23 replies to this topic

[Lufega]

Forskoling stimulated adelynate cyclase resulting in increased cAMP. For me, this translated to increased stomach acid production (which I needed 5 betaine HCL per meal to duplicate), fat loss and a subtle increase in muscle mass. However, I felt like forskolin made me depressed, reduced motivation and dumbed me down. There something about increased cAMP activity in the prefrontal cortex decreasing cognitive abilities?


Lithium, decreases cAMP in the brain and contributes to some cognitive enhancement. Is this effect of lithium on cAMP exclusive for the brain or does it affect the whole body? If taken together, will I retain the acid increasing, fat burning and muscle gaining action of forskolin while enjoying the cognitive and mood boost of lithium?

[bgwithadd]

http://www.neuroscie...l/aba1743.shtml

"HCN channels are activated by cAMP. The HCN channel blocker ZD7288 increased the firing of weakly tuned prefrontal cortex neurons to their preferred directions and reversed the stimulatory effect of guanfacine, suggesting that α2A-adrenoceptor activation strengthens the spatially tuned activity of prefrontal cortex neurons by blocking HCN channels.

Blocking HCN channels improves performance in working memory tasks."

Basically what's been learned lately is that stimulants would completely differently that is generally believed (aka what doctors and most internet people will tell you). More dopamine is not equal to better attention. The two big mechanisms seem to be blocking HCN channels (what norepinephrine does) and increasing DAT (the phenylethamine/amphetamine action). Norepinephrine is affected dramatically by stimulants. Only problem with it is that you get some serious hypertension/vasoconstriction from having lots of NE.

Guanfacine is actually shown to be just as effective for ADD as stimulants, hence the new long acting guanfacine version coming out from shire. Only problem is, most ADDers have low blood pressure (after all they tend to have low PEA, low vasopressin, low NE). Taking the full therapeutic dose of guanfacine would kill me for sure.

It's interesting that lithium works on cAMP. It's mechanism of action is sort of mysterious, but that could be one of the big ways it affects the brain.

I'm not certain if lithium only affects cAMP in the brain or in the whole body, but increased appetite is a well known effect of lithium so it's not really a dietary type of supplement. It could very well be that cAMP production is the reason lithium increases appetite. Also, to get the levels of cAMP change I see in the studies I am reading right now you'd have to take a very high amount of lithium, way beyond what could be considered supplementation. Without testing lithium levels, that's just not safe. You're also bound to get a lot of side effects...including a rabid appetie. With just 45mg of elemental lithium a day I was getting a ravenous appetite so I backed it down.

Thanks for the specualation and info about lithium. Working stuff out like that is the only way we can make the best use of supplements.

[Lufega]

More dopamine is not equal to better attention. The two big mechanisms seem to be blocking HCN channels (what norepinephrine does)... Only problem is, most ADDers have low blood pressure (after all they tend to have low PEA, low vasopressin, low NE).

I recently made this connection. I determined I have low dopamine levels and this causes to a degree, social anxiety, de-motivation, attention problems, etc. Tyrosine worked really well for this, until I introduced selegiline. I also suffer from....tadda....low blood pressure! Actually, I have neurogenic orthostatic hypotension for which I slightly improve with a high salt diet and more recently, Licorice. I realized dopamine was also involved here, but only because it's the direct precursor to norepinephrine. So, having low D, explains, in part, both problems.

The drug Tx of choice for this type of hypotension is Droxidopa. This is basically a direct amino acid precursor to norepinephrine. If NE can block HCN channels, I wonder if this drug will have a direct affect on attention span??

It's recently been discovered that the beneficial effects of norepinephrine are due to binding to the HCN channel to signal prefrontal cortex to stop manufacturing cAMP, which shuts down the prefrontal cortex in times of stress.

Edited by Lufega, 27 February 2009 - 06:05 AM.

[Lufega]

http://www.chelseath...ndications.html

Hypotension Associated with Fibromyalgia and Chronic Fatigue Syndrome

Independent clinical studies and ongoing research suggest that defects in the autonomic nervous system - such as altered norepinephrine levels and activity - may play a role in either the underlying cause or exacerbation of the symptoms associated with multiple diseases commonly grouped as dysautonomias. These indications include: chronic pain, urinary stress incontinence, postural orthostatic tachycardia syndrome, neurocardiogenic syncope, fibromyalgia and chronic fatigue syndrome.

Scientists and physicians have suggested a strong association and/or significant correlation of symptoms between low blood pressure (caused by either NOH or neurally mediated hypotension (NMH)) and two specific dysautonomias, fibromyalgia (FM), and chronic fatigue syndrome (CFS). Unlike OH, which is a problem with blood pressure regulation immediately after standing, NMH is characterized by a drop in blood pressure only after standing for long periods of time. NMH occurs due to a miscommunication between the heart and brain resulting in a failure to maintain appropriate increases in heart rate after standing for prolonged periods. This is believed to be a problem related specifically to deficient nerve function in the left ventricle (same place where the mitral prolapse occurs. I love how they say, "it is believed"....they know, just don't want to share info.!) that prevents the heart rate from increasing when needed. Instead of increasing, the heart rate actually drops, preventing the necessary amount of blood from being circulated. This leads to NMH symptoms like dizziness and fainting, which are often seen in patients with FM, CFS and other dysautonomias. As norepinephrine naturally regulates both heart rate and vasoconstriction, droxidopa could be an appropriate alternative therapy to treat these specific symptoms by enhancing the body’s ability to naturally regulate these functions. Further studies will be needed to determine the contribution of either NMH or NOH to other major components of autonomic diseases such as pain, fatigue, weakness, and incontinence. Furthermore, randomized trials will be needed to indicate whether droxidopa improves the hypotension and whether this in turn shows benefit in additional symptomology within these disease syndromes.

If I may get sidetracked for a second...

Trying to figure this stuff gives me a headache.....

I have mitral valve prolapse syndrome. It gets the label of a syndrome because it's accompanied by dysautonomia. Dysautonomia itself is presumed to be caused by a B1 deficiency (google derrick lonsdale). The main Sx of dys. is many variations of orthostatic hypotention. According to this article, OH/NMH (I have both, lucky me!) is related to CFS and fibromyalgia. The current ideology is that CFS and FM is infectious in origin either due to chronic EBV or Lyme disease. However, an epstein barr virus infection doesn't go into a chronic state unless another agent (Lyme co-infection?) disrupts the immune system.

So, the infectious agent somehow disrups B1 metabolism (as well as magnesium reabsorption by the kidneys) in the CNS/ANS. This screws up dopamine and norepinephrine production. Decreased activity in the mesocortical and dopaminergic pathway causes social widthdrawal, loss of motivation and loss of display of emotions leading to symptoms of social anxiety, apathy, depression, etc. These are all the negative symptoms of schizophrenia. Decreased norepi. because of low dopamine levels leads to hypotension and ADD.

It's so obvious to me how all this stuff is related. I just can't put it together well enough to make it stand out. This is very overly simplified, of course, but it's the best I can do at establishing a timeline of events.

In conclusion, if CFS and fibro is related to dysautonomia and this can be repaired by correcting the B1 status (if deficient), this should improve the problems with adrenal fatigue, CFS, fibro., low BP, low dopamine etc.. See my older post here.

Edited by Lufega, 27 February 2009 - 05:30 AM.

[Lufega]

I couldn't edit the original post so I'll add some studies here.

Forskoling stimulates adelynate cyclase resulting in increased cAMP. For me, this translated to increased stomach acid production (which I needed 5 betaine HCL per meal to duplicate), fat loss and a subtle increase in muscle mass. However, I felt like forskolin made me feel depressed, reduced motivation and dumbed me down. There something about increased cAMP activity in the prefrontal cortex decreasing cognitive abilities and mood?

Effects of mood stabilizers on the inhibition of adenylate cyclase via dopamine D(2)-like receptors.
Montezinho LP, Mørk A, Duarte CB, Penschuck S, Geraldes CF, Castro MM.

Department of Biochemistry, NMR Centre, and Centre for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.

OBJECTIVE: The mood stabilizing drugs lithium, carbamazepine and valproate modulate brain adenosine monophosphate (cAMP) levels, which are assumed to be elevated in bipolar disorder patients. The aim of this work was to investigate how these three mood stabilizing agents affect the regulation of cAMP levels by dopamine D(2)-like receptors in vitro in rat cortical neurons in culture and in vivo in the rat prefrontal cortex. METHODS: The production of cAMP was measured in the cultured cortical neurons or in microdialysis samples collected from the prefrontal cortex of freely moving rats using the [8-(3)H] and [(125)I] radioimmunoassay kits. RESULTS: In vitro and in vivo data showed that the treatment with the mood stabilizing drugs had no effect on basal cAMP levels in vitro, but had differential effects in vivo. Direct stimulation of adenylate cyclase (AC) with forskolin increased cAMP levels both in vitro and in vivo, and this effect was significantly inhibited by all three mood stabilizers. Activation of dopamine D(2)-like receptors with quinpirole partially inhibited forskolin-induced increase in cAMP in untreated cultures, but no effect was observed in cortical neuron cultures treated with the mood stabilizing drugs. Similar results were obtained by chronic treatment with lithium and valproate in the prefrontal cortex in vivo. However, surprisingly, in carbamazepine-treated rats the activation of dopamine D(2)-like receptors enhanced the responsiveness of AC to subsequent activation by forskolin, possibly as a consequence of chronic inhibition of the activity of the enzyme. CONCLUSIONS: It was shown that each of these drugs affects basal- and forskolin-evoked cAMP levels in a distinct way, resulting in differential responses to dopamine D(2)-like receptors activation.

Lithium, decreases cAMP in the brain induced by forskolin or other means and contributes to some cognitive/mood enhancement. So this may explain my depressed state as I was using forskolin (40 mg). How do D2 receptors play here? I didn't fully grasp that concept. Is this effect of lithium on cAMP exclusive for the brain or does it affect the whole body? If taken together, will I retain the acid increasing, fat burning and muscle gaining action of forskolin while enjoying the cognitive and mood boost of lithium?

[Lufega]

L-threo-DOPS = Doxydropa

[The effect of L-threo-DOPS on P-300 in parkinsonism]
[Article in Japanese]

Yokota J, Itoh T, Imai H, Narabayashi H. Department of Neurology, Juntendo University School of Medicine.

The P-300 has been recently utilized as an objective electrophysiological index of cognitive function in some neurological disease. Hansch et al first described prolonged latency for the P-300 component in Parkinson disease patients and suggested these measures reflects a common, disrupted aspect of cognitive function in this disease. This cognitive disorder may be caused not only from the dysfunction of dopaminergic system but from non-dopaminergic lesions such as norepinephrine ones. On the other hand, L-threo-DOPS, a non-physiological precursor of norepinephrine, has been used for the treatment of some neurological illness such as the freezing phenomenon in Parkinsonism. In the present study we investigate the effect of L-threo-DOPS on cognitive function in Parkinsonism by measuring P-300 component succeedingly. Twenty-four patients, i.e. 19 cases of Parkinson disease (PD), 3 Juvenile Parkinsonism (JP) and 2 cerebrovascular Parkinsonism, are studied. The latencies of P-300 are significantly shortened after treatment of DOPS compared with those of the previous treatment and placebo administration respectively (p less than 0.05, p less than 0.01). The main factors which have influence upon these shortened latencies are analyzed multivariate analysis. The factor analysis and principal component analysis suggest three main factors such as DOPS, age (onset of age), and duration of illness. The patients' groups are divided into three by cluster analysis. The most effective group mainly consists of JP. The least effective one mainly consists of older, long-duration Parkinson disease patients. And there is another group which consists of younger, short-duration PD cases with moderate effect of DOPS. This tendency seems to suggest the different pathological findings between JP and PD. It is postulated that L-threo-DOPS would raise the level of attention and arousal mediated by norepinephrine neuronal system which may improve the cognitive disorder in Parkinsonism.

So it seems like Doxydropa does exert a cognitive effect by directly increasing NE. I searched for side effects of this drug and really could not find any. Any ideas?

[Lufega]

Low blood pressure leads to cognitive decline

Abstract:
Low blood pressure has been found to be associated with cognitive decline and dementia in cross-sectional studies. Two mechanisms have been proposed to interpret this association: blood pressure levels decrease during the course of the dementia process, and low blood pressure induces or accelerates cognitive decline by lowering cerebral blood flow. Results of the prospective studies are contradictory. Low blood pressure and orthostatic hypotension have been found to predict cognitive impairment in the elderly population in some studies only. While hypotension may play a protective role in healthy elderly people, low blood pressure levels in frail elderly patients with associated diseases may cause cerebral hypoperfusion and accelerate cognitive decline.

Keywords: arterial hypertension; hypotension; brain; cognitive decline; cerebral hypoperfusion

Document Type: Research article

DOI: 10.1080/10641960802573344

Affiliations: 1: Division of Medicine and Hypertension, Department of Medicine and Experimental Oncology, S. Giovanni Battista Hospital, University of Torino, Torino, Italy

[Lufega]

I tried lithium today for the first time. The anti-depressant effect is very pronounced. I feel better than I have in a long, long time. I feel more motivated and energized. This is great stuff. I just hope this effects lasts. Kinda reminds me of my experience with selegiline. The first day was amazing then down-hill from there.

[bgwithadd]

It doesn't really go downhill. I have zero problems with depression now. I used to be able to get 'up' with zoloft or whatever (with massive side effects) but it felt very unnatural and I still felt very unhappy. St. John's Wort is very gentle and lifts me without feeling weird (over time and at high doses). Lithium has a different effect, but it's more like things just don't bother me quite so much and I can deal with things much easier. Nothing quite gives me that sense of wellbeing as I get from PEA and deprenyl (too bad that did not work out too well), but even when I used to be relatively happy I'd always have some negative or suicidal thoughts and I do think that the lithium makes me in a more happy state and not just an undepressed state. I take 30mg of elemental lithium a day. Beyond that and it starts to make my appetite higher.

Probably everyone should supplement with low level lithium around 5mg a day, and if you have mood problems then 30mg elemental lithium does a lot to improve things in me without side effects. When you get prescribed lithium you'd normally get 600mg of lithium minimum, which is about 100mg elemental lithium. At 200mg elemental lithium is where the cautious area begins (though in severe bipolar, this is often well exceeded) so anyone supplementing would want to stay well below this range. You are going to find other side effects long before you get into dangerous area, though, anyway. Like increased appetite, naseau, tremors, etc. Most people would stop then, because high dose lithium is really not too pleasant. Low dose, on other hand, seem to have a surprising amount of benefit with no side effects.

[bgwithadd]

Oh, and the low blood pressure thing...more info for you.

In PTSD and anxiety in general, it's believed in many cases that the people susceptible to it have low cortisol and high NE levels. I have noted before that people with anxiety problems usually seem to be highly intelligent, and basically low cortisol high NE would give you increased learning potential. Basically, with anxiety you are learning TOO well! You learn some bad lessons and can't unlearn them. In normal people, when your brain gets going too much cortisol will kick in. It causes homeostasis and makes it so that your brain doesn't come down too rapidly. It also blocks learning and memory...which can be helpful when you are in super traunatic situations.

Cortisol, btw, causes high blood pressure.

People usually think cortisol is the problem, not the solution. Interestingly, having high cortisol and low NE would cause low blood pressure and a lot of the same symptoms as the reverse!

This kind of thing is why people should not blindly take anything that increases learning. Learning isn't always good! People who are trying to get a genuine boost are going to be disappointed by anything they try. The only thing you can do is normalize levels and correct problems, make what you actually have function properly.

It's interesting to me personally, because I just have this crazy learning ability. I don't mean so much intelligence as just that I can soak up vast quantities of information and retain it in a way that's almost inhuman...I also have other good mental qualities but on the other hand I have all these other serious problems. Coincidence? Probably not. I am not sure if I have low cortisol, but I am sure there is more than one thing out of whack. At some point I'll have to get everything tested, but I take so many drugs and supplements I am not sure how useful the information I obtained would be.

[OneScrewLoose]

Why did the PEA and Deprenyl not work out too well?

[bgwithadd]

It's just too hard to get the dose right and the difference in dose between nothing, good effect, and hypertensive crisis is too close together. I might try again down the road when I have everything else stablized.

[Lufega]

bgwithadd,

I tested serum cortisol AM and PM and both were normal. I should have tested saliva but that isn't available here. My morning basal temperature was/is always on the low side 98, 97.something so I suspected adrenal fatigue or the like. I feel better physically when I use licorice. Licorise helps retain sodium and water and increases blood pressure. It also has cortisol mimicking properties. One thing I should note though, my blood cortisol levels were normal, yes, but normal low. So maybe the low cortisol high NE theory is relevant. I got the idea of low NE and low BP from a new pharma drug they are trying to push, droxidopa, which is a precursor to NE. I don't understand this stuff fully yet. I hope the lion's mane I just got will help me with that.

What you said about anxiety and never forgetting lessons in life. That is true with me. I never forget anything, ever. I still remember the kid in 6th grade that called me a book work....by name! Just waiting for the day I see him again....POW! lol

[Happy Gringo]

So back to the original question, how would you dose forskolin and lithium? Would it make sense to take the forskolin with breakfast and lunch and then take say 4 lithium orotate tabs (18mg elemental) before bed? It seems like both work by manipulating cAMP, so they shouldn't be taken together? Also, doesn't the lithium have a fairly long half-life? I think its 12 hours or so.

[Lufega]

I'm taking two tabs of lithium orotate in the morning and one in the afternoon. In the late evening, I then take 20 mg forskolin. This seems to be working for me.

[Happy Gringo]

Thanks. Does the lithium have any negative effects on your energy/alertness levels?

[k10]

Does anyone know what kind of an effect forskolin has on glutamate, if any?

[Lufega]

Thanks. Does the lithium have any negative effects on your energy/alertness levels?

None that I can tell. I find that since my mood is better on lithium, I've become more active and productive.

[Jacovis]

Guanfacine is actually shown to be just as effective for ADD as stimulants, hence the new long acting guanfacine version coming out from shire. Only problem is, most ADDers have low blood pressure (after all they tend to have low PEA, low vasopressin, low NE). Taking the full therapeutic dose of guanfacine would kill me for sure.

bgwithadd,
given that "Taking the full therapeutic dose of guanfacine would kill [you] for sure":
- would it be an option to take the full therapeutic dose of guanfacine with proven blood pressure increasers (which do not have to be neurostimulant medications) ?
- Guanfacine (along with Clonidine) is an Alpha-2 adrenergic receptor agonist. Prazosin is an Alpha-1 adrenergic receptor antagonist which also lowers blood pressure and also may be effective for ADHD (based on one study - see below). Do you have any comment on this?


[SCIENTIFIC AND CLINICAL REPORT SESSION 11-ADULT ADHD] No. 34 ALPHA-1 AGONIST PRAZOSIN FOR ADHD: THE ROLE OF NOREPINEPHRINE IN ADHD PATHOLOGY
Fletcher B. Taylor III, M.D., Rainier Associates, 5909 Orchard Street, West, Tacoma, WA 98467- 3824; Nancy Allison, P.D.
EDUCATIONAL OBJECTIVE: At the conclusion of the presentation, the participant should be able to understand the effects of d-amphetamine on alpha-1 adrenoceptors and their potential role in the pathophysiology of ADHD.
SUMMARY:
Objective: To explore the role of norepinepherine in the pathophysiology of ADHD and how D-amphetamine works for its treatment.
Methods: This double-blind, placebo-controlled study enrolled 16 ADHD adults, nine receiving ongoing d-amphetamine and seven not. They each received in a randomized fashion both placebo (lactose) and prazosin increased at .25 mg every one to two days to achieve optimal response. Measures included the ADHD Behavior Checklist for Adults (ADHD Checklist), the Clinical Global Impression of Improvement Scale (CGI), and the Stroop Color-Word Interference Test (Stroop). Adverse events were recorded.
Results: For the prazosin-only group, the final mean dosage was 1.04 mg/ day (range .5-2 mg). Patient-rated CGI scores (p < .05) and Stroop performance scores (p < .05) were significantly improved on prazosin as compared with placebo. ADHD Checklist and Stroop performance improvements were significantly correlated. For the prazosin with d- amphetamine group, the mean dosage was 1.40 mg/day (range 5.0-2 mg). Prazosin offered no benefit over the placebo condition, and in fact all measures tended to worsen.
Conclusions: These preliminary data suggest that 1) noradrenergic alpha- 1 receptor activity may be important in ADHD pathophysiology, and 2) the change in alpha-1 receptor activity provided by d-amphetamine may be important in its efficacy for this disorder.
REFERENCES:
1. Shi WX, Pun CL, Zhang XX, Jones MD, Bunney BS: Dual effects of d-amphetamine on dopamine neurons mediated by dopamine and nondopamine receptors. J Neurosci 2000; 20:3504-11.
2. Arnsten AF, Mathew R, Ubriani R, Taylor JR, Li BM: Alpha-1 noradrenergic receptor stimulation impairs prefrontal cortical cognitive function. Biol Psychiatry 1999; 45:26-31.


1: Eur J Pharmacol. 1996 Aug 1;309(1):1-11. Links
Prazosin inhibits MK-801-induced hyperlocomotion and dopamine release in the nucleus accumbens.

Mathé JM, Nomikos GG, Hildebrand BE, Hertel P, Svensson TH.
Department of Physiology and Pharmaccology, Karolinska Institutet, Stockholm, Sweden.
This study examined the putative inhibitory effect of the alpha 1-adrenoceptor antagonist prazosin (1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)pip erazine) on changes evoked by the psychotomimetic, non-competitive NMDA receptor antagonist, MK-801((+)-5-methyl-10,11-dihydroxy-5H-dibenzo-(a,d)cyclohepten-5, 10-imine), in locomotor activity and extracellular concentrations of dopamine and its metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the nucleus accumbens as assessed by microdialysis in freely moving rats. MK-801 (0.1 and 0.3 mg/kg, s.c.) induced a significant, dose-dependent increase in horizontal locomotor activity but did not affect rearing. Prazosin administration alone (1 mg/kg, s.c.) only slightly reduced horizontal activity during an initial 10 min measurement period, although it consistently reduced rearing. However, pretreatment with prazosin effectively suppressed the locomotor stimulation caused by either dose of MK-801 throughout the whole observation period, i.e. 40 min. Both doses of MK-801 significantly increased extracellular levels of dopamine in the nucleus accumbens up to approximately 90%. In addition, MK-801 dose dependently increased dopamine metabolite concentrations in the nucleus accumbens, but 5-HIAA was significantly increased only by the high dose of MK-801. When given alone, prazosin did not affect either dopamine, DOPAC, HVA or 5-HIAA levels. However, prazosin pretreatment effectively blocked MK-801-evoked increases in dialysate dopamine concentrations. Consequently, the potent and selective alpha 1-adrenoceptor antagonist prazosin was found to specifically suppress MK-801-evoked, but not basal dopamine release in the nucleus accumbens, while effectively blocking MK-801-evoked locomotor stimulation with only negligible effects on basal locomotor activity. Thus, alpha 1-adrenoceptor antagonism may act by reducing the sensitivity of the mesolimbic dopamine system to pharmacological or environmental challenge. Since most antipsychotic drugs exhibit both dopamine D2 receptor and alpha 1-adrenoceptor antagonistic properties, they may alleviate psychosis not only through blockade of postsynaptic dopamine receptors, but also presynaptically on the mesolimbic dopamine system, through their alpha 1-adrenoceptor antagonistic action. This latter action may contribute to reduce evoked dopamine hyperactivity, e.g. in response to stress.
PMID: 8864686 [PubMed - indexed for MEDLINE]

Edited by Visionary7903, 06 June 2009 - 12:04 PM.

[Lufega]

I completely forgot I had written this post. I started up on forskolin again and my hypotensive symptoms and other problems are much improved. However like before, forskolin made me depressed after a couple of days use.

This time around, I'm only using 10 mg forskoling (1 LEF pill) instead of 3 or 4 that I was using before. Forskolin does seem to improve so many parameters that I want to keep it as a mainstay. I just have to work around the depression problem. Maybe adding lithium (again) at the same time will solve this problem.

This is a good write up on Forskolin. http://www.highpump....-green-tea.html

I like the part about improving muscle mass and fat loss.

[Lufega]

http://www.naturodoc...s/forskolin.htm

Depression
Depression is believed to be due to an imbalance of neurotransmitters in the brain—most commonly either serotonergic (inhibitory) or dopaminergic (stimulatory). The response to various antidepressants depends on which neurotransmitter system has deviated farthest from the "norm." If the serotonergic neurotransmitters are most deficient, serotonin precursors like 5-HTP or L-tryptophan, or the selective serotonin reuptake inhibitors (SSRI) like Paxil, Prozac, or Zoloft are most likely to be of help. If the dopaminergic (i.e., catecholamines like epinephrine or noradrenaline) neurotransmitters are deficient, catecholamine precursors such as the amino acids L-Phenylalanine or L-Tyrosine, or monoamine oxidase inhibitors such as GeroVital (GH3) or Deprenyl are most likely to help.

German scientists have been working with a different approach to elevating catecholamines, using a class of drugs that stimulate both the presynaptic as well as the postsynaptic components of catecholamanergic transmission. This novel approach uses a drug, Rolipram, which acts by increasing cAMP (an action similar to that of Forskolin), and inhibiting phosphodiesterase. Although the researchers stopped short of recommending Forskolin for the treatment of depression, they stated clearly that "elevated brain cAMP levels are closely linked to antidepressant activity in animal models of depression."

Why forskolin makes me feel depressed will remain a mystery for me

[Lufega]

Lithium inhibition of forskolin-stimulated adenylate cyclase.
Andersen PH, Geisler A.

Abstract
The lithium sensitivity of forskolin- and fluoride-stimulated adenylate cyclase activity was investigated in rat brain homogenates in vivo and in vitro. The unstimulated and fluoride-stimulated activity was not affected by lithium, while the forskolin stimulation exhibited a pronounced inhibition by this cation. Furthermore, if Mn2+ was substituted for Mg2+ in the assay media, the forskolin-stimulated activity was even more sensitive to lithium. The results indicate an action of lithium mainly on the catalytic moiety in the adenylate cyclase system. However, the effect cannot be direct on this protein, since the unstimulated activity was unaffected. The action is rather on the microenvironment surrounding this protein, thereby interfering with a possible conformational change of the adenylate cyclase of importance for the activation of this enzyme.

PMID: 6542629 [PubMed - indexed for MEDLINE]

Effects of long-term treatment with lithium and antidepressants on [3H]forskolin binding to rat cerebral cortical membranes.
Odagaki Y, Koyama T, Yamashita I.

Department of Psychiatry and Neurology, Hokkaido University School of Medicine, Sapporo, Japan.

Abstract
1. The characteristics of [3H]forskolin binding in rat cerebral cortical membranes and the effects of long-term treatment with lithium, desipramine and tranylcypromine on the binding were investigated. 2. Specific binding of [3H]forskolin (10 nM) was augmented by the addition of magnesium, and in the presence of 5 mM MgCl2, sodium fluoride (NaF) increased further the specific binding in a concentration-dependent manner. 3. Guanyl-5'-ylimidodiphosphate (Gpp(NH)p) increased the specific binding only in the presence of 100 mM MgCl2. 4. Long-term treatment with lithium, desipramine or tranylcypromine altered neither the specific binding of [3H]forskolin nor the augmentation by MgCl2, NaF, or Gpp(NH)p. 5. The results indicate that these preparations alter neither the catalytic subunit of adenylate cyclase nor the activation of stimulatory guanine nucleotide-binding regulatory proteins (Gs).

PMID: 1956996 [PubMed - indexed for MEDLINE]

The effect of acute and chronic lithium on forskolin-induced reduction of rat activity.
Bersudsky Y, Patishi Y, Bitsch Jensen J, Mørk A, Kofman O, Belmaker RH.

Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel.

Abstract
Forskolin is a diterpene derivative that activates adenylate cyclase and raises cAMP levels in the cell. Both i.p. and i.c.v. forskolin cause behavioral hypoactivity. Lithium has been reported for many years to block cAMP accumulation, but the behavioral relevance of this biochemical effect is not clear. We studied the effect of acute and chronic lithium on icv forskolin-induced hypoactivity. Acute lithium had no effect, but chronic lithium significantly blocked forskolin-induced hypoactivity. The effect of chronic lithium occurred with both forskolin in DMSO and with a water-soluble forskolin derivative. These results suggest that this behavioral model can be used to investigate whether new inhibitors of adenylate cyclase possess lithium-like effects.

PMID: 9451726 [PubMed - indexed for MEDLINE]

From these three studies I conclude:

1. Lithium and Forskolin antagonize each other.
2. Mangesium enhances the effect of lithium on the body. I take magnesium AEP at the same time as the forskolin.
3. Manganese lessens the effect of forskolin, especially when lithium is present.
4. The behavioral hypoactivity mentioned in the third study is exactly how I feel. More calm, focused, less anxious and irritable, etc.

[Lufega]

The effect of lithium on noradrenaline-induced cyclic AMP accumulation in rat brain: inhibition after chronic treatment and absence of supersensitivity.

Abstract
Lithium (Li) has been reported to inhibit numerous adenylate cyclases, but often these reports used clinically toxic concentrations of Li and their relevance to a theory of Li action was questionable. The present report demonstrated Li inhibition beginning at 2 mM of the norepinephrine (NE)-induced cyclic AMP accumulation in a resuspended P2 pellet containing intact synaptosomes and in slices from rat cortex. The inhibition is demonstrable with isoproterenol as well and in the presence of a phosphodiesterase inhibitor. In cortical slices removed from rats treated for 21 days with therapeutically equivalent Li serum levels, NE-induced cyclic AMP accumulation is inhibited by over 70%. After cessation of 21 or 42 days of Li treatment, an enhancement of cyclic AMP accumulation to NE is not demonstrable. Rubidium and cesium do not inhibit NE-induced cyclic AMP accumulation. These ions cause an increase in basal cyclic AMP accumulation in the absence of NE, as does Li to a lesser degree. The effect of Li to inhibit NE-induced cyclic AMP accumulation is therefore specific to the Li ion, occurs at therapeutically equivalent concentrations, continues after chronic treatment and does not cause a compensatory supersensivity in the manner of the NE-receptor blocking drugs.

Now, how much lithium does one use to reach 2 mM ? Why is this important you ask ? A lot of people report brain fog after using lithium orotate and I think this is because it reduces cAMP in the brain. There was a study posted earlier that showed phosphodiesterase inhibitors restored memory functionality (partially) in sleep deprived subjects by elevating CAMP. When you're sleep deprived, you can't think straight, the mind is foggy. I think cAMP is what connects these two.

Edited by Lufega, 23 April 2011 - 01:53 AM.

[Thorsten3]

http://www.naturodoc...s/forskolin.htm

Depression
Depression is believed to be due to an imbalance of neurotransmitters in the brain—most commonly either serotonergic (inhibitory) or dopaminergic (stimulatory). The response to various antidepressants depends on which neurotransmitter system has deviated farthest from the "norm." If the serotonergic neurotransmitters are most deficient, serotonin precursors like 5-HTP or L-tryptophan, or the selective serotonin reuptake inhibitors (SSRI) like Paxil, Prozac, or Zoloft are most likely to be of help. If the dopaminergic (i.e., catecholamines like epinephrine or noradrenaline) neurotransmitters are deficient, catecholamine precursors such as the amino acids L-Phenylalanine or L-Tyrosine, or monoamine oxidase inhibitors such as GeroVital (GH3) or Deprenyl are most likely to help.

German scientists have been working with a different approach to elevating catecholamines, using a class of drugs that stimulate both the presynaptic as well as the postsynaptic components of catecholamanergic transmission. This novel approach uses a drug, Rolipram, which acts by increasing cAMP (an action similar to that of Forskolin), and inhibiting phosphodiesterase. Although the researchers stopped short of recommending Forskolin for the treatment of depression, they stated clearly that "elevated brain cAMP levels are closely linked to antidepressant activity in animal models of depression."

Why forskolin makes me feel depressed will remain a mystery for me

Perhaps due to its effects on histamine? It's well known to be protective against allergies, to some degree; plus, it induces sleep. There are studies showing it to reduce histamine release.

I mean, people tend to take it later in the evenings because it makes them tired. I've read anecdotes where people have claimed this supplement to be a lifesaver, as it ended up curing their chronic insomnia.

I can say that, for myself, it definitely induces sleep and makes me tired. I have also noticed the same decline in cognition and depressive effects from forskolin. It can make me quite lethargic and even irritable if people try to talk to me (like, participating in the conversation becomes an effort). I eliminated the fatigue problem by trying ATP boosters like polyrachis ant and rhodiola, however, the cognition issue still exists. Mentally, I feel pretty damn slow and stupid. My wit has dissapeared.

Perhaps, trying a histamine booster alongside it, might give me an answer to the histamine theory, I have.