The Non-Ray Peat Thread

[RedStaR]

This is my approach to some Ray Peat basics that I've come across on the forums, and additions. You may agree or disagree with the following, this is not a protocol, but a discussion in the end. So feel free to share your own thoughts and methods. I might post studies if needed later on. This list is not comprehensive

Exercise
I listed this first for a reason. Improves leptin sensitivity in muscle, cardiorespiratory fitness, insulin sensitivity, metabolism, thyroid function, BDNF release, endorphins, regulates neurotransmitter balance, hormonal profile, lipid profile, circadian cycle, waste excretion, releases growth factors, improves BMD, increases LBM, combats tumors, improves libido, improves erectile quality, reduces stress, prevents cognitive decline, alleviates anxiety, improves depression, improves ADHD, improves OCD, sharpen memory, boosts creativity, improves nutrition partitioning, increases calorie expenditure, lowers IL, increase joint strength, improves self-confidence, and that's just the start. Seriously, you could diet all you want, but if you are not exercising, you are missing out. We all know the jock or the exercise freak who eats twinkies and Nutella all-day, with great conditioning, youth, and excellent health. If you aren't exercising yet and tried everything for a health issue you have, then THIS is what you're looking for. I will also stress on both aerobic and anaerobic exercises. Studies are mixed as to which to start a session with, it depends on your goals, it generally doesn't matter. Overtraining is very real, don't overdo it.


Capsaicin (Cayenne pepper)
An alternative to Aspirin in some cases. Anti-inflammatory, reduces CVD, anti-oxidant, suppresses energy intake, increase in intracellular calcium levels, activates BAT, improves fat metabolism, stimulates alkali and mucus secretion (protective for lower GI, and against ulcers/bleeding), improves insulin resistance, improves lipid profiles. Sold in supplement form, but I prefer to garnish almost everything I eat with dried, ground Cayenne powder spice. CP has 30,000 - 50,000 Scovilles, not super hot, but you may need to work your way up. It took me 2-4 weeks before I could pour it on my food as much as I like.


Tadalafil (Cialis)
Surprised? Don't be. In addition to the awesome benefit of raging erections 24 hours a day at will, Tadalafil has shown to increase the T/E ratio, protect heart tissue, reduces fibroblast activity, improves BPH symptoms, improves LUT symptoms, improves hypertension, reverses cognitive dysfunction, improves penile ultrastructure and may increase penile volume, combats Ischemic Vascular Disease (IVD), improves endothelial function, reduces serum oxidative stress, improves spermatogenesis, and increases ejaculatory volume. Take 2.5-5mg/day, most studies used 5mg/day. I take 2.5mg/day personally, and they are almost as effective as 5mg/day in inhibiting PDE-5 (50-60% vs 80-90%), with slightly reduced adverse effects. Due to its long half-life of 17.5 hours, it reaches a SS concentration of 1.5x the dose after a week.


Leptin
The mother of all energy metabolic hormones. It plays a fundamental role in some important body functions including energy homeostasis, growth hormone release, regulation of neuroendocrine function, insulin resistance and metabolism, not just in surplus energy conditions but, most importantly, in the situations of insufficient energy and starvation. Obese mice injected with Leptin melt away the fat, recover from T2D, reverse lipodystrophy, and show significantly improved energy and mobility indicators. Some foods are thought to improve leptin sensitivity like leucine and capsaicin. It's important to note that Leucine almost deserved its own spot in energy metabolism, so take your BCAAs. Exercise and carbohydrate intake maybe the easiest natural ways of promoting leptin release and sensitivity. Remember that it's a balance, you want as high sensitivity of receptors as you can while ensuring periodic leptin release. This will keep the thyroid hormones flooding, suppress your appetite, and oxidize the fat. Too much leptin may cause leptin resistance, and you don't want that. If you were previously obese, went on long fasts, or overtrained frequently in the past, you may have leptin deficiency/resistance. You could try leptin therapy at home with Metreleptin (Myalept), start with 0.1mg/day, work up to 2.5mg/day, don't go for more than 10mg/day. Worst case scenario, nothing major happens. Best case, you are a new person. It's crazy expensive, you might be able to source it somewhere else.


Orlistat (Xenical)
Pretty self-explanatory. Take this on your Peat 'cheating-days'. Craving for some fried chicken, pizza, or Belgian waffles? Pop a Xenical and pass that evil PUFA right through your intestines. It might get messy if you dish it out, but some nuts or grilled chicken thighs with skin will be fine. This is what I use on a cheat day, and it certainly helps keep the weight manageable as well. Remember to only use it when you DON'T want to absorb the fat in your meal, but it's important not to use in your healthy choices.


I will post more studies on new experimentals, and other benefits of the existing ones as I come across them. Feel free to share your own.

 

[Serotoninja]

Tadalafil (Cialis)
Surprised? Don't be. In addition to the awesome benefit of raging erections 24 hours a day at will, Tadalafil has shown to increase the T/E ratio, protect heart tissue, reduces fibroblast activity, improves BPH symptoms, improves LUT symptoms, improves hypertension, reverses cognitive dysfunction, improves penile ultrastructure and may increase penile volume, combats Ischemic Vascular Disease (IVD), improves endothelial function, reduces serum oxidative stress, improves spermatogenesis, and increases ejaculatory volume. Take 2.5-5mg/day, most studies used 5mg/day. I take 2.5mg/day personally, and they are almost as effective as 5mg/day in inhibiting PDE-5 (50-60% vs 80-90%), with slightly reduced adverse effects. Due to its long half-life of 17.5 hours, it reaches a SS concentration of 1.5x the dose after a week.

Most of the studies showing these benefits are very dubious though. Also aren't you afraid of NO effects? It's crazy expensive too lol

 

[RedStaR]

Most of the studies showing these benefits are very dubious though. Also aren't you afraid of NO effects? It's crazy expensive too lol

NO adverse effects are overblown, we also need to be specific on which type of NO mediated effects. It's not crazy expensive, buy it in bulk powder. Plus it goes generic very soon.

 

[TheDrumGuy]

Regarding exercise and thyroid function, do you have any studies on that? Most of the studies I've seen are very short term or show an adverse change in thyroid hormones. I'd like to do some exercise but pretty much anything I do that's more intense or prolonged than household chores feels like it has a thyroid suppressing effect on me.

Also on the subject of exercise, I think it's important to distinguish between aerobic and anaerobic exercise, and to point out that what most people think of as 'cardio' has a large anaerobic component. That's probably why stuff like running gets a bad rap, because most people (including a lot of well trained athletes) have poorly developed aerobic systems and literally cannot run without accumulating lactate. I think aerobic base building style training (a la Maffetone) might be consistent with Peat's view. Most people should probably just walk. Even Japanese marathon runners will base build by walking up to 200 miles per week. More intense exercise is probably beneficial also as long as you avoid generating too much lactate. So maybe 20-30 yard sprints, or weightlifting with low-medium reps and long rest periods. That said, these are things I plan to do when I have a healthier metabolism, they make me feel terrible right now.

 

[RedStaR]

Regarding exercise and thyroid function, do you have any studies on that? Most of the studies I've seen are very short term or show an adverse change in thyroid hormones. I'd like to do some exercise but pretty much anything I do that's more intense or prolonged than household chores feels like it has a thyroid suppressing effect on me.

Also on the subject of exercise, I think it's important to distinguish between aerobic and anaerobic exercise, and to point out that what most people think of as 'cardio' has a large anaerobic component. That's probably why stuff like running gets a bad rap, because most people (including a lot of well trained athletes) have poorly developed aerobic systems and literally cannot run without accumulating lactate. I think aerobic base building style training (a la Maffetone) might be consistent with Peat's view. Most people should probably just walk. Even Japanese marathon runners will base build by walking up to 200 miles per week. More intense exercise is probably beneficial also as long as you avoid generating too much lactate. So maybe 20-30 yard sprints, or weightlifting with low-medium reps and long rest periods. That said, these are things I plan to do when I have a healthier metabolism, they make me feel terrible right now.

There are many you can find online, this is the first result I found. T3 and free T3 hormones increased up to 70% maximum heart rate.

http://www.braj.com/fitness/Exercise intensity and its effects on thyroid hormones.pdf

 

[TheDrumGuy]

There are many you can find online, this is the first result I found. T3 and free T3 hormones increased up to 70% maximum heart rate.

http://www.braj.com/fitness/Exercise intensity and its effects on thyroid hormones.pdf

They looked at hormone levels immediately after training. For all we know T3 crashed later in the day.

 

[RedStaR]

They looked at hormone levels immediately after training. For all we know T3 crashed later in the day.

Exercise improves leptin and insulin resistance, that's an indirect effect on metabolism and core body temperature (for those with issues).

Long-term effects of exercise show increase in RMR through higher FFM primarily. Extreme interventions, however, may induce reductions in RMR, in spite of the increased lean tissue mass, similar to the changes observed in animals in response to flight or stress.

This paper also illustrates why some hormone levels may go down at rest in response to exercise.

Hormonal Changes Associated with Physical Activity and Exercise Training

 

[RedStaR]

Tadalafil Promotes the Recovery of Peripheral Neuropathy in Type II Diabetic Mice

We previously demonstrated that treatment of diabetic peripheral neuropathy with the short (4 hours) half-life phosphodiesterase 5 (PDE5) inhibitor, sildenafil, improved functional outcome in diabetic db/db mice. To further examine the effect of PDE5 inhibition on diabetic peripheral neuropathy, we investigated the effect of another potent PDE5 inhibitor, tadalafil, on diabetic peripheral neuropathy. Tadalafil is pharmacokinetically distinct from sildenafil and has a longer half-life (17+hours) than sildenafil. Diabetic mice (BKS.Cg-m+/+Leprdb/J, db/db) at age 20 weeks were treated with tadalafil every 48 hours for 8 consecutive weeks. Compared with diabetic mice treated with saline, tadalafil treatment significantly improved motor and sensory conduction velocities in the sciatic nerve and peripheral thermal sensitivity. Tadalafil treatment also markedly increased local blood flow and the density of FITC-dextran perfused vessels in the sciatic nerve concomitantly with increased intraepidermal nerve fiber density. Moreover, tadalafil reversed the diabetes-induced reductions of axon diameter and myelin thickness and reversed the diabetes-induced increased g-ratio in the sciatic nerve. Furthermore, tadalafil enhanced diabetes-reduced nerve growth factor (NGF) and platelet-derived growth factor-C (PDGF-C) protein levels in diabetic sciatic nerve tissue. The present study demonstrates that tadalafil increases regional blood flow in the sciatic nerve tissue, which may contribute to the improvement of peripheral nerve function and the amelioration of diabetic peripheral neuropathy.

 

[RedStaR]

Capsaicin suppresses pancreatic tumor growth by inhibiting tumor cell metabolism

Tumor cell metabolism is considered to be a hallmark of tumorigenic progression. Pancreatic cancer cells are shown to develop addiction towards the metabolic pathways like glycolysis and mitochondrial respiration to meet energy demands. Pancreatic tumor cells predominantly utilize cytosolic aerobic glycolysis for energy production. In our previous studies, we have reported that capsaicin treatment inhibits the survival of AsPC-1 and BxPC-3 pancreatic cancer cell lines. In this study, we evaluated the effect of capsaicin on glycolysis and mitochondrial respiration in pancreatic cancer cells. Our results showed that capsaicin treatment reduced the extra-cellular acidification rate (glycolysis) and oxygen consumption rate (mitochondrial respiration) in AsPC-1 and BxPC-3 cells in a concentration-dependent manner after 24h of treatment. Capsaicin treatment caused 86% and 55% down-regulation of glycolysis process in AsPC-1and BxPC-3 cells respectively. Our results also indicate the inhibition of glycolytic capacity and glycolytic reserve by capsaicin treatment indicating the potential of capsaicin to inhibit glycolysis. In addition, capsaicin treatment reduced 98% of basal oxygen consumption rate and ATP production in AsPC-1 cells. Furthermore, capsaicin treatment inhibited spare respiratory capacity & proton leak in a concentration dependent manner in AsPC-1 cells. Treatment of AsPC-1 and BxPC-3 with capsaicin for 48h also inhibited the expression of LDH-A and its upstream regulators such as HIF-1α, pSTAT3 (Y705) and EGFR as evaluated by Western blot. Our study thus indicate that capsaicin suppresses pancreatic tumor growth by down-regulating glycolysis and mitochondrial respiration. Further mechanistic studies are in progress.

 

[RedStaR]

Capsaicin suppresses the metastasis of human NSCLC in vivo

Non-small cell lung cancer (NSCLC) is characterized by aggressive clinical course, rapid doubling time and a propensity for extrapulmonary metastasis. A substantial proportion of NSCLC presents with metastatic disease at the time of their diagnosis. Metastasis is a complex multistep process. One of the earliest events of the metastatic process is the invasion of malignant cells through the surrounding stroma into the blood and lymph. The long-term goal of our laboratory is to identify nutritional compounds (as single agents or in combination with standard chemotherapy), which will suppress metastasis of NSCLCs. Capsaicin is the pungent ingredient of chili peppers. Several convergent studies have shown that capsaicin inhibits the invasion and metastasis of several types of human cancers including melanoma, prostate cancer, and cholangiosarcoma. The present study examines the anti-invasive properties of capsaicin and two capsaicin-like compounds, capsiate and capsiconiate, found in a select variety of chili peppers on NSCLC. We measured the anti-invasive activity of these compounds by the Boyden chamber assay and spherical invasion assays. We found that capsaicin and capsiate displayed equivalent anti-invasive activity in NSCLC cells. In contrast, capsiconiate did not suppress the invasion of NSCLC cells. Furthermore, we tested the anti-metastatic activity of capsaicin in a syngenic mouse model of metastasis. We observed that the dietary administration of capsaicin potently decreased the area of lung metastatic foci relative to control untreated mice. Our data may form the basis of novel nutrition-based therapeutic regimens in NSCLC metastasis.

 

[RedStaR]

Chronic treatment with the phosphodiesterase type 5 inhibitors sildenafil and tadalafil display anxiolytic effects in Flinders Sensitive Line rats

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolyticlike behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood–brain barrier to elicit central effects.

In fact, Tadalafil was more effective than Prozac® in modulating anxiety, showing better results than BOTH controls and positive controls. That's insane.

Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice

Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement.

 

[Texon]

Chronic treatment with the phosphodiesterase type 5 inhibitors sildenafil and tadalafil display anxiolytic effects in Flinders Sensitive Line rats

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolyticlike behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood–brain barrier to elicit central effects.

In fact, Tadalafil was more effective than Prozac® in modulating anxiety, showing better results than BOTH controls and positive controls. That's insane.

Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice

Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement.

Interesting about cayenne especially regarding anti inflammatory effects. Unfortunately I just get severe irritation from it. Can't take ppi's h2 blockers etc. Herbs are inconsistent at best. VWish I could find the perfect GI anti inflammatory. Anyway what do you think the perfect protocol might be for someone already taking T cypionate injectable at 50 mgs e3d? Not looking for diagnosis just ideas. I am 65 yo and in great shape overall.

 

[Texon]

Chronic treatment with the phosphodiesterase type 5 inhibitors sildenafil and tadalafil display anxiolytic effects in Flinders Sensitive Line rats

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolyticlike behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood–brain barrier to elicit central effects.

In fact, Tadalafil was more effective than Prozac® in modulating anxiety, showing better results than BOTH controls and positive controls. That's insane.

Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice

Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement.

Very interesting thread BTW.

 

[Texon]

Chronic treatment with the phosphodiesterase type 5 inhibitors sildenafil and tadalafil display anxiolytic effects in Flinders Sensitive Line rats

There are conflicting results from behavioural studies regarding whether the activation or inhibition of the cGMP-nitric oxide (NO) pathway induces anxiolyticlike behaviour. Sildenafil, an inhibitor of cGMP-selective phosphodiesterase-5, increases anxiety acutely, but previous evidence suggests that its chronic administration may be anxiolytic, and could involve a cholinergic interaction. We used the Flinders Sensitive Line (FSL) rat, a genetic model of depression that presents with increased anxiety- and depression-like behaviour, to investigate the action of chronic treatment with the PDE5 inhibitors sildenafil or tadalafil, with/without atropine on social interaction behaviour, a correlate for anxiety. Fluoxetine was used as positive control, with validation performed using Flinders Resistant Line (FRL) rats. In order to relate behavioural changes to brain penetration, we determined the concentration of sildenafil in cortex and hippocampus of rats following the schedule above using LC-MS/MS. FSL rats displayed significantly reduced social interactive behaviour than FRL rats, while sildenafil, tadalafil, and fluoxetine significantly reversed these deficits. Atropine did not exert effects on social interactive behaviour, nor did it modulate the effects of sildenafil or tadalafil. Sildenafil was present in cortex and hippocampus regions in lower nanomolar concentrations after chronic treatment, in agreement with the binding to PDE5 required for pharmacological effects. This study emphasizes the complicated regulation of anxiety by the cGMP-NO system, and provides supporting evidence for an anxiolytic action after the chronic activation of this pathway. As far as we know this is also the first report to formally demonstrate that sildenafil effectively crosses the blood–brain barrier to elicit central effects.

In fact, Tadalafil was more effective than Prozac® in modulating anxiety, showing better results than BOTH controls and positive controls. That's insane.

Tadalafil enhances working memory, and reduces hippocampal oxidative stress in both young and aged mice

Tadalafil, a type-5 phosphodiesterase enzyme inhibitor with long half-life used to treat erectile dysfunction. Recently it has been reported that tadalafil improves cognitive function. Here, we aimed to investigate the age dependent effects of tadalafil on memory, locomotor, behavior, and oxidative stress in the hippocampus. Tadalafil was orally administered everyday (5 mg/kg) to young (2 months) and old (16 months) healthy mice for 4 weeks. Control mice from each group received equal volume of 0.9% normal saline for the same duration. Memory and locomotor activity were tested using radial arm maze and open field test respectively. The level of malondialdehyde (MDA), nitric oxide (NO), and advanced protein oxidation product (APOP) was analyzed and catalase activity was determined from the isolated hippocampus. Treatment with tadalafil in aged mice improves working memory than the corresponding tadalafil treated young mice in radial arm maze test. Tadalafil treated mice traveled less distance in the center and the mean speed of tadalafil treated aged mice was significantly lower than the tadalafil treated young mice in open field test. Tadalafil treatment elicited a decrease of MDA level in the hippocampus of aged mice than that of young mice. APOP level was decreased only in aged mice treated with tadalafil. Treatment with tadalafil decreased NO and increased catalase activity in both young and aged mice. On the basis of previous and our findings, we conclude that tadalafil treatment reduces oxidative stress while increased cGMP level in the hippocampus might be responsible for memory enhancement.

The catalase is very interesting for sure.