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[Bateau]

So its generally accepted around the forum that the advisable dose to take Methylene Blue for cognitive enhancement is 60 micrograms.  Is there any logic behind this?

 

The suggested dose from the data I'm aware of is 0.16-0.64 mg/kg, mainly because;

 

1. That is the  human equivalent dose (H.E.D.) for 1-4 mg/kg that has been repeatedly tested in healthy rats for cognitive enhancement. [1][2][3][4][5] (divide by 6.2 to get the H.E.D. from rat data - see attachments)
2. The proposed mechanisms behind cognitive enhancement (improved mitochondrial function through increased cytochrome C, redox activity) are again active around 1-5 mg in rats [4]
3. And the human Alzheimer's trials also use a similar dose, although they would take it three times daily instead of once daily, and admittedly at the higher end of the range. They're trying to treat a very aggressive disease, not trying to optimize a healthy brain. [see attachments]

 

So whats up with the practically homeopathic dosing going on around here? People have literally been taking less that 1% of what seems to be needed to have positive effects.

 

These experiments examined the effects of methylene blue on retention, by rats and mice, of an inhibitory avoidance response. The studies using mice investigated the effects of graded doses of methylene blue administered shortly before or after training. A 500-mg/kg dose impaired retention in mice (tested 3 days after training) if administered 15 min, but not 30 or 5 min, prior to training. Further studies with rats indicated that retention was enhanced by a low dose ( 1.0 mg/kg) administered immediately after training (tested 1 day after training). Retention in rats was not affected by a 1.0-mg/kg dose given 15 min before training, 6 h after training, or 15 min before testing. These results are interpreted in the light of methylene blue’s actions on blood hemoglobin and carbohydrate metabolism.

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Methylene blue (MB) increases mitochondrial oxygen consumption and restores memory retention in rats metabolically impaired by inhibition of cytochrome c oxidase. This study tested two related hypotheses using biochemical and behavioral techniques: (1) that low-level MB would enhance brain cytochrome c oxidation, as tested in vitro in brain homogenates and after in vivo administration to rats and (2) that corresponding low-dose MB would enhance spatial memory retention in normal rats, as tested 24 h after rats were trained in a baited holeboard maze for 5 days with daily MB posttraining injections. The biochemical in vitro studies showed an increased rate of brain cytochrome c oxidation with the low but not the high MB concentrations tested. The in vivo administration studies showed that the corresponding MB low dose (1 mg/kg) increased brain cytochrome c oxidation 24 h after intraperitoneal injection, but not after 1 or 2 h postinjection. In the behavioral studies, spatial memory retention in probe trials (percentage of visits to training-baited holes compared to total visits) was significantly better for MB-treated than saline control groups (66% vs. 31%). Together the findings suggest that low-dose MB enhances spatial memory retention in normal rats by increasing brain cytochrome c oxidase activity

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Methylene blue administered post-training improves memory retention in avoidance and appetitive tasks, and restores spatial memory impaired by an inhibitor of cytochrome oxidase. Methylene blue may improve memory retention by increasing brain oxygen utilization. We investigated which doses improve memory without nonspecific behavioral effects, and whether methylene blue enhances brain oxygen consumption. Different doses were evaluated 24 h after administration in wheel running, feeding, open field habituation and object recognition tests. The 1-10 mg/kg methylene blue-treated rats were not different from saline-treated rats in locomotion or feeding behavior. The 50-100 mg/kg doses decreased running wheel behavior. The 4 mg/kg dose improved behavioral habituation and object memory recognition. Dose-dependent effects of methylene blue on brain oxygen consumption revealed that low concentrations increased brain oxygen consumption in vitro and 24 h after in vivo administration. Therefore, methylene blue doses that increase brain oxygen consumption also facilitate memory retention.

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We investigated whether postextinction administration of methylene blue (MB) could enhance retention of an extinguished conditioned response. MB is a redox compound that at low doses elevates cytochrome oxidase activity, thereby improving brain energy production. Saline or MB (4 mg/kg intraperitoneally) were administered to rats for 5 d following extinction training of tone-footshock conditioning. Postextinction freezing was lower in rats receiving MB compared with saline, suggesting that MB improved retention of the extinction memory. The MB effect was specific to tone-evoked freezing because there were no differences in pretone freezing. Control subjects similarly injected with MB showed no evidence of nonspecific effects on measures of motor activity and fearfulness. MB-treated rats exhibited both greater retention of extinction and greater overall brain metabolic activity. Rats with higher retention of extinction also showed a relative increase in cytochrome oxidase activity in prefrontal cortical regions, especially anterior infralimbic cortex, dorsal and medial frontal cortex, and lateral orbital cortex. These regional metabolic increases were also correlated to the behavioral freezing index used to assess retention of extinction. It was concluded that MB administered postextinction could enhance retention of extinction memory through an increase in brain cytochrome oxidase activity.

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Methylene blue (MB) is a metabolic enhancer that has been demonstrated to improve memory retention when given post-training in low doses in a variety of tasks in rats, including inhibitory avoidance, spatial memory (in both normal and metabolically-impaired subjects), object recognition, and habituation to a familiar environment. MB has been also shown to improve memory retention of extinction of fear conditioning in the rat. No experiments have been conducted to determine the effects of MB on more complex learning such as in discrimination tasks that require repeated days of training. This study examined the effects of daily MB on spatial discrimination memory in a baited holeboard maze. Following three days of discrimination training, subjects treated daily with post-training MB (1 mg/kg) reliably discriminated between rewarded (baited) and non-rewarded (unbaited) trials as indicated by a greater number of correct responses on rewarded trials than non-rewarded trials during the last three days of discrimination training. No such discrimination effects were observed in the saline-treated control group during the same training period. To determine whether the memory-enhancing effects of MB are associated with an increase in metabolic energy capacity in the brain, cytochrome c oxidation was measured in brains from rats treated with 1 mg/kg MB or saline for three days. The number of daily injections was chosen based on the behavioral data which revealed group differences three days after the beginning of MB treatment. Brain cytochrome oxidase activity in the MB-treated group was approximately 70% higher than in saline-treated rats. The findings suggest that repeated post-training MB may improve memory consolidation between days of learning by an induction in the enzyme cytochrome oxidase, leading to increased metabolic capacity in brain regions requiring more energy during discrimination learning.

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MB serves as a redox compound that at low doses (1-5 mg/kg) improves mitochondrial respiration (Visarius et al. 1997) and prevents free radical damage (Salaris et al. 1991). Low-dose MB acts on the electron transport chain, and it increases cellular oxygen consumption by a well-known mechanism of action that involves accepting electrons from molecular oxygen (Lindahl and Oberg 1961).

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Attached Files

•  Methylene Blue Dose.png   59.67KB   11 downloads
•  Animal Conversions.png   113.61KB   10 downloads

Edited by Bateau, 18 August 2014 - 08:17 PM.