“When we block the D2 receptor in humans, it is expected they will develop glucose intolerance, obesity, and sedentary behavior.” -Jane Plain, in her series on The physiology of body fat regulation.  It’s probably true.

Randomized pilot study of cabergoline, a dopamine receptor agonist: effects on body weight and glucose tolerance in obese adults (Gibson et al., 2012)

Cabergoline is primarily used to treat prolinactinoma, or prolactin-secreting tumors.  In women (& men apparently), prolactin stimulates milk production; in men, it is associated with the refractory period after orgasm.  In both genders, dopamine inhibits prolactin secretion.  Cabergoline targets the D2 receptor, but it’s a dirty drug.  It’s used off-label for gyno and to improve sexy times (Kruger et al., 2003 <– yes, that was actually tested).

Divide and conquer

16 weeks, 0.5 mg cabergoline twice weekly, obese non-diabetics on a low cal diet.  Results: no effect on body weight, but insulin sensitivity increased:cabergoline data

This dosing protocol seems odd, but it worked – prolactin significantly decreased in the treated group.  Further, dose timing of dopaminergics (eg, cabergoline, bromocriptine, etc.) seems to be very relevant…

2.5 mg bromo taken twice daily, at 8AM & 8PM, improved circadian GH secretion and modestly reduced leptin levels in obese women (Kok et al., 2006 & 2008).

Cycloset (quick-release bromocriptine) is supposed to be taken immediately upon wakening, which somehow resets the circadian control of hepatic glucose output, ultimately reducing blood glucose levels throughout the day.  It is said to inhibit excessive sympathetic tone within the CNS.  From Jane’s article & a paper by DeFronzo: hibernation (obesity) = insulin resistance, increased hepatic glucose production, low dopamineCycloset

According to DeFronzo’s review, diabetes is characterized by low dopaminergic tone in the early morning which leads to increased central sympathetic activity.   Circadian rhythms, prolactin levels, etc., are altered by obesity – timed bromo intake appears to fix this; it makes sense, but I couldn’t find the study which showed the importance of dose timing per se.

Prolactinoma (cabergoline): twice daily 12 hours apart

Metabolic Dysregulation (bromo): once daily in the morning. Lyle McDonald wrote a whole book about bromo (is it really that interesting?). 

When it comes to the importance of circadian rhythms, photoperiod, seasonal fluctuations in metabolism, etc., I can get on board.  Not a strong, there’s-a-lot-of-hard-evidence-believer, but there are enough tangential studies and anecdotal observations that suggest it’s at least relevant.  Probably important.

Another study showed that high leptin levels were associated with high dopamine activity at the D2 receptor, which was reduced in obese subjects (Dunn et al., 2012).

Apomorphine is a another dirty dopaminergic with many useful clinical applications (eg, alcoholism, erectile dysfunction, Alzheimer’s, etc.).  Apomorphine inhibits prolactin and stimulates growth hormone, and one study showed that the response to apomorphine was blunted in obesity, further suggesting reduced dopaminergic tone in the obese condition (Brunerova et al., 2013).

“Circulating leptin was also positively associated with stress-induced dopamine release” (Burghardt et al., 2012).  However, it’s complicated, modulated differently in different brain regions, and regulated on a long-term basis as leptin therapy corrects many metabolic abnormalities in leptin-deficient humans and some of these, including dopamine signaling, remain corrected even after a month with no leptin injections (Ishibashi et al., 2012).  The interplay of leptin and dopamine in the brain is complicated.  Leptin reduces hunger and dopamine signaling on the one hand, but on the other hand increased dopamine improves metabolic outcomes.  “Location, location, location!” … which, in this case, might refer to location within the brain.

I’ve got a few articles on metreleptin & pramlintide in the tank, mostly animal stuff, but will post them soon.

calories proper

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  • Carole Sampson

    I love it when you talk dirty, Bill. 😉

    • William Lagakos

      You’re awesome, Carole.

      Keep on, keepin’ on, and you’ll get no complaints from me 😉

      • Carole Sampson

        I am just finishing your book and would like to do a serious post on it. Would you mind if I quoted a few sentences from it (10 or 12) to summarize your views on a few points?

        • William Lagakos

          I wouldn’t mind at all!

  • Nigel Kinbrum

    “Lyle McDonald wrote a whole book about bromo (is it really that interesting?).”
    Do you really need to ask? 😉
    Bucket of ice-cold water for Carole. Stat! 😀

    • Carole Sampson


  • William Lagakos

    Lyle’s 6-part series on Leptin:

  • Kindke

    ive tried cabergoline before, didnt lose any weight from it, it did however give me horrible anxiety aswell as slight insomnia.

    cabergoline is amazing for libido though damn, sex when your on this stuff is like 3 times as good. o0

    • William Lagakos

      Your cabergoline experience is in line with the study above (body weight… they didn’t assess libido et al.).
      Just out of curiosity, what was your dosing regimen?

      • Kindke

        same as the recommended, 0.5mg twice per week.

        I only did it for 4 weeks though. Maybe too short for weight loss? I couldn’t stand the anxiety.

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  • George

    Aren’t antipsychotic meds also antidopaminergic, and don’t they tend to produce metabolic syndrome and weight gain?

    I haven’t tried apomorphine (the only time I got my hands on some I was promptly arrested for burglary), but I have used pukatea bark. Pukateine and Laureline are analogues of apomorphine, methoxy- and methylenedioxy- if memory serves.
    Has a minty numbing taste and a bland depressive effect, but, when I broke my leg it potentiated codiene and helped me get some sleep, and smaller amounts can focus the mind nicely in fatigue states.

    Apomorphine was used with some notable success as a treatment for alcohol and morphine addiction. Its chief practitioner in the 1950s was Dr John Yerbury Dent 1888-1962 who, early on in his research, mistakenly believed that it was the emetic properties of apomorphine which were efficacious. Subsequently however he realised that it had deeper impact than mere aversion. It is now hypothesised that it is a neurobiological rebooter of the Dopaminergic system and as such rewrites the “reward pathway”

    • William Lagakos

      “I was promptly arrested for burglary” LOL! (sorry, it sounds serious, but the comedic phrasing was brilliant).

      Antipsychotics – another interesting DA interaction. Central (?) control of glucagon secretion could very well be a candidate for bromo’s efficacy in NIDDM.

      Apomorphine’s alleged modification of the “reward pathway” and subsequent [theoretical] control over hepatic glucose output via glucagon… lots of food for thought. Hurts my brain, but still very curious.

    • Jane Plain (Woo)

      I did LOL at the “prompt arrest for burglary” . This is unfortunate there may have been great scientific insights :)

      The AP effect is more deductive evidence of the ultimate metabolic control dopamine exerts on metabolism. Perfectly healthy obesity resistant humans can sometimes, quite often, explode into a total body/personality shift of obesity. Apathy, hypersomnia, hyperphagia, glucose intolerance, wt gain.

      • William Lagakos

        This seems big. Bromo –> a comprehensive lifestyle intervention. Perhaps its better that way; changing all behaviors simultaneously instead of making selective, small modifications which might be more easily overturned.

  • William Lagakos

    Enhanced nicotine self-administration & suppressed dopaminergic systems in a rat model of diabetes.
    The cause-effect relationship is becoming muddied:
    was: low DA –> diabetogenic –> all cured by Bromo
    this rat study: diabetes –> low DA –> likes nicotine more (corrects low DA but not diabetes)

  • William Lagakos

    The dopamine ?-hydroxylase inhibitor, nepicastat, suppresses chocolate self-administration and reinstatement of chocolate seeking in rats.

    Noted, and added to the list of drugs not to try.

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