14 replies to this topic

[rwac]

Chronic lithium treatment affects rat brain and serum dehydroepiandrosterone (DHEA) and DHEA-sulphate (DHEA-S) levels.
Maayan R, Shaltiel G, Poyurovsky M, Ramadan E, Morad O, Nechmad A, Weizman A, Agam G.

Laboratory of Biological Psychiatry, Felsentein Medical Research Center, Beilinson Campus, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.


Abstract
Lithium (Li) is an established effective treatment for bipolar disorder. However, the molecular mechanism of its action is still unknown. Dehydroepiandrosterone (DHEA) and its sulphate ester (DHEA-S) are adrenal hormones also synthesized de novo in the brain as neurosteroids. Recent studies have suggested that DHEA has mood-elevating properties and may demonstrate antidepressant effects. 3(2)-Phosphoadenosine 5-phosphate (PAP) phosphatase is a novel Li-inhibitable enzyme involved in sulphation processes. In the present study we examined the impact of 10 d Li treatment on serum and brain DHEA and DHEA-S levels in rats. Our results show that Li administration lowered frontal cortex and hippocampus DHEA and DHEA-S levels, in line with our hypothesis assuming that Lis inhibition of PAP phosphatase leads to elevated PAP levels resulting in inhibition of sulphation and reduction in brain DHEA-S levels. Future studies should address the involvement of neurosteroids in the mechanism of Lis mood stabilization.

PMID: 14725722 [PubMed - indexed for MEDLINE]

Lithium: evidence for reduction in circulating testosterone levels in mice following chronic administration.
Collins TJ, Chatterjee S, LeGate LS, Banerji TK.

Department of Anatomy and Neurosciences, University of Texas Medical Branch, Galveston 77550.


Abstract
Lithium, the widely-used antipsychotic drug, is known to exert adverse effects on a number of endocrine organs. In the present investigations, the effects of chronic lithium administration on circulating levels of testosterone and plasma and pituitary levels of luteinizing hormone (LH) were evaluated in order to examine whether or not the pituitary-gonadal axis is a probable target of lithium action. Adult male C57BL/6 mice, maintained on a fixed photoperiodism (LD 14:10), were administered lithium orally, by being fed on a specially prepared chow containing 0.4% lithium chloride for 15 or 30 days, while their matched controls were maintained on standard laboratory chow. At the termination of the respective experimental schedules, the animals were decapitated, their blood collected, and plasma was separated and stored frozen. Pituitaries were quickly removed, weighed, homogenized, centrifuged and their supernatants were stored frozen. Testosterone in plasma and LH in pituitary and plasma were quantitated by standard RIA methods. Plasma Li concentration was determined by using flame photometric methods. A significant suppression in testosterone levels was noted after both 15 (p less than .01) and 30 (p less than .05) days of lithium treatment, but both pituitary and plasma LH levels remained unchanged at both the periods. It is, therefore, suggested that lithium exerts its effect directly at the level of the Leydig cells rather than through the pituitary-gonadal axis. Since the noted lithium-induced reduction of testosterone was manifested when the plasma lithium levels were within (or around) the therapeutic range, these results may have important clinical implications.

PMID: 2848165 [PubMed - indexed for MEDLINE]

Anyone know how to estimate elemental Li for these studies. Both studies have used dosage as per kg food.
Additionally, we know that brain concentration of LiOrotate is higher than carbonate. Will this apply to the testes as well ?

[markymark]

hm,

to extrapolite about DHEA(S) from rodent studies to man is slippery......
Moreover,

I found this (the authors below, of course, did not check for neurosteroids in the brains of the volunteers):

Prog Neuropsychopharmacol Biol Psychiatry. 1997 Aug;21(6):937-50.
Effects of lithium carbonate on reproductive hormones in healthy men: relationship with body weight regulation--a pilot study.
Baptista T, Alastre T, Contreras Q, Martinez JL, Araujo de Baptista E, Burguera JL, de Burguera M, Hernández L.

Laboratory of Behavioral Physiology, Medical School, Universidad de Los Andes, Mérida, Venezuela.
Abstract

1. To test the hypothesis that lithium-induced body weight gain is related to an unbalance in the reproductive hormones, lithium carbonate (900 mg/day) or placebo was administered to healthy men for 1 month. 2. Body weight, skin folds and the serum levels of thyrotropic hormone, tetraiodothyroxine, prolactin, follicle-stimulating hormone, luteinizing hormone, testosterone (T5), dehydroepiandrosterone sulfate (DHEAS), estradiol (E2), cortisol, the ratios E2/T5 and T5/DHEA-S, and blood lipids were evaluated before and during treatment. 3. Body weight, skin folds, hormones and lipids serum levels were not significantly affected by the treatment with Li. These results agree with previous reports of lack of effects of 1 month-Li administration on appetite and body weight in normal male subjects (Chen et al., 1992), and question the appropriateness of studying Li-induced obesity in healthy volunteers, given the short-term administration and low doses of Li that must be used.

[ajnast4r]

.4% is a HUGE amount of lithium. those results wouldnt translate to anything meaningful in humans... the study markymark posted is more relevant.

900mg lithium carbonate is ~170mg elemental lithium... significantly higher than the doses(1,5,10mg) used by most people here.

turn off the sirens, lithium is safe

[Happy Gringo]

Thanks, I feel better. I think I will continue to take 25 mg. of DHEA in the mornings as I am 47 and it doesn't seem to have any adverse effects at such a low dose. I take it with Ginkgo and it seems to help me recover after lifting heavy at the gym, maybe by reducing cortisol a bit. I am taking lithium orotate before bed for 5 mg. lithium. Any more drugs me out the next day.

[chrono]

C57BL/6 mice eat about 4g of food per day [1]. At 0.4%, that's .016g LiCl/day, or .0026g elemental Li. Divide this by 12.3 to get an equivalent human dose according to BSA values.

Rather than a huge amount, it seems to be infinitesimal. Though I'd welcome any thoughts on why this might not be the case. On the plus side, I think we get this much lithium just by eating food, so maybe these effects are already "accounted for" in the human body, and these inbred BL6 lab mice reacted this way because it wasn't part of their normal diets.

Additionally, we know that brain concentration of LiOrotate is higher than carbonate.

In that other thread, I think we determined that this was only the case with a single injected dose. The study I posted using chronic oral dosing showed no difference in brain levels.

Edited by chrono, 31 July 2010 - 05:25 AM.

[rwac]

C57BL/6 mice eat about 4g of food per day [1]. At 0.4%, that's .016g LiCl/day, or .0026g elemental Li. Divide this by 12.3 to get an equivalent human dose according to BSA values.

You forgot to normalize for weight. The average mouse weighs 20-25g. so multiply by 75000, divide by 25 = multiply by 3000 to normalize to human weight. That's ~600mg of lithium, fairly large.

In that other thread, I think we determined that this was only the case with a single injected dose. The study I posted using chronic oral dosing showed no difference in brain levels.

I still wonder why we notice strong effects from 5mg of the orotate, when the typical pharmacological dose is much larger. (~100-200 mg)

Edited by rwac, 30 July 2010 - 12:47 PM.

[Logan]

I still wonder why we notice strong effects from 5mg of the orotate, when the typical pharmacological dose is much larger. (~100-200 mg)

Because the typical pharmacological dose is used to treat people who have a much more active manic brain chemistry. Bipolar patients in the middle of some type of mania simply are not sensitive to lower doses of lithium. They may feel the effects of lower doses, it is just not enough to take them out of their manic state. People that are not bipolar obviously have a different chemistry and are in a different state that would be more sensitive to lower doses of lithium. Even someone that has a predisposition toward developing bipolar manic states but has not developed manic symptoms may be more sensitive to low doses of lithium. I have read about several people with bipolar, that were experiencing milder symptoms, having success treating those symptoms with taking just a few 5mg lithium orotate tablets/capsules a day.

[chrono]

C57BL/6 mice eat about 4g of food per day [1]. At 0.4%, that's .016g LiCl/day, or .0026g elemental Li. Divide this by 12.3 to get an equivalent human dose according to BSA values.

You forgot to normalize for weight. The average mouse weighs 20-25g. so multiply by 75000, divide by 25 = multiply by 3000 to normalize to human weight. That's ~600mg of lithium, fairly large.

I don't think that's necessary when converting from animal studies; most rat/mouse dosages are already 6-12x what a human would take to get similar effects.

See this thread for an explanation of how body surface area (BSA) is used to estimate human equivalent dosages: Converting dosages from animal studies. There's enough studies on lithium serum measurements that I'm sure a more accurate conversion is possible, but BSA values are probably still in the ballpark (unless lithium acts much differently than other pharmaceuticals).

I think morganator is right about the LiOr issue. A dose we 'feel' doesn't necessarily equate to a dose which would successfully treat a psychiatric problem. 300mg lithium carbonate (~55mg Li) is the smallest dose available, I believe. There have been a few papers suggesting that lower dosages than this might be efficacious for certain disorders, and would avoid some concerns about toxicity.

Edited by chrono, 31 July 2010 - 05:26 AM.

[rwac]

I don't think that's necessary when converting from animal studies; most rat/mouse dosages are already 6-12x what a human would take to get similar effects.

See this thread for an explanation of how body surface area (BSA) is used to estimate human equivalent dosages: Converting dosages from animal studies. There's enough studies on lithium serum measurements that I'm sure a more accurate conversion is possible, but BSA values are probably still in the ballpark (unless lithium acts much differently than other pharmaceuticals).

So mouse dose in mg/kg and human dose in mg/kg are related by a factor.
But you still need to account for the relative weights of humans and mice to calculate human dose.

Or,
(Human dose)=(BSA factor)*(Mouse dose)*(Human weight)/(Mouse weight)

[chrono]

haha, yes, you're correct. Apparently I was having an epic brain fart yesterday wrt absolute vs. mg/kg dosing. Ironically, it's probably due (in part) to lithium; I forgot to take it with me out of town this week, and when I got back yesterday it hit me pretty hard. Kids, don't do math on lithium

So, in that study, the equivalent human doses would be 8.4-10.5mg/kg, which is a medium-high therapeutic dose.

The study in post #2 showing no change in human DHEA-S/T5 levels used ~170mg/day elemental Li.

Edited by chrono, 31 July 2010 - 05:40 AM.

[Sillewater]

Here's an online calculator utilizing allometric scaling:

http://home.fuse.net.../allometry.html

[e Volution]

We really need a more evidence based dosing amount for Lithium. 5mg feels so arbitrary; really just the minimum amount per pill that is sold on iHerb I know we can consider an unofficial RDA of Lithium at around 1mg/day so it seems 5mg is potentially too much (for the very conservative do-no-harm approach). I mean put another way, we rarely recommend 200% of other minerals, and if supplements sold Li in 2.5mg pills I bet that would be the most commonly taken amount on this forum.

Maybe I'm just too lazy as cutting up that stupid little pill got too cumbersome

Edited by e Volution, 31 July 2010 - 05:42 AM.

[chrono]

If all you're looking for is supplementation of an essential nutrient, then 5mg might be too much. I use the Advanced Research brand, which is very easy to break into quarters with just your fingers. As you said, the 1mg RDA isn't really a tolerable upper limit, but based on studies of Li in food and drinking water (Lithium: Occurrence, Dietary Intakes, Nutritional Essentiality). That is to say, I'm not aware of any studies saying that doubling or tripling this dose increases risk of adverse effects.

5mg is pretty arbitrary, but as a psychiatric dose, seems pretty safe. Unfortunately, there's a dearth of papers which deal with this dosage range (between drinking water and 'therapeutic'), and they don't support any firm conclusions, except perhaps that in it's much less toxic than even lowest therapeutic dosages.

[levianthan]

The effects of short-term and chronic lithium administration on the concentrations of plasma testosterone (T) and luteinizing hormone (LH) were evaluated in C57BL/6 mice, maintained on a fixed photo-period of LD 14:10 (white lights on at 06:00 h, CST). Lithium chloride was injected intraperitoneally twice daily (at 09:00 and 16:00 h) in groups of adult male mice at a dosage of 2.5 meq/kg for 7 days, and 1.25 meq/kg for 21 days. Circulating levels of T and LH were measured by standard radioimmunoassay (RIA) methods. Plasma T levels showed a significant increase in mice treated with lithium for 7 days as compared to those in saline-injected control animals. However, there was no significant difference in the concentrations of plasma T between chronic (21 days) lithium-treated mice and the matched control. Plasma LH levels remained unchanged following both short-term and chronic lithium treatment.

Serum luteinizing hormone and testosterone were determined weekly during the course of a comparison of the effects of lithium versus placebo on impulsive aggressive behavior in 16-24 year-old male prisoners. The duration of drug treatment for each individual was up to 3 months. A significant reduction of serious agressive behavioral incidents occurred in the third month on lithium and was accompanied by a significant rise in serum luteinizing hormone, with no change in serum testosterone.

Edited by levianthan, 31 May 2013 - 12:50 PM.

[spookytooth]

lithium gave me severe brain fog and short-term memory loss.
orotate form.

Edited by spookytooth, 01 June 2013 - 08:57 PM.