cAMP and ADHD - Best of both worlds? - AnabolicMinds.com

cAMP and ADHD - Best of both worlds?

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    cAMP and ADHD - Best of both worlds?


    There is a fundamental opposition between ADHD treatment and bodybuilding/general health optimization.

    Brief summary here on the science -
    ADHD impairs function of the pre-frontal cortex in the brain. This controls executive function, organization, planning, etc...

    cAMP is a secondary messenger involved in many different functions and is a favorable target for bodybuilding supplements. Increasing cAMP causes a cascade of beneficial effects including vasodilation, boosting testosterone production, increasing lean body mass, and more.

    Recent studies have shown that the pre-frontal cortex (PFC) is modulated by cAMP and alpha adrenergic receptors. These two systems oppose each other. Increases in alpha receptor agonism increases working memory and overall performance in the PFC. Increases in cAMP effectively shut off circuits in the PFC and impairs performance.

    So here's the issue! For those with ADHD, increases in cAMP are only desirable in the peripheral systems. Forskolin and other beta agonists however cause widespread cAMP stimulation. Is there any way to constrain cAMP increases to peripheral effects? Or is there any substance that does not cross the blood-brain barrier but still increases cAMP in the body?

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    interesting. i need to pubmed this
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    Behav Brain Res. 2002 Mar 10;130(1-2):197-201.
    Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD).
    Andersen SL.
    Source
    Department of Psychiatry, Harvard Medical School, Belmont, MA 02478, USA. andersen@mclean.org
    Abstract
    The transitions that occur in the ascending dopamine systems between childhood and adulthood parallel the emergence, course, and severity of attention-deficit hyperactivity disorder (ADHD) symptoms. Behaviorally, rats are more active in open field during periadolescence, and activity levels decline by 50% in males by adulthood. This peak in behavior parallels a transient overproduction in D1 and D2 dopamine receptors that occurs at puberty in rat striatum (STR) and prefrontal cortex (PFC), followed by a decline in receptor density into adulthood. While tempting to speculate that receptor density plays a role in the waning of ADHD symptoms, receptor overproduction does not occur in the nucleus accumbens (NA), which demonstrates only a modest rise in receptor density (10-20%). Given the importance of the accumbens in locomotor activity, an alternative explanation for increased activity was sought. The second messenger system cyclic adenosine monophosphate (cAMP) has classically been associated with dopamine receptors. The results of these studies demonstrate that cAMP accumulation in the accumbens and the STR parallel the observed rise and fall in activity levels in rats. At puberty, basal cAMP levels are 35% higher relative to adulthood in male accumbens, while a modest 7% change was observed in STR. Forskolin-stimulated cAMP was 240-300% higher in STR and accumbens at puberty before declining with maturation. These findings suggest that, the adolescent dopamine system has a much higher 'tone' relative to adults. However, pharmacological responsiveness of cAMP to D1 or D2 stimulation demonstrates an overall blunted response during puberty relative to adulthood. This finding is consistent with a hyposensitivity to stress and pharmacological agents at puberty in animals that are in a hyperdopaminergic state. These findings of combined elevated cAMP accumulation and reduced cAMP sensitivity during adolescence have clinical implications for hypothesized mechanism and course of ADHD and its treatment. The maturational decline in cAMP activity may explain why this disorder recedes, while, simultaneously cAMP becomes more responsive to D1 and D2 receptor stimulation in adulthood.
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    Quote Originally Posted by aarfai View Post
    interesting. i need to pubmed this
    Here's one of the references. There's mention of this system being the target for development of new drugs, and the current alpha agonists that are sometimes given are not strong enough to inhibit the cAMP increase by something like supplemental forskolin.

    Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex.

    Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510 USA.
    Abstract

    Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.


    Quote Originally Posted by Touey View Post
    Behav Brain Res. 2002 Mar 10;130(1-2):197-201.
    Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD).
    Interesting. Haven't come across that one before. Seems to suggest that at least the hyperactivity sometimes seen as a symptom is actually improved by increased cAMP signaling.
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    Forskolin: Friend or Foe? Stories and Studies About Fat Loss, Lean Gains, Topical Cellulite Treatment, Testosterone, Cancer, Hepatotoxicity, Drug Interactions & More


    There is a single human study that would suggest that forskolin would make you get closer to this classic physique w/out tons of salad (who said that's necessary anyway?).
    Since Maxim asked in one of his more recent comments about the usefulness and/or downsides of forskolin, I dediced to dedicate this Sunday (finally again?) to answering a user question and am going to briefly sum up some older and the few novel findings on forskolin I am aware of.

    For those of you who find that boring: Don't blame Maxim alone, another reason for this decision was that I have seen discussions on forskolin resurface elsewhere on the Internet. By the way, I write re-surfaced, because forskolin has once been hailed as a testbooster and fat loss adjuvant, but as the prices increased and people came out with faked or low-quality products that did not yield results, the market collapsed.

    What is forskolin and where does it originate from?

    As usually there is more than a single answer to this question. The most straight forward general ones are probably (a) it is a white to white with yellow cast powder, or (b) a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory and adenylate cyclase activating properties. Moreover, forskolin is able to activate the adenylate cyclase and thus increase the intracellular cyclic AMP levels in most tissues and cells. And hat it's called forskolin, because it is derived from the Indiant plan Coleus forskohlii is probably something 99% of you knew already.

    The reason I suppose that Maxim got interested in it, is that it is commonly used in cell studies to raise the levels of cyclic AMP (cAMP; cf. Alasbahi. 2012) and did a pretty impressive job in the recently discussed PGC-1a study. On the other hand, it did also increase the expression of the aromatase enzyme in the Yang study mentioned in the "Natural Sildenafil & Testosterone Alternative" post on which Maxim replied with the initially mentioned comment.

    "Wait, wasn't it supposed to be a testbooster and now it also inhibits myostatin and increases estrogen? What does this stuff not do?" - Well, forskolin is, above all, a cAMP modulator


    Forskolins chemical structure. Sometimes it's also referred to as Colforsin; 7-beta-acetoxy-8, 13-epoxy-1-alpha, 6-beta, 9-alpha-trihydroxylabd-14-en-11-one; or Coleonol (img. from Sigma-Aldrich's product database)
    I know that sounds confusing, but in essence forskolin does nothing but increasing cAMP levels in almost all types of cells. cAMP a breakdown product of ATP (=> cAMP => AMP) in turn is one of those molecules which exert most their effects as intracellular signal transducer. In that, it is involved in the activation of protein kinases and regulates the effects of adrenaline and glucagon. It also modulates the calcium channels and contributes to growth hormone release; unfortunately, cAMP has also been implicated in the proliferation of not very beneficial cell growth aka cancer. The same ion-flux mediation has recently been implicated in the etiology of ADHD, as well (Arnsten. 2012).Name:  a (1).jpg
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    Still, it's not all about c-AMP. Probably cAMP unrelated downsides of coleus forkohlii are for example:
    forskolin induces hepatic CYP2C enzymes and coleus forskohlii extract and thus attenuates the anticoagulant action of warfarin. (Yokotan. 2012)
    even more than isolated forskolin, coleus forskohlii messes with the hepatic enzyme cascade (P450) and has even been shown to be hepatoxic in a study published in the July issue of the Journal of Toxicology (Virgona. 2012)
    On the other hand there are a handful of benefits, e.g.

    Figure 1: Effects of 12 weeks on 2x250mg (10%) forskolin on testosterone (free and total) and lean & fat mass (Godard. 2005)
    In a 2005 study (Godard. 2005), which caused quite a stir in the health and fitness community back then, Godard et al. observed profound beneficial effects of testosterone and body composition (cf. figure 1) after the ingestion of 2x250mg of a 10% standardized forskolin (Forslean). Name:  a (4).jpg
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    Now, the unfortunate truth is that the15 subjects (average age, BMI, and body fat percent were 24.4 +/- 5.9 years, 32.5 +/- 4.1 kg/m2 , and 35.2 +/- 8.3%) who had been randomized to the active arm of the study, and the 15 participants in the placebo arm (28.7 +/- 8.6 years, 32.6 +/- 3.8 kg/m2 , and 35.0 +/- 7.3%) were non-active sedentary overweight/obese (BMI 26 kg/m2 or more) individuals. Add the funding by Sabinsa (Forslean producer) to the equation and decide for yourself how relevant you think the results are going to be for you...
    In several in-vitro studies, forskolin has been used as a positive control to compare the effects of other compounds on the testosterone release in leydig cells. Lin et al. for example used it in 2001 as a comparison for lactate and found a ~3x increase in testosterone release in incubated leydig cells (Lin. 2001). A similar study by Yu et al. showed that the addition of green tea catechins lead to an additional stimulation of forskolin induced testosterone production in cell cultures (Yu. 2010).

    Figure 2: Results of 12-week intervention w/ forskolin containing topical cream (Roure. 2011)
    As part of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, retinol and, obviously, forskolin it has shown some promise as a topical anti-cellulite and toning agent (Roure. 2011). The clinical study was however financed by Johnson & Johnson and I am not sure how much of the effects were actually brought about by forskolin (the placebo was a basic gel with the same texture containing mainly water, gelifying and preservative systems). So take the data in figure 2 with a grain of salt, ladies - I bet 12 weeks on this product are not going to be exactly inexpensive.
    The administration of forskolin in conjunction with rutin (the glycoside between the flavonol quercetin and the disaccharide rutinose), vitamin B1 & B2 in a 2010 study by Pescosolido et. al. lead to a significant reduction in intra-ocular pressure in 15 glaucoma patients after 40 days (Pescosolido. 2010). Similar results were observed in a 2012 study for forskolin and rutin alone (Vetrugno. 2012)Name:  a (2).jpg
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    An in-vitro study by Cristobal et al. provides first evidence for the ability of forskolin to restore PPA2 in acute myeloid leukemia. That would make it a potential candidate for the treatment of this type of cancer, but to my knowledge there is as of yet not even a rodent study that would support these in-vitro results. Moreover, previous studies have suggested that Forskolin may even favor the proliferation of other types of leukemia (Kobayashi. 1994)
    Time to weigh the "established" benefits and downsides


    Figure 3: Effect of different doses of forskolin with and w/out epinephrine on FFA release from rat adipocytes - watch out this is from yet another in-vitro study with rodent cells (Litosch. 1982)
    In view of the fact that the aforementioned study by Godard is the only human study is only backed up by in-vitro data from rodent studies (Litosch. 1982, cf. figure 3), the fat loss benefits are as Jeukendrup et al. point out in their 2011 review of purported fat burners...
    "[...] promising, there is [yet] only one study at the present time and more work is required before forskolin can be recommended as a fat metabolism-enhancing substance." (Jeukendrup. 2011)
    If you add to this the host of wanted and unwanted, known and unknown side effects that occur in response to the coleus foskohlii induced cytochrome P450 modulation (e.g. the mice in the aforementioned study by Virgona lost some visceral fat, but the costs were increased fat deposition in the liver and elevated transaminase levels). Name:  a (5).jpg
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    With the questionable "fat loss" benefits (remember stress is also a powerful lypolitic and the problem is not to get the fat out of the cell, but rather to burn it), and the almost non-existant human data on the purported testosterone boosting effects, this should be reason enough not to buy more than one bottle for a test-run. After which I highly suggest to do some lab work to see if whatever good or bad you believe you are feeling is an actual boost in T (check T-levels) or hepatic side effects (check ALT, AST & ALP).

    Note (update in response to comments): As far as the hepatoxicity is concerned the suggested dosage of 2x 250mg coleus forskholii most supplements come with may be higher than the medium dose in the study by Virgona, but is still probably "liver save" if you double dose on that, you are however landing in the no-man's land (=not tested for) gray zone between the medium dosage and the "danger zone" of ~49mg/kg per day (human dose equivalent) that was tested in the study. Don't freak out, if you did that in the past, the levels return to normal afterwards and temporarily elevated ALT + AST or ALP levels do not necessarily mean that your liver is whacked forever ;-)

    References:
    Alasbahi RH, Melzig MF. Forskolin and derivatives as tools for studying the role of cAMP. Pharmazie. 2012 Jan;67(1):5-13.
    Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012 Mar;85(1):45-58. Epub 2012 Mar 29.
    Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res. 2005 Aug;13(8):1335-43.
    Jeukendrup AE, Randell R. Fat burners: nutrition supplements that increase fat metabolism. Obes Rev. 2011 Oct;12(10):841-51.
    Kobayashi K, Nishikawa M, Omay SB, Toyoda H, Deguchi K, Shirakawa S. Forskolin potentiates G-CSF-induced proliferation of a murine myeloblastic leukemia cell line. Leuk Res. 1994 Feb;18(2):111-7.
    Lin H, Wang SW, Wang RY, Wang PS. Stimulatory effect of lactate on testosterone production by rat Leydig cells. J Cell Biochem. 2001 Jun 26-Jul 25;83(1):147-54.
    Pescosolido N, Librando A. Oral administration of an association of forskolin, rutin and vitamins B1 and B2 potentiates the hypotonising effects of pharmacological treatments in POAG patients. Clin Ter. 2010;161(3):e81-5.
    Roure R, Oddos T, Rossi A, Vial F, Bertin C. Evaluation of the efficacy of a topical cosmetic slimming product combining tetrahydroxypropyl ethylenediamine, caffeine, carnitine, forskolin and retinol, In vitro, ex vivo and in vivo studies. Int J Cosmet Sci. 2011 Dec;33(6):519-26.
    Vetrugno M, Uva MG, Russo V, Iester M, Ciancaglini M, Brusini P, Centofanti M, Rossetti LM. Oral administration of forskolin and rutin contributes to intraocular pressure control in primary open angle glaucoma patients under maximum tolerated medical therapy. J Ocul Pharmacol Ther. 2012 Oct;28(5):536-41.
    Virgona N, Taki Y, Yamada S, Umegaki K. Dietary Coleus forskohlii extract generates dose-related hepatotoxicity in mice. J Appl Toxicol. 2012 Jun 22.
    Yokotani K, Chiba T, Sato Y, Taki Y, Yamada S, Shinozuka K, Murata M, Umegaki K. Hepatic cytochrome P450 mediates interaction between warfarin and Coleus forskohlii extract in vivo and in vitro. J Pharm Pharmacol. 2012 Dec;64(12):1793-801.
    Yu PL, Pu HF, Chen SY, Wang SW, Wang PS. Effects of catechin, epicatechin and epigallocatechin gallate on testosterone production in rat leydig cells. J Cell Biochem. 2010 May 15;110(2):333-42.
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    Any thoughts on a peripheral-only cAMP increasing agent? Something that doesn't cross the BBB perhaps?
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    @mr.cooper69

    I am interested in your feedback for this.
    I have ADHD and I use Forskolin. Am I making things worse for myself?
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    that sucks. i just bought some forskolin...
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    Coleus forskohlii (Plectranthus barbatus) is a tropical plant in the mint family that has been used around the world for a variety of reasons, the most common of which was the treatment of cardiovascular ailments. More currently, this herb has been touted by Dr. Oz on his self-titled TV show as one of his favourite “belly blaster” supplements. This activity is due to the main constituent of Coleus forskohlii, known as forskolin. Forskolin is found in highest concentrations in the root.
    Forskolin and cAMP
    The major action of forskolin is to rapidly activate a cellular enzyme called adenylyl cyclase. This enzyme is responsible for the synthesis of cyclic AMP (cAMP), which is a messenger molecule in our cells that helps to control their response to signals from the body. Some of these signals involve the regulation of glycogen, sugar, and lipid (fat) metabolism in the cell. Thus, through increasing the cellular production of cAMP, forskolin can help to boost the amount of fat and sugar used by the cells of the body. In a test tube, the application of forskolin has been shown to directly reduce the size of fat cells. This is promising for the ability of forskolin to help increase metabolism.

    Weight loss and Bone Health in Men
    When tested in a group of overweight and obese men, supplementation of forskolin over a 12-week period was found to favourably alter their body composition. It reduced body fat percentages, and actually helped to improve bone mass. These results may be limited to men, but may be particularly useful in overweight men suffering from bone loss due to andropause. For more information, please see our Andropause article.

    Asthma
    One preliminary study found that forskolin was equally as effective as beclomethasone for the prevention of asthma attacks after two months of treatment in mild and moderate asthma sufferers. Further research is needed to be sure of the results, but daily supplementation with low dose forskolin may help to prevent some asthma attacks. For more information, please see our Asthma article.

    Coleus Forskohlii– QUICK FACTS
    PARTS USED
    Root

    APPLICATIONS

    Weight Loss, asthma prevention

    OPTIMUM DOSAGE
    Weight loss: 125-250mg of extract standardized to 10-20% forskolin. Asthma: 10mg daily (Clinical doses may differ as recommended by your practitioner).

    WORKS WELL WITH
    Diet, exercise, green tea extract


    IMPORTANT INFORMATION

    Stimulation of cAMP has also been found to worsen some cognitive deficits present in age-related dementia, and ADHD.
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    According to this, everybody is taking more Foskolin than necessary
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    @Touey where did you find that?
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    COLEUS FORSKOHLII
    Articles by a Naturopathic Doctor ( N.D.)

    http://www.nationalnutrition.ca/Herb...orskohlii.aspx
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    Well there it is, I shouldn't be taking forskolin because I have ADHD. Super
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    Quote Originally Posted by drewsicle3210 View Post
    Well there it is, I shouldn't be taking forskolin because I have ADHD. Super
    Have you been? Maybe the lower dose 25-50 mg wouldn't have an effect regarding that...?
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    Quote Originally Posted by schizm View Post
    Have you been? Maybe the lower dose 25-50 mg wouldn't have an effect regarding that...?
    I have been. I also started Adderall 10 day ago. About 5 days ago I went down to 2 caps a day of forskolin 95. That is the clinical dosage anyways.
    I honestly don't see a difference at all from Adderall, but Inam still on low dosage. I guess we have to work up to find what dosage works the best.
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    Quote Originally Posted by drewsicle3210 View Post
    I have been. I also started Adderall 10 day ago. About 5 days ago I went down to 2 caps a day of forskolin 95. That is the clinical dosage anyways.
    I honestly don't see a difference at all from Adderall, but Inam still on low dosage. I guess we have to work up to find what dosage works the best.
    What dose are you on for Adderall? Are you a heavy caffeine user?
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    Quote Originally Posted by Jon_b View Post
    What dose are you on for Adderall? Are you a heavy caffeine user?
    I was a heavy caffeine user, but all i do is a preworkout at like 0500, then my adderall at 9-10 ish.
    I am at 15mg XR, but I have an appt with the doc on Tuesday and she will bump it up a bit
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    Quote Originally Posted by drewsicle3210 View Post
    I have been. I also started Adderall 10 day ago. About 5 days ago I went down to 2 caps a day of forskolin 95. That is the clinical dosage anyways.
    I honestly don't see a difference at all from Adderall, but Inam still on low dosage. I guess we have to work up to find what dosage works the best.
    Just suggestion obviously you will do as you are wanting but why not take out of equation things like forskolin, etc. until your are feeling comfortable upon the scripts you are working with your doctor, it may take some months to getting any new meds adjusted without the adding unnecessary variables which may prolong a process in which for most a stressful one until stabilized.
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    I have ADHD and have never noticed any worsening of effects from Forskolin. Just my own anecdotal feedback.
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    Quote Originally Posted by Touey View Post
    Just suggestion obviously you will do as you are wanting but why not take out of equation things like forskolin, etc. until your are feeling comfortable upon the scripts you are working with your doctor, it may take some months to getting any new meds adjusted without the adding unnecessary variables which may prolong a process in which for most a stressful one until stabilized.
    Thanks Touey, I actually understood everything you wrote here, and you are right. I stopped everything (except preworkout and fish oil) and I will gauge the effectiveness of my ADHD meds.

    Thanks again
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