Image Map

guy curling huge dumbbell“The ideal would be an oral drug similar to bromocriptine but with more specific D1 activity. The only candidate I’ve found is a drug called pergolide.” – Lyle McDonald, Bromocriptine

Those who know me fairly well (girlfriend, the guy who works the desk at the gym, the ‘DA,’ etc.) know I’m not a big believer in fairness. All human beings were created equal? Bullshit. Nothing’s fair. Life’s not fair; the weather where I go to school ain’t terribly fair; online black-jack certainly isn’t fair, and neither is the genetic lottery that determines an innumerable number of our physiological traits before they are ever even formed in the womb. But while I find notions of ‘genetic fairness’ generally laughable, I also consider it rather unproductive to just admit I was born to be slow, puny, and pudgy so I can jadedly jog (or lumber) my way over to Krispy-Kreme for my daily baker’s dozen. No. Personally, I’ve got a different strategy for cashing in on the ticket fate dealt me in that stacked little genetic-lottery-lead-in to my life. Me, I just cheat, any, and every time I get the chance.

Let’s put on our thinking caps and kick back and rationalize things for a second. Unless you’re one of the rare few who inherent the ‘pro-athlete’ phenotype, to look even remotely good, you have to pay attention to two key facets of your life– your diet, and your training. Well, for starters, there certainly aren’t any rules when it comes to training. Okay, granted, if you’re an un-castrated (and moreover, mostly uneducated) male lifter, Monday has to be ‘Bench-day’ so your pecs will be ‘hyooge.’ But– beyond that– there’s a lot of potential ways you can train, and even more ways to name them.

When it comes to diet, it’s basically the same story; if you’re meeting your protein needs and consuming an adequate amount of EFAs, you can pretty much tweak your macro and micronutrient ratios to your heart’s content. After all, even the best diets will only yield slim, slight improvements in one’s genetically and hormonally-determined phenotype; and, even then, such changes take months, sometimes even years, to reach the point where the payoffs actually manifest themselves distinctly. Obviously, for all us ‘genetically average Joes,’ this is not only frustrating, but– at times– downright maddening. It just doesn’t seem right, how some guys can end up jacked on a diet of Pop-Tarts and pizza and an activity regimen of thumb-twiddling, while the other 95% of us have to sweat, toil, stop, suck it up, and then go toil some more.

That is, used to have to, because– with a little smarts, a little ingenuity, a little willingness to suffer, and a little more cash– you can cheat your way along with one of the illest pharmaceutical short-cuts to the look you’ve always lusted after. Imagine, if you will, a body that sort of ‘forgets’ about its set-point, one that always yearns to be leaner, and, at the same time, is willing to fight tooth and nail to keep things that way. Then, couple that with a brain that thinks you’re being overfed around the clock so that when you diet, your body ultimately gets things ‘bass-ackwards.’ Even though lipolysis may be rolling, even though your metabolism is oxidizing FFAs at an optimum rate, even if you’re hardly eating a damn thing, your brain keeps sending the “we’re fed and life is good signal,” so that ultimately even with the most stringent of diets, it really is. So, without further ado ladies and gentlemen, I’d like to introduce you to the drug that can do this virtually single-handedly: Pergolide Mesylate, the ‘DNP’ of the dopaminergic drugs.

To truly appreciate the pharmacology of Pergolide, I’d first like to branch off briefly to discuss a key facet to everybody’s favorite little hormone leptin. Namely, its signaling route into and through the brain. The simple version is that leptin reaches the brain primarily via two pathways, the blood stream, and the cerebrospinal fluid (CSF) flow (1,2). In order to actually get into the brain however, leptin must first cross the blood-brain barrier (BBB). To do so, it needs a carrier. This carrier is Ob-R (short form), which transports leptin through the BBB to subsequently activate signal transduction (3,4,5). Long story short, leptin gets in, binds to the OB-R (long form) isoform receptor, and gets on with its signaling-self (6,7). Oh but wait, there’s just one more thing of interest in regards to the Ob-R long receptor: it also just happens to be a dopaminergic neuron (6,7).

That’s right, as Lyle McDonald first pointed out in his groundbreaking work Bromocriptine there is an intimate and inextricable connection between brain dopamine (DA) levels and leptin’s signaling effects in the brain (8). That’s because further ‘downstream’ Ob-R (short) will bind to dopamine receptors (more specifically, the D1 & D2 receptors) which, once activated, relay more messages to the hypothalamus, which regulates a nearly-innumerable number of biological processes concerning energy expenditure and hormonal regulation (9).

Indeed, in regards to several key physiological processes, DA levels are the ‘finish line’–not the actual amount of circulating leptin. It is important to point out that the two (DA and leptin) are NOT one and the same, and DA– no matter how much activation you can elicit– can never veritably duplicate leptin. However, it is quite effective at ‘hood-winking’ not one, but several signaling systems that operate further down the signaling chain from leptin. You may now cue any “Eurekas!” “F’in Ehs!” and/or maniacal laughter that you see fit. Because– if you think about it– rather than figuratively running a marathon trying to cope with leptin, why not just take the RIGHT short-cut, detour through the park, catch a cab or two, and then just jaywalk (I tend to ‘Crip-walk,’ but that’s just a personal preference thing…) across the finish line? Let’s return to Pergolide, shall we?

For those who like big words, are ‘all ‘bout that technical shiz-nit,’ and continue to get off on structural nomenclature, Pergolide is an ergot-derivative, combined D1-D2-receptor agonist that gets synthesized in labs as 8B-[(Methylthio)methyl]-6-propylergoline monomethanesulfonate (10). In the pharmaceutical world, Pergolide is mainly used as an AntiParkinson’s agent, due to its direct ability to powerfully stimulate both key postsynaptic DA receptors in the nigrostriatal system (11). Powerfully you ask? Well, to offer a comparison, various in vivo and in vitro tests on Pergolide have shown it may be as much as 1,000 times as potent as Bromocriptine on a mg per mg basis (10). I personally wouldn’t gauge it quite that high, but I’d say triple-digit-times more potent wouldn’t be too far off. Just the fact that it displays D1 activity in addition to D2 activity alone should make Pergolide of interest to the dieter, as it’s been speculated that D1 agonists are markedly more effective at regulating neurological feeding impulses than drugs that only selectively work via D2 (12).

Amarin Pharmaceuticals, the company that actually makes Pergolide, refers to the drug as a “potent agonist.” Yeah, potent like a friggin’ Mack truck. Seriously, compared to Pergolide, ‘Bromo’ is benign by comparison– like popping Pez or something, which is why stepping up to the plate with the ‘big kahuna’ of dopaminergics is not without some risk. But, as I’ve always been more than ready to assert, sometimes radical runs at body composition changes require radical methods. So, for those who are daring (or simply dumb enough like I am) to get ridiculously drastic in terms of DA-modulation and look into running a Pergolide cycle, listen up, because hurdling the leptin pit with this lil’ hunny is, needless to say, a treat of a rather singular sort.

Before I go any further, I’m just going to lay it out: it is my esteemed opinion that high dose Pergolide is currently the second-best (single) weight-loss substance available to ‘Joe-dieter’ (with DNP being the first). Period. It is not an end-all-be-all, but it is one anorectic and lipolytic BMF. Oh, and it’s not like Pergolide and DNP can’t be stacked together, which I must say makes for a far more delectable dieting combination than even T3 and Clen.

Now, extrapolations from clinical trials (more on these later) back up this assertion quite nicely, but also send us all soaring off to ‘Theoretical Land’ where people like Par shine, 99% of us get lost, and Lyle just ends up really pissed at all the ‘PubMed voodoo.’ That’s why I’m also going to spend time in “Segment II” of this article discussing the modifications I’ve been able to make on my own body using the drug, because they– along with those of the anonymous ‘Mr. n=1’ whose correspondences were related in Bromocriptine– are pretty damn hard to dismiss.

On Pergolide, when you cut calories, you don’t get hungry and you don’t have cravings. On Pergolide, your body seems to crave leanness, and will partition calories like you had the genes of an ectomorphic pro-athlete. On Pergolide, you can literally starve yourself down well into the single digits in terms of bodyfat percentage; your body will still crave fat for fuel and wouldn’t dare try to rob you of your precious muscle tissue if it can help it. On Pergolide, you can’t really gain muscle, but you can certainly reach a point where you’re awfully ripped with what you’ve got. Oh, and lastly, Pergolide is also a close chemical cousin to the narcotic d-lysergic acid diethylamide (re: L.S.D.), so that while all this is going on your brain seems to be drifting somewhere in between reality, conscious inertia, and Never-Never-Land (13).

Yes, there are somnolent sleep-fits. Yes, there is the occasional trip if you don’t take the proper precautions with your dosages. But no– and thankfully– Michael Jackson stays out of the picture. So we’re going to use a drug to fake a fed signal, big-time. Because, if you can feign the ‘fed state’ strongly enough (and Pergolide can, believe me) then suddenly you’re in the driver’s seat when it comes to altering and improving your body, and your genetics (especially your set-point). You can diet down to your heart’s content and maintain it on you own terms, with the only limits being A.) Whether or not you can obtain Pergolide and at what cost & B.) How well you can tolerate it to be able to keep using it.

Now, to see how this all pans out, let’s look at some clinical research. In animals, the fat-loss and behavioral changes observed as a result of treatment with combined D1/D2 agonists falls somewhere between ‘silly’ and ‘hey, just how much stock do YOU HAVE in pergolide!?!?’ Primates treated with similar dopaminergic compounds take fasting to heart while simultaneously increasing daily energy expenditure, and in rodents, fat cells literally efface themselves (a process called adipocyte apoptosis), even in trials where the animals were treated with DA-agonists weaker and less-multifaceted than Pergolide (14,15,16). It should also be noted that, in these latter groups, when phenotype change was specifically being tested for, D1 and D2 agonist-administration caused circulating levels of energy-expenditure homeostatic hormonal regulators like neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) to return themselves to levels that would be seen in animals whose brains were registering a state of positive energy balance (17).

Furthermore, the final conclusion of the single rodent study of this sort that I am aware of that actually used Pergolide also fuels the intrigue a bit. Quite simply, the researchers summarize their findings by stating that Pergolide administration “significantly suppressed food intake and body weight” (18). Ultimately, it’s quite clear that if your favorite hamster or rhesus monkey ever started to get a little too tubby for your likings, a consistent period of Pergolide administration would get that little critter more cut than you would think possible.

But while that’s all fine and dandy, the real question remains– is Pergolide effective in humans? Well, as if it’s no surprise, the literature on the subject isn’t terribly telling, because there simply aren’t any studies that look at what we want, namely, whether Pergolide causes statistically significant weight loss in human subjects. For one, in the drug world, Pergolide is a relative infant compared to other ergot derivatives like Bromocriptine, which have been available for study for decades. Another simple fact is that the role of dopamine in human obesity (and, by extension, the use of dopaminergic compounds to treat said condition) is still a relatively new and generally underdeveloped area of study in the realm of weight-loss research. With that said, I am 100% convinced that Pergolide lives up to the praise I gave it a few paragraphs back, and now I’m going to try to briefly play scientific ‘connect-the-dots’ to show you why.

Interestingly enough, one potential place of interest can be found in the realm of cocaine studies, where many researchers have come to believe that a simultaneous and significant activation of the D1 and D2 receptors may be highly synergistic when it comes to modulating stimulant cues (19, 20). Since cocaine binds strongly to synaptic DA reuptake pumps in the nucleus accumbens (which renders them unable to reduce the drug-stimulated DA build-up), it exerts an effect at D1, D2, and D3 (although D3 should be considered irrelevant for our purposes) that– to cite a single specific effect– literally effaces the reward-feedback derived from food consumption (21). You just don’t get the munchies on blow, seriously. Might you get them on Pergolide? Well, although it is only able to activate the former two receptors (and through a much different mechanism), it’s not a far cry to speculate that its pharmacokinetics can likely accomplish the same feat. It’s also clear that elevated DA levels (and one would assume levels of DA activation) do stimulate lipolysis and a rise in REE in humans (22,23). Once again the key is to what extent Pergolide’s activities can produce the desired response(s) we’re looking for.

Needless to say at present, even without my own observations and experiences on the drug, I would still view multi-receptor DA modulation in rather optimistic terms, especially since the positive effects of D2-agonist treatment on weight loss with weaker and more selective dopaminergic compounds than Pergolide is fairly compelling and these days, even more fully documented (24). In quite a few clinical trials, drugs whose potencies can barely hold a candle to Pergolide’s have produced statistically significant reductions in bodyfat in obese subjects while significantly improving insulin sensitivity and glucose tolerance/utilization (25,26,27,28). Want to hear a keen and ingenious thinker with a delightfully wry sense of humor wax poetic about said research and the conclusions that can be drawn from it? Then fork over some cash to the ‘Bromocriptine-guy’ (Editor’s Note: For those that don’t know, he’s referring to Lyle McDonald) for a copy of his book, because this article is going to be long enough already. No, I want to look specifically at the information out there about the effects of Pergolide itself on body composition.

Sucks to be a reader here because—surprise, surprise—there is very, very (megaphoned-emphasis on ‘very’) little out there available to us. Since for the purposes of adequately addressing the topic, I’m going to save my own experiences with Pergolide in next issue’s Segment. And, because I’d get my ass sued pronto if I related the cryptic-albeit-alluringly-intriguing ‘Pergolide Feedback’ addendum in Bromocriptine, I’m just going to go on to discuss one other guy who used Pergolide in the ‘drop-that-spare-tire-in-a-couple-days’ dosage-range I’ve been hinting at. Yeah, one lowly guy. That’s all I’ve got; please don’t hate me.

The third member of the mysterious ‘Pergolide triumvirate?’ A 65 year old, non-obese white male who started treatment with the drug looking to treat a case of RSL (restless leg syndrome)(29). At first glance, the study doesn’t really make for enthralling reading. Guy has RSL, takes Pergolide for two and a half years, eventually has to drop out of the study due to pulmonary complications. Kids, isn’t that FANTASTIC!?!? But, if you read between the lines, there seems to be a little more to it than that. For starters, our lone subject entered the trial at relatively normal BMI– this was not some Ho-Ho guzzling Jabba the Hutt who would’ve done well to lose a pound or two. Nonetheless, over the course of those 2.5 years our subject lost fifty pounds taking Pergolide at 3.5mg/ED, with the researchers noting “systemic symptoms of weight loss” which began once he started using the drug, and– similarly– disappeared when he stopped taking it. No change in other medications. No change in diet. No change in activity levels. Just picked up Pergolide. Now we’re cooking with propane. Now, I don’t want to just say, “he took Pergolide; he got ripped” and leave the study at that, because it wasn’t all sunshine and lollipops for our noble tester, nor are things that cut-and-dry.

During the course of the trial, this poor guy seemed to suffer from every affliction under the sun, and eventually came down with a severe case of Pleuropulmonary Disease (which the researchers attributed, probably correctly, to the Pergolide) forcing testing to come to an end. Obviously, these conditions make this a problematic study to judge. Our tester had a notable history of medical problems dating back thirty years even before he began the trial, and was taking high daily therapeutic doses of Glipizide, Losartin, and Warfarin throughout the study. Consequently, it’s hard to really control for drug-on-drug interactions, past conditions, and just general infirmity of health, which is why I counsel readers to take the information I’m relating for what it’s worth. And if you’ve yet to read Bromocriptine I wouldn’t be surprised if many of you are going to be a tad disappointed with this installment of Loki’s ‘PPE.’ But trust me, this is a foundation I’m laying for a reason, and I wouldn’t have wasted my time writing this friggin’ Don Quixote of an article if I didn’t think this drug was wholly legit.

In the concluding installment, which will be featured in the next issue, I’m going to recount in depth my own experiences and experimentations with Pergolide, how much these experiences kicked ass from a body composition standpoint, suggestions for how and when to use it (and what to use it with) so that it will kick ass for you too (without literally kicking your ass, because it can and it will if abused or misused), and also address some risks and reasons why you might not just want to take a blind, running jump toward the Pergolide Mesylate band-wagon just yet.

So, until then, take up a hobby– read poetry to Paraplegic orphans or something. And, if you’re still skirting around in terms of your goals, or what type(s) of tissue you want to lose or gain, just kick back, wait a few, and get ready to enjoy yourself (in the most insular, blatantly masochistic and phenotype-obsessive sense of the word), because Avant is about to bring a whole lotta’ exciting shit to a ‘table near you.’ Can cutting-season be made into a cake-walk?? I guess we’ll all just have to wait and see. Cheers.


1. RH Unger. Leptin physiology: a second look. Reg Peptides (2000) 92:87—95.

2. Schwartz MW, Peskind E, Raskind M, Boyko EJ, Porte D Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Department of Medicine, University of Washington School of Medicine, Seattle 98105, USA.

3. Fruhbeck G. A heliocentric view of leptin. Proc Nutr Soc (2001) 60: 301-318.

4. Ruth B.S.Harris Leptin – much more than a satiety signal. Ann Rev Nutr (2000)

5. Bjorbaek C, Uotani S, da Silva B, Flier JS. Divergent signaling capacities of the long and short isoforms of the leptin receptor. J Biol Chem 1997 Dec 19;272(51):32686-95

6. Szczypka MS, Rainey MA, Palmiter RD. Dopamine is required for hyperphagia in Lep(ob/ob) mice. Howard Hughes Medical Institute and Department of Biochemistry.

7. Tartaglia LA. The leptin receptor. J Biol Chem. (1997) 272:6093-6.

8. McDonald, L. Bromocriptine. Lyle McDonald Publishing; (2002), 66-69.

9. Rossetti L. Perspective: Hexosamines and nutrient sensing. Endocrinology 2000 Jun;141(6):1922-5

10. Permax– Pergolide Mesylate. Eli Lilly & Co. 5.0 PV 2271 UCP_v2

11. Clarke C E, Speller J M. Pergolide for levodopa-induced complications in Parkinson’s disease (Cochrane Review). The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

12. P Terry, DB Gilbert and SJ Cooper. Dopamine receptor subtype agonists and feeding behavior. Obesity Research 3: 515S-523S (1995)

13.Wilson JM. et al. Dopamine D2 and D4 receptor ligands: relation to antipsychotic
action. Eur J Pharmacol (1998) 351:273-86.

14. Cincotta AH and AH Meier. Reductions of body fat stores and total plasma
cholesterol and triglyceride concentrations in several species by bromocriptine
treatment. Life Sci (1989) 45: 2247-2254.

15. Platt DM, Rowlett JK, Spealman RD. Modulation of cocaine and food self-administration by low- and high-efficacy D1 agonists in squirrel monkeys. Psychopharmacology (Berl). 2001 Sep;157(2):208-16.

16. Bergman J, Rosenzweig-Lipson S, Spealman RD. Differential effects of dopamine D1 and D2 receptor agonists on schedule-controlled behavior of squirrel monkeys. J Pharmacol Exp Ther. 1995 Apr;273(1):40-8.
17. Bina KG, Cincotta AH. Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice. Neuroendocrinology. 2000 Jan;71(1):68-78.

18. Greene SB, Mathews D, Hollingsworth EM, Garbin CP. Behavioral effects of pergolide mesylate on food intake and body weight. Pharmacol Biochem Behav. 1985 Aug;23(2):161-7.

19. Barrett RL, Appel JB. Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine. Psychopharmacology (Berl). 1989;99(1):13-6.

20. Callahan PM, Appel JB, Cunningham KA. Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine. Psychopharmacology (Berl). 1991;103(1):50-5. 21. Soares BGO, Lima MS, Reisser AAP, Farrell M. Dopamine agonists for cocaine dependence (Cochrane Review) The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.

22. Regan CJ, Duckworth R, Fairhurst JA, Maycock PF, Frayn KN, Campbell IT. Metabolic effects of low-dose dopamine infusion in normal volunteers. Clin Sci (Lond). 1990 Dec;79(6):605-11.

23. Bertolini S, Castello C, Astengo F, Risso M, Fuliano P, Fattorini A, Balestreri R. Effect of ergot alkaloids on lipolysis and on glucagon-induced insulin secretion in normal and obese subjects. Boll Soc Ital Biol Sper. 1977 Nov 30;53(22):1989-97.

24. Larsson LO, Blom HL. Unexpected positive effect of bromocriptine on obesity and the use of psychopharmaceuticals Lakartidningen. 1985 Dec 11;82(50):4425, 4427.

25. Cincotta AH, Meier AH. Bromocriptine (Ergoset) reduces body weight and improves glucose tolerance in obese subjects. Diabetes Care 1996 Jun;19(6):667-70

26. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, Netusil N, Fowler JS. Brain dopamine and obesity. Lancet 2001 Feb 3;357(9253):354-7

27. Doknic M, Pekic S, Zarkovic M, Medic-Stojanoska M, Dieguez C, Casanueva F, Popovic V. Dopaminergic tone and obesity: an insight from prolactinomas treated with bromocriptine. Eur J Endocrinol 2002 Jul;147(1):77-84

28. Goodwin GM, Fairburn CG, Cowen PJ. The effects of dieting and weight loss on neuroendocrine responses to tryptophan, clonidine, and apomorphine in volunteers. Important implications for neuroendocrine investigations in depression. Arch Gen Psychiatry. 1987 Nov;44(11):952-7.

29. Danoff SK, Grasso ME, Terry PB, Flynn JA. Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest. 2001 Jul;120(1):313-6.