning state even when it thinks it’s starving.

So now that we’ve got the ethics and reason for using weightloss supplements out of the way, let’s get right to it. I do not plan to undertake a painstakingly intense scientific evaluation of the mechanism of action of the major supplements on the market. Rather, I will provide a brief overview of the literature regarding the effectiveness and safety of certain supplement ingredients. Admittedly, there are many more supplements on the market than I can critically evaluate in a single review. So, I’ll just present those that are prominent in the literature or those I have a personal interest in. I mean, it’s my damn article so I’ll present whatever I damn well please J. I won’t get caught up on what’s available on the market and what must be obtained underground. Honestly, I don’t care. I’m also not promoting the use of any of these supplements but, rather, am only providing a brief overview so that you may make the educated decision regarding which supplements are right for you.

Fish oil – Honestly, I’d be surprised if anyone trying to lose weight nowadays is doing so without the use of fish oil. This stuff is jam packed with omega 3 fatty acids that are powerful weightloss agents. The reasoning behind this might sound a little confusing at first. How can consuming fat make you lose fat? And doesn’t that mean you’d be taking in more calories? Yes, it does. But remember, there are two parts of the weightloss equation. The first part is to decrease the calories you consume and the second part is to increase the calories you burn. Fish oil helps you increase the calories you burn. It does this through the help of a wonderful enzyme (transcription factor to be exact) named PPAR alpha. Anyone who’s read Par’s writings is already familiar with this miraculous enzyme, so I’ll keep this brief. PPAR alpha becomes activated when it comes into contact with certain compounds. One of the more potent activators is the omega 3 fatty acids found in fish oil. PPAR alpha (being a transcription factor) then goes on to increase the transcription of genes involved in lipolysis. The end result is that you increase the amount of enzymes available to burn fat. Needless to say, this increase in fat-burning potential results in an elevated basal metabolic rate and reduced body fat. I won’t even get into the scientific literature supporting the use of fish oil but will simply say that its use is highly recommended in any weightloss effort. Side effects are virtually non-existent even at very high doses (with the possible exception of infants… which you’re not). In addition, fish oil have beneficial roles in many cellular events such as immune function, aging, neonatal development, and act as anti-inflammatory agents.

Sesamin (Sesathin) – Sesamin is one of the lignans most abundantly present in sesame seed and oil. As of late, it has been promoted (and rightly so) as a potent weightloss agent. Like fish oil, sesamin is a PPAR alpha agonist. This means it has the same PPAR alpha effects on weightloss as fish oil does. Peaked your interest yet? Okay, but that’s just the beginning. Sesamin also exerts its effects through another enzyme (transcription factor) called SREBP-1 (subtype unclear); an enzyme not apparently controlled by omega 3 fatty acids (ie fish oil). This enzyme has the opposite effect as PPAR alpha, meaning it increases both the amount and activity of many of the enzymes involved in lipogenesis (ie making fat). Not only does sesamin decrease the amount of SREBP-1, it also decreases SREBP-1 activity. This stops your body from storing fat (obviously a good thing). In fact, the effect on SREBP-1 activity is much more profound than on expression. Even more remarkable, effects on SREBP-1 activity are observed at very low doses of sesamin and effects on PPAR alpha are observed at much lower doses than needed with fish oil. Now, I’m not saying to toss the fish oil… it’s still essential to ANY diet, but you may be able to lower the dose. Now, here’s where things get really interesting. Unlike fish oil, sesamin also has profound effects on peroxisome oxidation. Sesamin was able to increase mitochondrial oxidation (energy burning) by 2-4 times with significantly lower doses than required for fish oil. However, the same doses resulted in a 12 times activation of peroxisomal oxidation (Ide et al., 2003). Thus, fat burning is further potentiated. Finally, just to note, sesamolin is another lignan found in sesamin oil and may have similar effects to sesamin. Perhaps this will show up in conjunction with sesamin in future supplements.

Guggul – Guggelsterones E & Z increase circulating thyroid hormone levels (T3) (Panda et al., 1999). T3 has a strong effect on weightloss, which is why some individuals use cytomel to lose weight. To date, evidence of the efficacy of guggul in promoting weightloss looks very promising (Paranjpe et al., 1990). Side effects are minimal. However, oftentimes supplements don’t contain as much of the guggul extracts as claimed (Mesrob et al., 1998).

DNP – This is a synthetic mitochondrial uncoupler that functions similarly to UCP1 (brown fat). Simply put, it speeds up your metabolism by making your energy systems less efficient. Normally, sugar and fats are burned via mitochondrial oxidatation leading to the production of energy (ATP). DNP uncouples this process, yielding heat instead of ATP. This means your cells have to burn much more fuel to obtain the same energy, thus speeding up your basal metabolic rate. The effects on weightloss are obvious. However, this is not a drug to be taken lightly. This is one of the more dangerous weightloss drugs so definitely do your homework regarding dosing and potential side effects before even contemplating buying it. The increase in body temperature is very noticeable and can be quite uncomfortable for some. Perfuse sweating is almost certainly going to be another side effect. In general, DNP may leave you feeling like a bag of hell the entire time you’re on it. Nevertheless, if you want to lose weight bad enough, DNP will definitely help you do it.

Clenbuterol – Clenbuterol is a selective beta 2 adrenergic agonist. For this reason, it does not possess many of the unwanted side effects associated with ephedrine (which hits beta 1 and beta 2). Evidence suggests that clenbeterol is a potent fat-loss supplement. Moreover, it may possess anabolic properties as well. A group in the UK found that obese rats had a 19% loss in fat content accompanied by a simultaneous 13% increase in protein content. A similar effect on muscle protein content was observed for lean rats (Rothwell et al., 1987). In addition to its direct benefits to weightloss, clenbuterol also has beneficial effects on insulin sensitivity (Pan et al., 2001). Nevertheless, safety concerns do exist (although I personally feel it is relatively safe).

Ephedra / Ephedrine – Ephedra sinica (Ma Huang) is found in central Asia. Ephedrine is the major active compound in this plant and can be found in a variety of supplements, usually as Ephedrine HCL. There have been numerous studies conducted on this supplement, especially since the world found out it makes your heart explode. But before we talk about the safety concerns, lets first evaluate the effectiveness of these supplements. Many studies on ephedrine also include caffeine. This is because ephedrine and caffeine appear to have a synergistic effect on weightloss. Studies indicate that ephedrine/caffeine supplementation causes significant weightloss (Greenway, 2001). However, a variety of side effects were reported such as high blood pressure, GI problems, heart palpitations, nervousness, headaches, sweating, dizziness, nausea, insomnia and tremors (Pittler et al., 2003; Greenway, 2001; Shekelle et al., 2003). Personally, this is my absolute favourite supplement and I’m not totally sold on the potential dangers… but that’s just my opinion. Be sceptical and make up your own mind. Ephedrine can also be cycled with clenbuterol for an added effect.

Yohimbe – this supplement comes from the plant Pausinystalia yohimbe. It is an alpha 2 adrenergic receptor antagonist. This means it blocks the alpha 2 receptor from working. Since alpha 2 adrenergic stimulation promotes the accumulation of fat, blocking its activity promotes weightloss. It is often promoted as an erectile dysfunction and weightloss agent. The effects on weightloss are controversial, but one study found a dramatic decrease in weightloss after only 3 weeks supplementation with 20mg daily (Kucio et al., 1991). Side effects include impaired sleep, nervousness, and headache (Sax et al., 1991).

Leptigen – due to the vast amount of information already discussed in this magazine and on the Avant Labs forum and homepage, I will not talk about this supplement in great detail. Leptigen serves to increase endogenous leptin production. The effects of leptin are mediated both periphery and centrally. Peripherally, leptin directly stimulates energy expenditure. Centrally, leptin acts on the hypothalamus to affect metabolism and eating behavior. Although this is not my major concern, I feel obligated to mention that the effects of leptin are not limited to weight management. Leptin is also involved in regulation of blood pressure, angiogenesis, brain and bone development and wound healing. It also has roles in the immune system. Anecdotal evidence pertaining to the effectiveness of leptogen thus far seems promising.

Guarana – This is often used as a substitute for caffeine. Guarana is prepared from the seeds of Paullinia cupana. Guarana contains a relatively large amount of caffeine and has been shown to slow gastric emptying (Jadad et al., 1996). Delaying the rate of gastric emptying could have beneficial effects on blood sugar levels as well as leaving you feeling full longer. Both of these effects would contribute to weightloss. Additionally, stimulatory effects cannot be ignored. Adverse events include irritability, heart palpitations, and anxiety (Greenway, 2001; Shekelle et al., 2003).

Oleoylethanolamide (OEA) – a fatty acid structurally related to endogenous cannabinoids but does not bind to or activate cannabinoid receptors. OEA is an endogenous PPAR alpha agonist (see fish oil). OEA induces satiety and decreases weight gain. (Fu et al., 2005). Don’t think it’s on the shelves yet, but give it time. Safety shouldn’t be a major concern.

Bitter orange (Citrus aurantium) – This compound acts as an alpha 1 agonist. Scientific literature on this compound is lacking. However, anecdotal evidence seems promising. Potential side effects are similar to those observed with ephedrine use.

Chromium picolinate – chromium is an essential trace mineral and a cofactor for insulin. Hence, increased chromium consumption could increase insulin sensitivity. In my previous article, I discussed the benefits of increased insulin sensitivity on weightloss so here I’ll just say it’s a good thing and leave it at that. A recent review suggests that chromium picolinate does cause weightloss but that the effects are not clinically meaningful (Pittler et al., 2004). This is not necessarily bad news. They were evaluating the clinical applications to overweight and obese individuals. Clinically significant would thus indicate dramatic weightloss. The important thing is that this supplement DOES cause weightloss. Hence, it may be used in combination with other supplements to achieve the desired goal. It must be stated, however, that the individuals tested were overweight and were probably somewhat insulin resistant, making them more responsive to the effects of the supplement.

Orlistat (brand name Xenical) – Inhibits pancreatic lipase by covalently binding to it. Pancreatic lipase is partially responsible for the breaking down of fat for absorbtion. Hence, by inhibiting the breaking down of fat, the gut cannot digest and absorb dietary fat. However, this drug also inhibits water absorption so patients often complain of cramping and severe diarrhea. Nevertheless, weightloss is achieved. Up to a 25% decrease in fat absorption has been observed (Jandacek et al., 2004).

Sibutramine – Sibutramine is an antidepressant. It inhibits Norepinephrine (ie noradrenaline) and seratonin reuptake. However, these hormones are involved in numerous other processes so various side effects and even deaths have been reported with it’s use. It reduces food intake and reduces body weight modestly (~5%) with small increases in blood pressure and heart rate in some people (Yanovski et al., 2002).

Hydroxy-methylbutyrate (HMB) – HMB is a metabolite of Leucine shown to have anticatabolic actions by inhibiting protein breakdown (Nissen et al., 1996). It is primarily used by bodybuilders to help maintain muscle mass while ‘cutting’. The effects on fat mass reduction are well documented (Nissen et al., 1996; Vukovich et al., 1997), and adverse events are either minor or non-existant (Nissen et al., 1996).

Yerba mate (Ilex paraguariensis) – Very little data is available indicating its effectiveness. The only double-blind randomized clinical trial did not report any adverse events (Anderson et al., 2001). Chronic ingestion of hot beverages containing this supplement has been associated with oesophageal cancer (Castellsague et al., 2000). However, this is from epidemiological studies and it may just be that chronic thermal injury is the cause. In combination with guarana, significant effects on weightloss were reported (Anderson et al., 2001).

Pyruvate – Research has shown that pyruvate supplementation enhances exercise performance and improves body composition (Stanko et al., 1994; Stakno et al., 1996). However, the effects were weak at best. Still, no side effects were observed and when you want to drop a few pounds every bit helps.

Chitosan – Chitosan is a polysaccharide produced from chitin (derived from the exoskeleton of crustaceans). It binds intestinal fat or the hydrolysis products of fat breakdown. This reduces fat bioavailability. Evidence suggests that it is not overly effective in lowering body fat (Mhurchu et al., 2004). Side effects include GI symptoms such as constipation and flatulence.

Octopamine – Octopamine is a B3 adrenergic agonist. Beta-adrenergic agonists stimulate cyclic AMP production and thereby activate hormone sensitive lipase. This is the enzyme responsible for breaking down fat. B3 agonists are very effective thermogenic anti-obesity and insulin-sensitizing agents in rodents (Arch et al., 2002). In humans, B3 adrenoreceptors are in human white adipose and skeletal muscle and play a role in the regulation of energy balance and glucose homeostasis. Theoretically, all weightloss would be lipid, and lean mass may actually increase. It is difficult to identify ‘pure’ B3 agonists because oral bioavailability of selective B3 agonists is low and cross-reactivity with B1/B2 receptors is common. This can lead to unwanted side effects (such as increased heart rate). I have not been able to find any information on the specificity of octopamine for B3 receptors or any respectable studies demonstrating its effectiveness. Also, oral availability of selective B3 agonists is questionable. Nevertheless, B3 agonists are actively pursued in the quest for weightloss and even the possibility that octopamine activates this system (along with anecdotal evidence promoting its effectiveness) warrants its use.

Olestra (brand name Olean) – a sucrose molecule esterified with 6-8 LCFAs has the physical properties of dietary fats but is not hydrolysed in the intestine. Its use is analogous to aspartame as a sugar replacement. I can’t really evaluate its effectiveness since it is highly dependent on the amount you consume and how much fat this allows you to cut out of your diet. ‘Skidmards’ could be a problem, as could other gastrointestinal problems, but these have been limited by using higher melting point fatty acids.

Plantago psyllium – a water soluble fibre from Plantago ovata. Although no adverse effects are apparent, the supplement does not appear to have any noticeable effect on fat loss (Rodriguez-Moran et al., 1998). In other words, if you see it as one of the ingredients in a supplement, don’t worry about it. Just don’t expect it to help too much with the weightloss.

Guar gum – Guar gum is a dietary fibre derived from Cyamopsis tetragonolobus. Like psyllium, this ingredient appears to be useless (Pittler et al., 2003).

Read, learn, and supplement wisely.


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Stanko RT et al: Inhibition of regain of body weight and fat with addition of 3-carbon compounds to the diet with hyperenergetic refeeding after weight reduction. Int J Obes Relat Metab Disord 20:925-30, 1996.

Stanko RT et al: Pyruvate supplementation of a low-cholesterol, low-fat diet: effects on plasma lipid concentrations and body composition in hyperlipidemic patients. Am J Clin Nutr 59:423-7, 1994.

Vukovich MD et al: The effect of dietary beta-hydroxy-beta-methylbutyrate (HMB) on strength gains and body composition changes in older adults. FASEB J 11:A376 (abstr), 1997.

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