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Tickle Your Damn Amygdala's You Neurotic Fools!

amygdala visualization frontal lobes brain exercise

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#331 Mr Serendipity

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Posted 03 April 2022 - 08:15 PM

Great paper below.

https://www.ncbi.nlm...les/PMC6007750/

 

Mitochondrial Agents for Bipolar Disorder

 

N-Acetyl Cysteine

N-acetyl cysteine (NAC) is increasingly being used as an adjunctive therapy in psychiatry (Berk et al., 2013). Its use across psychiatric disorders is due to the number of mechanisms of action relevant to mental illness. In addition to providing rate-limiting cysteine for glutathione production, NAC has also been shown to be an antiinflammatory, enhance neurogenesis, decrease apoptosis, modulate glutamate pathways, and, importantly, alter mitochondrial activity (Samuni et al., 2013). In both mouse (R6/1) and rat (3-nitropropionic acid) models of Huntington’s Disease, NAC has been shown to restore mitochondrial respiration (Wright et al., 2015) and complex activity (Sandhir et al., 2012). Restoration of mitochondrial respiration has also been shown in rat models of traumatic brain injury as well as improvements in mitochondrial complex activity and mitochondrial glutathione (Patel et al., 2014).

There is promising clinical evidence in support of adjunctive NAC in diverse psychiatric disorders (Deepmala et al., 2015). A systematic review and meta-analysis has shown that overall, adjunctive NAC treatment seems beneficial for both unipolar and bipolar depression (Fernandes et al., 2016).

To date, there have been 2 multi-site trials of NAC specifically exploring its use as an adjunctive treatment for BD. Several substudies have also been reported from these data. The initial study was conducted in participants with BD (n=75) that were experiencing any symptoms (or euthymic). At 6 months post-baseline, participants that received 2000 mg/d NAC (in addition to standard treatment) reported improved measures of BD symptoms, functioning, and quality of life. This improvement persisted up to 4 weeks following NAC treatment cessation. Adverse effects did not significantly differ between the NAC and placebo groups (Berk et al., 2008).

Posthoc exploratory analyses were performed on a variety of data from this trial to assist in identifying who might benefit most from adjunctive NAC treatment in BD. This series of studies included the investigation of mania (or hypomania), bipolar II, major depressive episodes, cognition and comorbid systemic illness (Magalhães et al. 2011a2011b2013Dean et al., 2012). When exploring major depressive episodes within the context of a BD sample, there were improvements following adjunctive NAC compared with placebo (Magalhães et al., 2011b). The investigation of those experiencing mania indicated within-group improvements in the NAC group (Magalhães et al., 2013). Similarly, when exploring a subgroup of participants (n=14) with bipolar II (divided in 2 groups of 7 patients each randomized to placebo or NAC), NAC was found to improve symptoms in 6/7 participants, compared with 2/7 in the placebo group (Magalhães et al., 2011a). NAC was also shown to improve functional outcomes for people experiencing cardiovascular or endocrine comorbidities when compared to those who did not (Magalhães et al., 2012). Finally, a paper on posthoc analyses has reported no change in cognition in a small subset of participants following NAC (Dean et al., 2012).

The next study included a maintenance design with an initial open-label phase. Participants were given 2000 mg/d of NAC (n=149) for a total of 8 weeks and were then randomized to continuation of adjunctive NAC treatment or a placebo. The open-label phase showed significant improvements in participants experiencing bipolar depression (Berk et al., 2011). However, in the maintenance (randomized) phase, participants in both arms generally stayed well, which resulted in no significant treatment effects (Berk et al., 2012).

We further searched ANZCTR and Clinicaltrials.gov to ascertain if there are upcoming studies in this area. A protocol has been published describing a study of NAC and a combination of other agents that enhance mitochondrial function, compared with placebo, over 16 weeks of treatment (Dean et al., 2015).

Overall, NAC is a potentially useful adjunctive therapy for BD and, in particular, bipolar depression during the acute phase. NAC has been shown to enhance mitochondrial function in preclinical models. However, no clinical studies that have investigated NAC for BD have evaluated outcomes related to mitochondrial function. Further research is required to explore the interactions of NAC clinical efficacy and changes in relevant pathways, including pathways relevant to mitochondrial function.

Coenzyme Q10

Coenzyme Q10 (CoQ10), also known as ubiquinone, is a powerful lipid-soluble antioxidant that reduces the flow of electrons on the ROS-producing regions of Complex I, II, and III of the mitochondria (Lenaz et al., 2002Nierenberg et al., 2013). CoQ10 reduces ROS by neutralizing the free radical alpha-tocopheroxyl to alpha-tocopherol (vitamin E) and plays a role in the biosynthesis of adenosine triphosphate (ATP) (Morris et al., 2013Nierenberg et al., 2013). The genes associated with these complexes and the transportation of electrons across them are expressed differently in BD compared with healthy controls (Sun et al., 2006b). Supplementary CoQ10 has poor oral bioavailability; however, it does cross the blood-brain barrier (Matthews et al., 1998).

Morris et al. (2013) discussed the reduction in CoQ10 levels in psychiatric and mitochondrial disorders such as depression, chronic fatigue syndrome, fibromyalgia, and Parkinson’s disease and postulated that CoQ10 supplementation could be a treatment for these disorders. However, a meta-analysis of CoQ10 supplementation compared with placebo showed no significant benefits for participants with Parkinson’s disease (Negida et al., 2016).

There have been several studies proposing the use of CoQ10 supplementation as a mitochondrial enhancing agent in general and for BD in particular (Morris et al., 2013Nierenberg et al., 2013). Despite this, there have been only 2 studies directly looking at CoQ10 supplementation and BD. One study explored CoQ10 in combination with other mitochondrial agents (such as NAC and b-group vitamins) as an adjunctive treatment for bipolar depression (Dean et al., 2015). This study has been completed but results are still pending.

Forester et al. (2012) investigated an 8-week intervention of CoQ10 in a sample of 10 outpatients aged 55 years and older with a DSM-IV diagnosis of bipolar depression in an 8-week study. Participants were administered CoQ10 and compared with 8 healthy controls who did not receive CoQ10 supplementation. The maximum dose of CoQ10 was 1200 mg/d, starting at 400 mg/d and titrated up by 400 mg/d every 2 weeks. Participants on CoQ10 showed modest but significant improvements in their depression symptoms (measured on the Montgomery–Åsberg Depression Rating Scale MADRS) over the 8-week study. Furthermore, this study also investigated mitochondrial function via phosphorus magnetic resonance spectroscopy and reported no significant differences between groups for creatine kinase (a mitochondrial protein). This small study is limited by the sample size and lack of placebo control but highlights the potential of CoQ10 as an antidepressant and treatment for BD.

Alpha-Lipoic Acid

Alpha-lipoic acid (ALA), also known as thioctic acid, is a pleiotropic substance (Gomes and Negrato, 2014). ALA is a strong antioxidant (Suzuki et al., 1991Moini et al., 2002). It increases levels of glutathione (Han et al., 1997Yamada et al., 2011Kleinkauf-Rocha et al., 2013), raises hepatocyte ascorbate levels (Lykkesfeldt et al., 1998Michels et al., 2003), downregulates nuclear factor kappa-light-chain-enhancer of activated B cells (DeMarco et al., 2004), and is a metal chelator (Ou et al., 1995Suh et al., 2005), an antiviral in glial cells (Scumpia et al., 2014), and a glucose uptake promoter (Estrada et al., 1996Henriksen et al., 1997Saengsirisuwan et al., 2004), increasing GLUT4 levels and insulin action (Hughes et al., 1993). Relevant to the current review, ALA also has a role as a mitochondrial agent. It can be endogenously synthesized in the mitochondria where it acts as a coenzyme for the formation of pyruvate dehydrogenase and α-ketoglutarate—both essential components of the Krebs cycle. Because pyruvate dehydrogenase converts pyruvate to acetyl CoA, ALA decreases lactate levels, thus inhibiting glycolysis (Gomes and Negrato, 2014). It also modulates the key regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PPAR-GC-1α) (Liu, 2008). PPAR-GC-1α stimulation has been linked to neuroprotection and its suppression to mitochondrial dysfunction and neurodegeneration (Cui et al., 2006St-Pierre et al., 2006). ALA also affects the mitochondrial pathway of apoptosis, prompting research in oncology as an agent with antimetastatic potential (Dörsam and Fahrer, 2016). This provides a rationale for its action in mood and cognitive disorders.

In a corticosterone-induced model of depression in mice, ALA showed antidepressant properties and reversed brain-derived neurotrophic factor reduction in the hippocampus and striatum (de Sousa et al., 2015). In a d-amphetamine-induced model of mania, ALA was able to both prevent and reverse symptoms with comparable efficiency to lithium (Macêdo et al., 2012).

Only one clinical trial has explored ALA as an adjunctive treatment for bipolar depression. The trial tested a combination of ALA (600–1800 mg/d) and acetyl-L-carnitine (ALC) (1000–3000 mg/d) or placebo for 12 weeks in 40 participants with bipolar depression. Previous treatment (stable for at least 4 weeks) was continued. The primary outcome was depression, measured on the MADRS. No significant changes were found between groups (Brennan et al., 2013). As the authors note, the shorter duration of the study (12 weeks) compared with a positive RCT of a mitochondrial agent (NAC) in BD (24 weeks) (Berk et al., 2008), the inclusion of bipolar I and II types, concomitant medication use, and possible low oral bioavailability of the agents are all potential confounders that should be addressed.

More research is required to determine the efficacy of ALA in BD. Moreover, there is one study (described earlier) in bipolar depression that is currently being completed that includes a combination of agents including ALA, ALC, and NAC (ACTRN12612000830897).

ALC

In addition to the role of ALC in mitochondrial β-oxidation and energy production (Hoppel, 2003), ALC has antioxidant properties (Gülçin, 2006Mescka et al., 2011). Additionally, ALC has been proposed to mediate the transfer of acetyl groups for acetylcholine synthesis, modulate nerve growth factors and gene expression (Nałecz and Nałecz, 1996Binienda, 2003Nacz et al., 2004), and counter glutamate-induced excitotoxicity (Zanelli et al., 2005).

Data from animal models provide further evidence for ALC’s therapeutic potential due to its role as an antioxidant and in improving mitochondrial energy production (Rao et al., 1997Aureli et al., 1998Hagen et al., 2002bAl-Majed et al., 2006), its neuroprotective action in trauma (Karalija et al., 2014) and ischemia (Rosenthal et al., 1992Barhwal et al., 2007), its antidepressant effect in the forced swim test (FST) (Wang et al., 2015), and its ability to reverse memory loss in older rats (Liu et al., 2002).

Two patients with geriatric depression treated with ALC showed increases in PCr and β-nucleoside triphosphate (β-NTP) levels (Pettegrew et al., 2002). PCr serves as a reservoir for high-energy phosphates, and β-NTP is acknowledged as an index of brain levels of ATP. Thus, these results provide support for a link between the antidepressant action of ALC and improved energy production within the brain.

However, the only RCT in BD reported no effect when administered in combination with ALA (Brennan et al., 2013) (see above). Furthermore, the change in PCr and β-NTP, previously found in geriatric depression patients (Pettegrew et al., 2002), was not observed (Brennan et al., 2013). Two case reports of ALC-associated relapse in BD also suggest some caution with clinical use. The first case-reports detail a psychotic episode in a known BD type I patient, 5 days after starting treatment with nutritional supplements including vitamin C, vitamin E, and ALC (500 mg/d) (Evcimen et al., 2007). Manic symptoms associated with self-prescribed ALC treatment (2000 mg/d) in a man with BD type I resolved 3 days after cessation of ALC (Goodison et al., 2016).

S-Adenosylmethionine

S-Adenosylmethionine (SAMe) results from the combination of ATP and methionine and plays a crucial role as a methyl donor in reactions involving methyltrasnferases (Bottiglieri, 2002). SAMe is also a precursor molecule for glutathione production, which plays an essential role in reducing oxidative stress. In the brain, SAMe repairs and degrades proteins and activates thyroxine hydroxylase through methylation, which is critical in the synthesis and regulation of monoamines (i.e., dopamine, serotonin), which are known to be dysregulated in BD (Bottiglieri et al., 20002002). Recently, an RCT of SAMe as an add-on to an approved mood stabilizer in 20 participants with BD (type I and II) was conducted. To enroll, subjects were required to have not responded previously to either 2 antidepressants (of different classes) or to 2 different mood stabilizers. No significant differences were observed in MADRS, Hamilton Rating Scale for Depression (HAM-D), or Young Mania Rating Scale (YMRS) between the SAMe and placebo groups. No switches to mania were reported (Murphy et al., 2014). Carney et al. (1989) reported 3 open label trials and 1 placebo-controlled trial after a drug-free period of at least 7 days. There were 14 unipolar depression and 11 BD participants. Nine of the 11 BD participants switched to hypomania, mania, or “elevated mood.” The other 2 participants did not respond to treatment (Carney et al., 1989). In an open-label trial of i.v. SAMe monotherapy for depression, 7 of 9 patients improved or had depression remission. There were 2 case reports of mood switch in BD patients, 1 of mania, and 1 of hypomania (Lipinski et al., 1984). Due to the potential for manic switching, SAMe for BD should be investigated with caution. In unipolar depression, a meta-analysis in 2002 showed that SAMe is superior to placebo improving HAM-D scores (Hardy et al., 2003). A recent systematic review collected clinical information from 115 clinical trials and 17 preclinical studies on the effect of SAMe on several neuropsychiatric conditions. Positive but limited evidence was found for the use of SAMe in major depressive disorder (MDD) as both a monotherapy and adjunctive therapy (Sharma et al., 2017). Recently, 2 studies have demonstrated benefits of SAMe as an augmentation antidepressant therapy. In a 6-week, double blind, placebo RCT with serotonin reuptake inhibitors or serotonin norepinephrine reuptake inhibitors nonresponders, participants undergoing SAMe augmentation had lower HAM-D score and higher remission rates (final HAM-D score <8) than placebo (Papakostas et al., 2010).

Creatine Monohydrate

Creatine is the precursor of PCr. Long-term decrease of PCr decreases ATP production, attributable to mitochondrial dysfunction (Erecińska and Silver, 1989). Oral supplementation of creatine monohydrate increases creatine and brain concentrations of PCr (Dechent et al., 1999Lyoo et al., 2003a). In BD, decreased PCr concentrations have been reported (Stork and Renshaw, 2005). Furthermore, creatine has been shown to have antioxidant properties in animal models of oxidative stress (Sullivan et al., 2000Tarnopolsky and Beal, 2001Lawler et al., 2002)

A 4-week open-label trial with 10 participants experiencing treatment-resistant depression (8 unipolar and 2 bipolar) showed improved depression scores with 3 to 5 g/d creatine monohydrate augmentation, provoking switch to elevated mood in both BD patients (Roitman et al., 2007). Two trials focusing on a combination of cytidine and creatine in bipolar depression are currently being conducted (NCT01543139NCT02625779). A 6-week, double blind, placebo RCT to evaluate the efficacy of creatine monohydrate as an adjunctive therapy for BD type I depression (NCT01655030) is also currently recruiting.

Melatonin

Melatonin regulates several homeostatic processes such as circadian rhythm maintenance, growth hormone stimulation, and insulin secretion (Paredes et al., 2014Simões et al., 2016Zhang et al., 2016). Relevant to mitochondrial physiology, melatonin improves oxidative phosphorylation, increasing the activity of the I and IV dose-dependent complexes and membrane fluidity and closes the mitochondrial permeability transition pore (a protein complex spanning the inner and outer mitochondrial membranes), preventing ATP depletion and necrotic cell death (Acuña-Castroviejo et al., 20012007Martín et al., 2002Leon et al., 2005). Moreover, melatonin and some of its metabolites play an important antiinflammatory and antioxidant role through scavenging oxygen and nitrogen-based ROS (López-Burillo et al., 2003Korkmaz et al., 2009). Melatonin directly boosts mRNA expression of genes implicated in the production of glutathione peroxidase and superoxide dismutase, 2 antioxidant enzymes (Rodriguez et al., 2004Acuña-Castroviejo et al., 2007Anderson and Maes, 2014). Furthermore, peripheral melatonin, produced outside the brain, is decreased in BD compared with healthy controls, suggesting supplemental melatonin may be a relevant intervention in this population (Anderson and Maes, 2014).

In an 8-week, double blind, placebo control trial, 44 participants (24 participants with SZ and 20 with BD) treated with second-generation antipsychotics received low dosages of melatonin (5 mg/d) and placebo. The melatonin group showed lower diastolic blood pressure and less weight gain, these results being greater in the BD group (Romo-Nava et al., 2014). In an open-label trial, melatonin improved mania scale scores and sleeping patterns (Bersani and Garavini, 2000) but had no significant effects on mood or sleep in a double-blind, placebo-controlled trial using the same dose with 5 rapid-cycling DSM-III-R BD patients (Leibenluft et al., 1997).

McElroy et al. (2011) tested ramelteon (a highly selective melatonin MT1/MT2 receptor agonist) as an adjunctive treatment in 21 outpatients with bipolar I disorder with mild-to-moderate manic symptoms and sleep disturbance in an 8-week, double-blind, fixed-dose (8 mg/d) study. A global improvement in a global rating of depressive symptoms was reported; however, no significant differences in ratings of insomnia, mania, and global severity of illness were observed. Norris et al. (2013) conducted a double-blind, randomized, placebo-controlled trial of adjunctive ramelteon in euthymic bipolar patients with sleep disturbances and reported that participants receiving ramelteon were significantly less likely to relapse compared with placebo. Recently, a RCT comparing placebo with sublingual ramelteon in different dosages (0.1 mg, 0.4 mg, 0.8 mg, once daily) as adjunctive maintenance therapy in stable BD patients did not show significant differences between any dose of ramelteon and placebo (Mahableshwarkar et al., 2017). The study was terminated before the expected sample size due to meeting the futility criteria. All studies showed ramelteon was well tolerated and associated with no serious adverse events.

Agomelatine (an agonist of melatonin 1 and 2 receptors and antagonist of serotonin 2C receptors drug) has also been investigated as an adjunctive treatment for bipolar depression. In an open-label trial with 21 type I BD patients in a severe depressive episode (14 treated with lithium and 7 with valpromide), agomelatine was added at 25 mg/d for at least 6 weeks and, if participants opted-in, up to 1 year. At week 6, 81% of patients improved >50% in HAM-D score from baseline and almost 50% in the first study week. Three patients switched to mania or hypomania from the sixth week until the complete year follow-up (Calabrese et al., 2007). In a similar study, 28 type II BD patients in a severe depressive episode (11 treated with lithium and 17 with valproate) were treated with agomelatine at fixed dosages of 25 mg/d from at least 6 weeks to a possible 30-week extension. At 6 weeks, 64% of patients improved >50% in HAM-D score from baseline and 86% responded at 36 weeks. There were 4 drop-outs in total due to polarity change (1 manic and 3 hypomanic episodes) (Fornaro et al., 2013). Recently, 344 type I BD patients undergoing a current major depressive episode that were treated with lithium or valproic acid for at least 6 weeks were randomized to treatment with agomelatine or placebo (n=172 each group) in a double-blind study (Yatham et al., 2016). No significant differences between both groups in MADRS total score or response or remission rates from baseline to endpoint were found. The number of manic or hypomanic symptoms was comparable between both groups at each assessment time. As a number of sites had placebo response rates of 100%, when these were excluded in a posthoc analysis, a signal favoring agomelatine over placebo emerged. While the meta-analyses in unipolar depression confirm the antidepressant effects of agomelatine (Singh et al., 2012Taylor et al., 2014), melatonin supplementation did not significantly improve treatment or prophylaxis of unipolar depression (Hansen et al., 2014).

Pyrimidines

The pyrimidine nucleosides such as uridine, triacetyluridine, and cytidine have effects on mitochondrial function, glutamatergic transmission, catecholamine synthesis, and cerebral phospholipid metabolism, which has been linked to the pathophysiology of BD (Yoon et al., 2009Kondo et al., 2011). Uridine (1000 mg/d) was studied in a 6 weeks open-label trial of 7 teenagers with bipolar depression. Children’s Depression Rating Scale-Revised and the Clinical Global Impressions scale were used to measure the treatment results. Uridine was well tolerated and depressive symptoms decreased (Kondo et al., 2011).

In another 6-week study (n=20), 18 g/d day of triacetyluridine (TAU), a uridine prodrug, or placebo was given to patients with bipolar depression. BD patients who had a reduction in MADRS scores ≥50% showed a greater difference in pH changes (assessed by phosphorus magnetic resonance spectroscopic imaging (PMRSI)) compared with TAU nonresponders, suggesting that TAU treatment can have benefits in depressive symptoms and in mitochondrial function (Jensen et al., 2008). Cytidine, available from dietary sources and converted in uridine in the human body, was investigated in a 12-week, randomized, placebo trial with 35 patients with bipolar depression. Participants were randomly given valproate plus placebo or valproate plus cytidine. At 2, 4, and 12 weeks, the cerebral levels of glutamate/glutamine were measured using PMRSI. The results showed that cytidine supplementation resulted in earlier improvement in symptoms of depression and greater reduction in glutamate/glutamine levels. These data suggest that the observed therapeutic effect of cytidine may be mediated via a decrease in cerebral glutamate/glutamine levels (Yoon et al., 2009).

Choline

Choline is a constituent of the neurotransmitter acetylcholine, a major methyl-donor, and needed for structural integrity and intracellular signaling within cell membranes. In an open-label trial, Stoll et al. (1996) studied the effects of lithium augmentation with choline in 6 rapid-cycling BD outpatients. Five participants experienced a reduction in manic symptoms and 4 had a reduction in all mood symptoms during choline therapy. The impact on depression was variable. Lyoo et al. (2003b) studied 8 lithium-treated, rapid-cycling BD I and II patients randomized to receive either choline or placebo, and reported significantly decreased brain purine levels, a marker of energy metabolism.

Vitamin A

Both deficient and excessive levels of vitamin A disrupt many human systems, including the central nervous system (CNS) (Chapman, 2012). Vitamin A is required for vision, gene transcription, immune system, and skin cell differentiation (Haybaeck et al., 2015). The role of vitamin A in gene expression and its role in redox activation suggest a possible role as a mitochondrial agent in the treatment of BD. Vitamin A also plays a very important role as a co-factor in redox activation, binding to protein kinase C (Hoyos et al., 2012Hammerling, 2016). Retinoid receptors are concentrated in the striatum, hippocampus, frontal cortex, and hypothalamus, all key brain areas involved in depression (Bremner et al., 2012). Being involved in neuroplasticity in the hippocampus, vitamin A deficiency can also affect memory, appetite, and growth (Haybaeck et al., 2015Stoney and McCaffery, 2016). Haybaeck et al. (2015) found the brains of patients with SZ, BD, or MDD to have significantly increased expression of vitamin A-inducible or induced gene 1, pointing to altered signaling pathways. Another study found mRNA levels of key elements of vitamin A signaling were significantly reduced in the postmortem dorsolateral prefrontal cortex/anterior cingulate cortex from elderly depressed patients (Qi et al., 2015). A similar signal was detected in a chronic unpredictable mild stress model in rats (Qi et al., 2015). There is evidence of a link between isotretinoin use and depression and suicide (Bremner et al., 2012Hu et al., 2016), clinical exacerbation of BD, and possibly to psychosis (Ludot et al., 2015). Vitamin A therapy at high doses is also associated with cognitive decline (de Oliveira et al., 20092015) and increased levels of oxidative stress markers in both human and animals (de Oliveira et al., 2009).

Vitamin C

Vitamin C is an antioxidant capable of scavenging free radicals and other ROS formed in cell metabolism. In addition to its role as an antioxidant, vitamin C is a co-substrate of many important oxidoreductases and may regulate gene transcription (Arrigoni and de Tullio, 2002). Because of these characteristics, vitamin C has been tested as a possible adjunctive therapy in psychiatric disorders. A double-blind, placebo RCT in high school students showed lower levels of anxiety after 14 days of vitamin C supplementation compared with placebo (de Oliveira et al., 2015). Positive results were also reported in a 6-month, double-blind, randomized control pilot trial with 1000 mg/d vitamin C as an adjunct to 10 to20 mg/d fluoxetine in children (n=24) diagnosed with MDD (Amr et al., 2013). However, the only RCT testing vitamin C as an adjuvant (1000 mg/d) in the treatment of adults (n=43) with MDD (added to 60 mg/d citalopram) showed no statistically significant results (Sahraian et al., 2015).

In BD, vitamin C was proposed as a treatment in a double-blind, placebo control cross-over trial, where 23 BD participants receiving 3 g/d of vitamin C reported improvement in depressive symptoms (Naylor and Smith, 1981). Kay et al. (1984) conducted a 28-day, double-blind, randomized active-control study with 61 BD inpatients (29 with manic symptoms and 32 with depressive symptoms). The depressed participants received either 150 mg/d amitriptyline (n=14) or 4 g/d vitamin C plus 4 g/d ethylene diamine tetra acetic acid (EDTA) (n=18). The manic participants were also divided into 2 groups—13 were medicated with 800 g/d lithium and 16 received only vitamin C plus EDTA. Manic participants responded better to lithium than to vitamin C. There was no significant difference in depression symptoms between amitriptyline or vitamin C in the depressed group on HAM-D and Beck Depression Inventory (BDI) ratings.

Vitamin D

Vitamin D is a fat-soluble antioxidant involved in the regulation of calcium and phosphate metabolism. Moreover, vitamin D is implicated in the production of melatonin and in seasonal affective disorder (Gloth et al., 1999). The association between low levels of vitamin D and mood disorders (MDD, BD, and dysthymia) has been established (Anglin et al., 2013Belzeaux et al., 2015), and it was also identified as a risk factor for development of postpartum depression in pregnant women (Robinson et al., 2014). Furthermore, vitamin D influences monoamine metabolism by modulating the hypothalamic-pituitary-adrenal axis through vitamin D receptors (VDRs) (Puchacz et al., 1996Prüfer et al., 1999Eyles et al., 2005). VDRs also affect nuclear transcription, regulate the expression of the dopamine receptor gene (Trinko et al., 2016), and may also be involved in the regulation of mitochondrial function and lipid metabolism (Silvagno and Pescarmona, 2017). VDR is now known to translocate into mitochondria, which raises the possibility of vitamin D having a direct impact on cellular bioenergetics by altering mitochondrial function and VDR to work as a modulator of energy balance in humans (Silvagno and Pescarmona, 2017). Studies on cancer cells (Consiglio et al., 2014), keratinocytes (Consiglio et al., 2015), adipocytes (Ricciardi et al., 2015), and VDR-null mutant mice (Wong et al., 2011) found that VDR can influence the transcription of proteins of the mitochondria respiratory chain, inhibiting it and redirecting Krebs cycle intermediates toward biosynthesis (Consiglio et al., 2014). However, establishing the treatment effect of vitamin D supplementation has been somewhat problematic as studies are likely too heterogeneous (including depression, seasonal affective disorder, obesity, postmenstrual tension, and hospitalized patients). Therefore, varying the selection criteria wields both positive and negative meta-analysis results: A meta-analysis of 15 RCTs (with samples between 15 and 2117) was favorable for vitamin D supplementation (≥800 I.U. daily) (Spedding, 2014), while another meta-analysis using 6 RCTs (n=1203, 71 depressed) showed no significant effect of vitamin D supplementation on postintervention depression scores (Li et al., 2014). A more recent double-blind RCT of 40 MDD patients on vitamin D monotherapy (50 kIU/d for 8 weeks) showed beneficial effects on the depressive symptoms measured by the BDI on indicators of glucose homeostasis and on oxidative stress levels (Sepehrmanesh et al., 2016). Regarding BD, an 8-week open-label trial tested the effect of adjunctive vitamin D supplementation in mania in young bipolar spectrum disorder patients (aged 6–17 years old). There was a significant decrease in YMRS scores and improvement in levels of glutamate and γ-aminobutyric acid (GABA) measured in the anterior cingulate cortex (Sikoglu et al., 2015).

Vitamin E

Vitamin E or tocopherol is a fat-soluble antioxidant, which has a stabilizing function in the mitochondrial membrane attributed to radical scavenging and lipid peroxidation reduction (Kagan et al., 1990Pham-Huy et al., 2008). Studies have suggested that vitamin E may be more effective when combined with CoQ10 or vitamin C (Kontush and Schrkatolina, 2004Dhitavat et al., 2005). To our knowledge, the efficacy of vitamin E in BD or MDD has not been examined. Some animal studies found positive results—chronic administration of high doses of vitamin E improved lifespan, neurological performance, and brain mitochondrial function in aging mice (Navarro et al., 2005). Likewise, studies in Alzheimer’s disease are also promising. A multi-center RCT studied the effect of vitamin E supplementation in 613 participants with mild-to-moderate Alzheimer’s disease, medicated with memantine, and reported slower functional decline and decreased caregiver burden (Dysken et al., 2014). A cross-sectional and prospective study of 104 patients with Alzheimer’s disease showed reduced prevalence and incidence of Alzheimer’s on those consuming vitamin E plus C supplementation (Zandi et al., 2004). A clinical trial with combined therapy with vitamin C for MDD in elderly patients is now in the recruiting phase (NCT02793648).

Vitamin B Complex

The vitamin B complex contains water-soluble vitamins B1, B2, B3, B5, B6, B7, B9, and B12. They play an important role in a variety of critical brain pathways and participate in mitochondrial energy production and cellular function (Dean et al., 2012). Vitamin B complex is known to influence cognitive performance and mood. Its influence in CNS function has been suggested to occur in 2 interrelated ways: direct via of hypomethylation and indirectly by homocysteine levels resulting in structural changes in the brain (Calvaresi and Bryan, 2001). They often work in synergy and thereby are best administered as a complex (Dean et al., 2012).

 

Vitamin B9 

Vitamin B9, or folate, is involved in the synthesis, repair, and methylation of DNA and in the formation of monoamine neurotransmitters, thus being important in the pathogenesis of affective disorders (Mattson and Shea, 2003Folstein et al., 2007Miller, 2008Sharpley et al., 2014). Together with vitamin B12, vitamin B9 plays an essential role in mitochondrial energy production through 1-carbon transfer pathways (Dean et al., 2015). Folate deficiency has been associated with several neuropsychiatric disorders, especially in inpatients (Hall et al., 1997Dean et al., 2015) such as depression, BD, and cognitive dysfunction (Bell et al., 1990Godfrey et al., 1990Hasanah et al., 1997Selhub et al., 2000Bryan et al., 2002Reynolds, 2002Gilbody et al., 2007). Furthermore, in long-term lithium-treated patients, low serum folate levels were associated with higher affective morbidity (Coppen and Abou-Saleh, 1982). Schou et al. (1986) also found low levels of folate in untreated BD patients (25% lower than controls) and their normalization after 6 months of lithium. Behzadi et al. (2009) conducted a preliminary RCT with 88 BD type I manic patients treated with sodium valproate and adjuvant folic acid (synthetic form of folate). After 3 weeks, a statistically significant difference in the YMRS was found. Another double-blind RCT of 75 lithium-treated BD patients on a daily supplementation of 200 μg folic acid for 52 weeks showed a significant reduction in affective morbidity (Coppen et al., 1986). L-methylfolate was also recently studied in the first open-label trial for bipolar depression. Ten patients with BD type I on standard treatment for bipolar depression (but with no antidepressant) received 15 mg of folate daily for 6 weeks. A 55% improvement in depression symptom ratings (MADRS) and a small mean decrease in YMRS was found, suggesting its potential as BD adjunctive treatment (Nierenberg et al., 2017). L-methylfolate has potential as an adjunctive treatment for unipolar depression. Two multicenter sequential parallel comparison design trials were conducted with MDD patients (n=148 and n=75) with partial or no response to serotonin reuptake inhibitors. L-methylfolate supplementation was given for 30 days at the dosing of 7.5 mg/d and augmented later to 15 mg/d in the following month in trial one. In trial two, 15 mg/d of L-methyfolate was given for 60 days. The second trial had positive results on primary outcomes—degree of improvement in depressive symptom score and response rate (Papakostas et al., 2012). Folic acid was also found to improve the therapeutic effect of fluoxetine in depressed patients in another 2 placebo-controlled RCTs. Studies with samples of 127 and 42 patients with MDD, respectively, were treated with folic acid plus 20 mg of fluoxetine and showed greater improvement in the HAM-D and in the BDI (Coppen and Bailey, 2000Venkatasubramanian et al., 2013). Moreover, long-term treatment of post-stroke survivors (n=273) with folic acid, B6, and B12 was associated with a reduction in the risk for MDD (Almeida et al., 2010). The effect of vitamin B9 as a possible early intervention was studied in a double-blind, placebo RCT in healthy teenagers (n=112) with increased familial risk of depression and BD. Folic acid did not reduce the incidence of a mood disorder diagnosis but may have delayed the first mood episode and its clinical presentation tended to be milder (Sharpley et al., 2014).

 

Vitamin B1 

Vitamin B1, or thiamine, functions as a cofactor essential for the oxidative decarboxylation of the Krebs cycle (Depeint et al., 2006). Vitamin B1 deficiency is associated with neurological problems, including cognitive deficits and encephalopathy (Depeint et al., 2006Gibson et al., 2016). Healthy elderly women with marginal vitamin B1 deficiency experienced with thiamin supplementation a significant increase of appetite, body weight, energy, and activity, and decreased fatigue, improvement of sleep patterns, and of general well-being (Smidt et al., 1991).

 

Vitamin B3 

Vitamin B3, or niacin, is a precursor for NADH and nicotinamide adenine dinucleotide phosphate, which is involved in more than 500 enzymatic reactions pertaining to mitochondrial respiration (oxidative phosphorylation), glycolysis, and lipid oxidation (Depeint et al., 2006). The potential of NADH as an antidepressant was first tested in the FST model in Wistar rats, yielding a similar effect to fluoxetine (Rex et al., 2004). Vitamin B3 supplementation was also shown to prevent development and progression of mitochondrial myopathy in mice (Khan et al., 2014). More relevant to BD, evidence of mood elevation was reported in a 54-year-old man with no previous mental illness, who had a manic episode after commencing vitamin B3 for his dyslipidemia (Loebl and Raskin, 2013).

 

Vitamin B6 

Vitamin B6 refers to 3 primary forms: pyridoxine, pyridoxal phosphate, and pyridoxamine. The last 2 serve as coenzymes for protein metabolism, conversion of tryptophan to niacin, and neurotransmitter function. Some of the protective effect of vitamin B6 may occur via modification of mitochondrial function by preventing the oxygen radical generation and lipid peroxidation (Kannan and Jain, 2004). Higher dietary intake of vitamin B6 and folate was associated with lower prevalence of depression symptoms (measured with the Center for Epidemiologic Studies Depression Scale) in a large cross-sectional study of 6517 community adolescents (aged 12 to 15) (Murakami et al., 2010). Another study in 38 healthy older men on 20 mg of vitamin B6 supplementation showed cognitive benefits such as improved memory but failed to improve mood (Deijen et al., 1992). A double-blind RCT in 211 healthy women showed similar results (Bryan et al., 2002). Another 4-week, double-blind RCT with 14 geriatric depressed inpatients tested the augmentation of tricyclic antidepressant treatment with vitamins B1, B2, and B6 (10 mg/d). The active vitamin group demonstrated greater improvement in scores on ratings of depression and cognitive function (Bell et al., 1992). A 24-week, open-label clinical trial with 10 participants with SZ patients that were already receiving antipsychotics were given 1200–2400 mg/d of pyridoxamine. The patients had high levels of plasma pentosidine, a carbonyl stress biomarker. The results were measured with the Positive and Negative Syndrome Scale score and the Brief Psychiatric Rating Scale. Treatment augmentation with pyridoxamine showed partial results in participants with enhanced carbonyl stress; however, only 3 patients had reduction of psychopathology. Four patients showed improvement on iatrogenic parkinsonism. However, 2 patients had Wernicke’s encephalopathy-like adverse drug reactions, reversed by thiamine supplementation (Itokawa et al., 2018).

 

Vitamin B2 

Vitamin B2 is a precursor of flavin adenine dinucleotide and flavin mononucleotide and is required for electron transport chain in complexes I and II. They work synergistically with other B vitamins for mitochondrial respiration (Depeint et al., 2006). Henriques et al. (2016) showed that vitamin B2 supplementation could functionally compensate for mitochondrial ß-oxidation enzymes. Four nonrandomized trials have been reported effectively treating mitochondrial diseases with complex I and/or complex II (Bernsen et al., 1993Bugiani et al., 2006Gerards et al., 2011) and III and IV (Ghezzi et al., 2010) deficiency.

 

Vitamin B5 

Vitamin B5 is the precursor of CoA, important in the Krebs cycle and fatty acid oxidation. In vitro and in vivo studies suggest that vitamin B5 can restore ATP synthesis levels as well as the activity of antioxidant enzymes and can prevent the collapse of mitochondrial membrane potential (Depeint et al., 2006). There are established associations between vitamin B5 deficiency and neurodegenerative diseases, dermatitis, hypoglycemia, convulsions, and encephalopathy with liver failure (Depeint et al., 2006).

 

Vitamin B7 

Vitamin B7 is a coenzyme for 5 mitochondrial carboxylases and is essential for growth, development, and normal mitochondrial and cellular functions, including fatty acid oxidation and gluconeogenesis. Reductions in vitamin B7 result in the loss of mitochondrial complex IV, which leads to increased production of oxidative species by the mitochondria (Depeint et al., 2006). Several clinical disorders are associated with B7 deficiency, such as cutaneous conditions (skin rashes, alopecia, and conjunctivitis), neurological conditions (depression, seizures, paresthesia), and diabetes (Depeint et al., 2006).

 

Vitamin B12 

Vitamin B12, or cobalamin, is a cofactor for methionine synthesis, required for DNA and myelin synthesis and maintenance of neuronal integrity as well as neurotransmitter regulation. Vitamin B12 deficiency is a common but often under-recognized condition causing neurologic, cognitive, psychiatric, and mood symptoms (Lindenbaum et al., 1988Issac et al., 2015). Further, deficiencies of B12, folate, or B6 can lead to macrocytic or pernicious anemia with symptoms of fatigue, psychomotor, cognitive, and mood deficits (Selhub et al., 2009). In an RCT in elderly participants with depressive symptoms, long-term daily supplementation with folic acid and vitamin B12 improved cognitive functioning, particularly immediate and delayed memory performance (Walker et al., 2012). More relevant to BD, there is a case-report of an acute onset of mania in a 94-year-old man with no previous mental illness and profound cobalamin deficiency who responded to cobalamin therapy (Jacobs et al., 1990). In a double-blind RCT of vitamin B12 supplementation in winter seasonal affective disorder, no significant differences were found (Oren et al., 1994). No benefit for B12 replacement was found in cognitive symptoms in dementia (van Dyck et al., 2009) or depressive symptoms in an elderly man (Ford et al., 2008).

Other Potential BD Agents
Taurine

Taurine is a free amino acid that has important functions as a neuromodulator and antioxidant. It protects against glutamate-induced neurotoxicity and has been hypothesized to prevent membrane depolarization and mitochondrial energy failure (Timbrell et al., 1995Ye et al., 2013). Recently, taurine has been reported to reduce oxidative stress and maintain mitochondrial function in cortical neurons (Xu et al., 2015). Moreover, taurine acts as an agonist for glycine and γ-aminobutyric acid receptors (Albrecht and Schousboe, 2005). In the FST model in rats, taurine supplementation has antidepressant-like effects (Toyoda and Iio, 2013). In a double-blind RCT in people with first-episode psychosis, taurine improved symptoms of depression and reduced psychotic symptoms as well as improved measures of functioning but failed to impact cognition (O’Donnell et al., 2016). While a double-blind RCT in BD adolescents with a manic episode was conducted (CT00391001), the study was terminated and no results have been published. Another double-blind RCT was carried out but despite its completion, no results have been revealed at this time (NCT00217165).

Bezafibrate

An agonist of the PPAR usually prescribed as an hypolipidemic drug, bezafibrate can restore fatty acid oxidation activity in cells from carnitine palmitoyltransferase-2 and very-long-chain acyl-CoA dehydrogenase deficiencies in in vitro conditions (Bastin et al., 2008). Data suggest that the PPAR signaling pathway is directly implicated in mitochondrial physiology. Exposure to bezafibrate increased the transcription of HADHA and HADHB genes (responsible the encoding of alpha and beta subunit of the mitochondrial trifunctional protein) (Aoyama et al., 1998), immune-detectable alpha and beta subunit proteins, activities of long-chain 3-hydroxyacylCoA dehydrogenase and long-chain 3-ketoacylCoA thiolase, and stimulated fatty acid oxidation capacities in human fibroblasts (Djouadi et al., 2016). To the best of our knowledge, no clinical data are available in the literature regarding the role of benzafibrate in psychiatry. However, an 8-week, open-label pilot trial of bezafibrate 400 mg/d added to lithium in 20 participants with bipolar depression is being conducted to assess its safety, tolerability, and antidepressant efficacy (NCT02481245).

 


#332 Mr Serendipity

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Posted 05 April 2022 - 09:01 AM

Well it’s been 9 days and I’ve lost 3kg on Keto and some other factors that aren’t as consistent (walking, OMAD). Start weight 116kg. Believe it or not, my mood is actually levelling. I think sticking to taking 500mg niacinamide before bed is also helping, as well as having 1360mg lecithin in my morning stack. I’ve just now added creatine, PQQ, unbiquinol, and ribose, in a hopes that it will help repair my mitochondria over time. One thing that’s been very observable is the reduction in anxiety and OCD thoughts. A lot of the time I worry over situations or conversations I’ve previously had, but that seems to be gone for now.

 

There is actually one connection I have from my mini pop. In the first year of uni, me and my friends all started taking creatine. The only problem with this is I can’t remember exactly when I was taking it, and how consistent I was at taking it (no records), around the time I popped. I would have also been weight lifting at the time also. However assuming I was taking it consistently, and making connections to my mitochondrial dysfunction today, it could have literally been creatine that helped me achieve that pop. One of the things I distinctly remember when I experienced it, was my brain really woke up, like currently we’re all half asleep, in a daze, but when you pop your brain wakes up properly for the first time and you become receptive to a more full reality of emotions. So my theory is a pop requires a lot of brain energy, which requires healthy efficiently working mitochondria. And at the time taking creatine boosted the phosphocreatine and ATP in the brain giving it the necessary energy to pop. It would also make sense that if I have been suffering from mitochondrial dysfunction for years and since the start of this thread, every time I pushed the brain work harder using amygdala tickling, I manifested strong mental illness symptoms because I couldn’t meet my brains energy demands.

 

Another theory but to me this one has the most credence.

 

I should also note some other things relevant to this

 

1. Using forskolin in the past was the only thing to give an immediate and noticeable mood boost. Forskolin increases cAMP which is part of the mitochondria.

2. I became allergic to coq10 and l-carnitine in the past by megadosing them. Both are related to the mitochondria.

3. I couldn’t even eat liver or heart anymore without experiencing brain fog and extreme tiredness because of its coq10 content.

4. ALCAR makes me really angry these days and gives me major insomnia, even a small dose of 500mg (which is why I chucked it).

5. Creatine has given me rage in the past also according to my notes.

 

So a lot of things pointing to mitochondrial dysfunction. As aforementioned I’ve actually started taking coq10 again in the form of ubiquinol at a low dose (100mg). I can handle a little brain fog and tiredness, but I can’t handle the rage and insomnia ALCAR gives me. So I’m settling on trying lecithin, d ribose, ubiquinol, creatine, pqq, niacinamide, and of course ketosis to help fix my mitochondria issues for now.

 

Let the new adventure begin. And lots of tickling to push my brain to make it or break it.



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#333 Mr Serendipity

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Posted 08 May 2022 - 05:16 PM

So I stuck to the keto basically zero carb diet for about 3 weeks. It didn't have an effect on my emotional stability.

 

However I think I've finally found the missing thing for my emotional stability; lecithin. I was already taking lecithin on and off, but only 1 pill at a time. Now I've bought lecithin granuals, and my emotions feel stable. Another thing I've noticed is my wound healing which has plagued me these past couple of years has gotten better. I can't seem to find any research on ingesting lecithin and wound healing, but there is a study on topical lecithin and wound healing. 

 

https://pubmed.ncbi....h.gov/31116027/

 

In vitro antioxidant activity and in vivo wound-healing effect of lecithin liposomes: a comparative study

Aim: This study was conducted to determine the potentials of egg lecithin (egg-l) and soy lecithin (soy-l) liposomes in antioxidative and wound healing properties. Materials & methods: The suspensions of egg-l and soy-l were prepared using the fusion technique. The free radical scavenging activity of both lecithin liposomes was evaluated by DPPH and ABTS methods. Tissue staining was used to assess wound-healing parameter. Results: Liposomal lecithins showed an increasing trend of 1-10 mg/ml in radical-scavenging activities (p < 0.0001). Wound-healing assessments showed a significant effect (p < 0.0001) in treatment with topical lecithin liposomes. The results of wound healing also showed better outcomes of egg-l in comparison with phenytoin 1% cream. Conclusion: Antioxidant lecithin liposomes may enhance the treatment of wound injuries.

 

https://pubmed.ncbi....ih.gov/7051871/

 

Lecithin in the treatment of mania: double-blind, placebo-controlled trials

The authors report double-blind, placebo-controlled trials of pure lecithin in the treatment of mania. As in preliminary trials, lecithin appeared to be nontoxic and effective. Improvement with lecithin was significantly greater than improvement with placebo in five of the six patients studied. The concurrent use of anticholinergic agents did not prevent the antimanic effect of lecithin. The authors discuss the possible mechanism of action of lecithin, including cholinergic and membrane-altering effects.

 

https://www.ncbi.nlm...les/PMC4476977/

 

 

 

Beneficial effect of phosphatidylcholine supplementation in alleviation of hypomania and insomnia in a Chinese bipolar hypomanic boy and a possible explanation to the effect at the genetic level

 

In this study, we have reported on a 16-year-old Chinese boy with bipolar hypomania symptoms who was initially psychotic, and upon treatment with medication, responded well and stabilized. However, he still suffered from monthly episodes of insomnia accompanied by hypomania for 5 months despite adherence to medication. After that, he was put on a supplement of one capsule mainly containing 600 mg phosphatidylcholine. In the month following the initiation of phosphatidylcholine supplementation, no hypomania and insomnia was observed after the full moon and all hypomania symptoms disappeared. He has been taken off all his medication after half a year of supplementation and has been symptoms free for approximately one year. This finding was consistent with Chen’s report, in which they found that the choline level, considered as sex-specific urinary metabolite biomarkers for diagnosing male and female bipolar disorder patients, was decreased in bipolar disorder male subjects (Chen et al. 2014). The decline of phosphatidylcholine might be caused by the unbalance of metabolism of DAG and PA, in which DGK enzymes phosphorylate DAG into PA when receptors in phosphoinositide pathway receiving activation. This hypothesis suggested that DGK enzymes are likely to play a vital role in the pathogenesis of bipolar hypomania symptoms.

 

 

 


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#334 Mr Serendipity

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Posted 20 August 2022 - 01:14 AM

Ok I might have actually figured out a supplement that helps my hypomania.

 

First to note is I haven’t been practicing amygdala tickling for months, but I still suffer from hypomania regularly regardless.

 

Anyway a couple of days ago I was going through some strong hypomania and pressured speech, and at the end of the day I took a couple of high dose DHA, specifically Now Foods DHA-500, so 1g of DHA, and my mind calmed down. I’ve been taking it regularly throughout today and have been stable.

 

What’s also interesting is soy lecithin, which I have noted in the past has helped lower my hypomania, specifically when I drank alcohol when having taken some earlier that day, and I didn’t end up going hypomanic crazy.

 

Which finally leads me to believe, if my mini pop back in 2011 at university had anything to do with my diet or supplements, it was because I use to consume raw eggs yokes regularly, often 6 a day.

 

Not only does eggs yolks have lecithin which it well known for, but also DHA, though the chicken diet does change the % of DHA in the yolk (Google the study).

 

I also noticed dopamine enhancing supplements make my hypomania worse. And I find tryptophan doesn’t benefit me either, but causes brain fog. 
 

So I think I’ll stick to normal/low doses of lecithin, and high doses of DHA, and see where it takes me.



#335 Mr Serendipity

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Posted 24 August 2022 - 12:45 AM

https://omegaquant.c...polar_disorder/

Screen-Shot-2016-06-20-at-6.23.42-PM.png

 

The authors found that DHA levels in red blood cells were significantly lower in individuals with bipolar type 1 compared to individuals without the disorder. The forest plot above shows the effect sizes of DHA levels across the 6 individual studies. Basically, if the lines (95% confidence interval) on either side of the dot (standardized mean effect size) are below 0, that means there was a significant reduction in DHA levels in cases vs. controls. The dot+line at the bottom of the graph is the combined effect from all the studies, which in the case of DHA, shows a robust difference between cases and controls. EPA effect sizes were slightly lower than 0 but not as clearly as the DHA levels. Other long-chain polyunsaturated fatty acids, linoleic acid and arachidonic acid, were not different between cases and controls.

 



#336 Mr Serendipity

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Posted 24 August 2022 - 12:52 AM

https://scitechdaily...in-development/

 

A recent study shows that taking 500 milligrams of the nutrient choline helps the body more effectively metabolize an omega 3 fatty acid that is crucial for the fetal brain, cognition, and vision development.

 

Choline helps the body use an essential nutrient during a baby’s development

The nutrient choline has already been proven to have long-term advantages for children whose mothers eat it throughout pregnancy. However, a recent study has found that it can also help the body more effectively utilize an omega 3 fatty acid that is crucial for the fetal brain, cognition, and eyesight development.

The research was published in the American Journal of Clinical Nutrition on May 16th, 2022.

The results demonstrate that choline supplementation helps cellular metabolism more effectively manage and release the omega 3 fatty acid, DHA, from a pregnant woman’s liver. DHA, once in the circulation, can reach all tissues, including the placenta.

“During pregnancy, mom is primed to get nutrients out of the liver and make them available to the baby, so by supplementing choline and DHA [together], we are increasing DHA bioavailability,” said senior author Marie Caudill, professor of nutritional sciences in the College of Agriculture and Life Sciences at Cornell University. Kevin Klatt, Ph.D. ’18, a research scientist and registered dietitian at the University of California, Berkeley, is the paper’s first author.

These forms of nutrient-nutrient interactions are not new, according to Caudill. In the intestines, for example, vitamin D improves calcium absorption while vitamin C increases iron availability.

Caudill and colleagues at Cornell have also demonstrated that high maternal choline intake reduces an infant’s stress response, improves information processing, and has long-term benefits in sustained attention (as demonstrated in a study that followed children up to age 7), and that choline reduces a factor that contributes to preeclampsia in pregnant women.

In this study, a group of 30 women in gestational weeks 12 to 16 were randomly divided into two groups: One was given 500 milligrams of choline per day, plus 50 milligrams per day of choline labeled with deuterium, so it could be tracked through the body. The other group served as a control and was given 25 milligrams per day of just the labeled choline. All participants were also given a daily 200-milligram DHA supplement, a prenatal vitamin and mineral supplement, and could eat their normal diet. Blood and urine were taken after fasting at the start of the experiment for a baseline, and then during gestational weeks 20-24 and weeks 28-30. Maternal blood and cord blood were also taken at delivery.

By tracking the labeled choline, the researchers identified a chemical reaction in which choline donates small molecules called methyl groups that are added to a molecule called phosphatidylethanolamine. Through a biological pathway, phosphatidylethanolamine is converted to a new choline-containing molecule, phosphatidylcholine, which is enriched with DHA. In this form, DHA gets transferred out of the liver and into a mother’s bloodstream, where it is available for use in tissues.

 



#337 Mr Serendipity

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Posted 24 August 2022 - 12:57 AM

https://pubmed.ncbi....h.gov/27038174/

 

 

Dietary Crude Lecithin Increases Systemic Availability of Dietary Docosahexaenoic Acid with Combined Intake in Rats

 

Crude lecithin, a mixture of mainly phospholipids, potentially helps to increase the systemic availability of dietary omega-3 polyunsaturated fatty acids (n-3 PUFA), such as docosahexaenoic acid (DHA). Nevertheless, no clear data exist on the effects of prolonged combined dietary supplementation of DHA and lecithin on RBC and plasma PUFA levels. In the current experiments, levels of DHA and choline, two dietary ingredients that enhance neuronal membrane formation and function, were determined in plasma and red blood cells (RBC) from rats after dietary supplementation of DHA-containing oils with and without concomitant dietary supplementation of crude lecithin for 2-3 weeks. The aim was to provide experimental evidence for the hypothesized additive effects of dietary lecithin (not containing any DHA) on top of dietary DHA on PUFA levels in plasma and RBC. Dietary supplementation of DHA-containing oils, either as vegetable algae oil or as fish oil, increased DHA, eicosapentaenoic acid (EPA), and total n-3 PUFA, and decreased total omega-6 PUFA levels in plasma and RBC, while dietary lecithin supplementation alone did not affect these levels. However, combined dietary supplementation of DHA and lecithin increased the changes induced by DHA supplementation alone. Animals receiving a lecithin-containing diet also had a higher plasma free choline concentration as compared to controls. In conclusion, dietary DHA-containing oils and crude lecithin have synergistic effects on increasing plasma and RBC n-3 PUFA levels, including DHA and EPA. By increasing the systemic availability of dietary DHA, dietary lecithin may increase the efficacy of DHA supplementation when their intake is combined.



#338 Mr Serendipity

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Posted 29 August 2022 - 11:26 PM

https://www.ncbi.nlm...les/PMC2838627/

 

Abstract

 

Increasing evidence suggests that docosahexaenoic acid [DHA, 22:6(n-3)], the principal (n-3) fatty acid in brain gray matter, has neurotrophic and neuroprotective properties. Preliminary clinical evidence also suggests that the perinatal accrual, and the subsequent dietary maintenance of, cortical DHA is positively associated with cortical gray matter volumes. The pathophysiology of recurrent affective disorders, including unipolar and bipolar depression, is associated with (n-3) fatty acid deficiency, DHA deficits, impaired astrocyte mediated vascular coupling, neuronal shrinkage, and reductions in gray matter volume in the prefrontal cortex (PFC). Preclinical studies have also observed neuronal shrinkage and indices of astrocyte pathology in the DHA-deficient rat brain. Together, this body of evidence supports the proposition that DHA deficiency increases vulnerability to neuronal atrophy in the PFC of patients with affective disorders. Because projections from the PFC modulate multiple limbic structures involved in affective regulation, this represents one plausible mechanism by which (n-3) fatty acid deficiency may increase vulnerability to recurrent affective disorders.
 


#339 Mr Serendipity

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Posted 14 September 2022 - 10:30 PM

I’m going to do a quick update here without going into all my experiences and reasonings, as I might’ve actually found something that manages my bipolar symptoms.

 

Basically taking DHA-500 (high concentration omega 3) and eating Atlantic mackerel everyday for the phosphatidylserine (to help lower cortisol), seems to help prevent any depressive episodes.

 

And using nicotine (via vaping) to act on the acetylcholine system seems to work as the best anti manic. Also note vaping in the past would make me depressed and stressed out, which I think is being counteracted by the omega 3’s and phosphatidylserine.

 

Pretty stable right now considering I’ve tried everything else under the sun to help me. I will update at a later point in time to say if it’s still working or not.



#340 Mr Serendipity

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Posted 17 September 2022 - 01:07 AM

I decided to stop eating the atlantic mackerel after 2 weeks continuous, because it would cause maggots/larvae in the bin, which we never got previously. So I ordered some high strength soy based phosphatidylserine (PS) Now Foods brand, first time taken today. I'm hoping it will work just as well as the PS found in fish.

 

I'm feeling different. I can't quite put my finger on it. I'm not quite there yet. But every day I'm getting subtle improvements in my mental health/bipolar. I think lowering/normalizing cortisol with DHA and PS was the answer I've been looking for.

 

I found a great scientific review I'm now going through, which goes into detail of high levels of cortisol, how it effects the brain, and mental illness.

 

 

 

Therefore, the aim of the following paper is to systematize information on HPA axis dysregulation and the influence of cortisol levels on the possibility of developing a mental disorder, such as depression, bipolar disorder (BD), or an episode of psychosis. Moreover, this work presents changes in the level of cortisol during the course of the disease, as well as the influence of the applied therapy on levels of the hormone.

 

Leaving it here for future reference: https://www.ncbi.nlm...les/PMC8584322/

 

I just hope if this is the issue, that my brain can heal back. I'm already getting subtle improvements, but have no idea how far I will improve. But I am glad my emotional stability and hypomania has improved so far. It's been about a month of high doses of DHA, and 2 weeks of eating Atlantic mackerel everyday (which I'm not switching for the soy based PS supplement).

 

 



#341 Mr Serendipity

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Posted 27 September 2022 - 01:32 PM

Interesting experience I found on Reddit when looking for experiences on Phosphatidylserine:

 

 

Yes I have tried it and also I have Bipolar and ADHD. I felt that it stabilizes my mood. It definitely helps regeneration of the brain and actually makes you chill out too. Also I know this may be weird but I experience some tingly feelings on my frontal lobe whenever I use related supplements like Krill Oil or Citicoline etc. Lmao, it’s just something I feel after experiencing nootropics for some time.

For me so far the combo of PS + Omega 3 seems to be the best thing I’ve come across for my bipolar, and incredibly my memory has shot up leaps and bounds (I created a separate thread in the brain health sub-forum about this). I’m also remembering a lot of my dreams, and it feels like my brain is generally becoming healthier. I’ve even stopped looking for different supplements or medicines to fix my mental issues, as this feels like it’s doing just that. Doses are 1g DHA/500mg EPA, 600mg PS, as part of my morning stack.

 

I’ve even started the amygdala tickling practice again and it isn’t sending me insane/severely hypomanic like it use to. I’ve even started to laugh a lot more, and starting to find music more enjoyable again.

 

So good news all around. I’m hoping now I can get some interesting positive experiences with amygdala tickling in the coming months. 


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#342 Mr Serendipity

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Posted 28 September 2022 - 05:00 PM

Let's go through some of the theories and other stuff I've learnt.

 

First of all you can find my other thread in the following link: Omega 3 + Phosphatidylserine Is making my memory insanely good

 
What I've noticed is I'm at a point where 600mg PS in the morning is too much, yesterday it completely knocked me on my ass where I didn't want to do anything. Whether this is because I've been taking too much all this time, or it's built up in my system I cannot tell. But I took 300mg this morning, and I still feel my cortisol on the lower side, but I actually have energy to do stuff. I'll probably stick to this dose in the morning, and maybe start consuming some caffeine as well.
 
I'll post research related to bipolar and anhedonia as that is what I suffer with.
 
Cortisol/HPA Dysfunction Theory
 
1. High cortisol because of HPA dysfunction is implicated in mental illnesses and shrinkage of brain parts.
 
 

Recurrent stress causes changes in the structure of neurons. When stress is short lived, the onset of atrophy is reversible, but long-term stress can lead to the death of neurons located in the hippocampus. PET (positron emission tomography) and fMRI (functional magnetic resonance imaging) studies indicate that, in the case of diseases such as depression or post-traumatic stress disorder, there is a reduction in the volume of this region of the brain, as well as in that of the prefrontal cortex and amygdala [10]. It is not certain, however, whether the increase in cortisol secretion itself or the dysregulation of cortisol secretion are the cause of atrophy. In addition, a reduction in hippocampal volume is also seen in borderline personality disorder [10] and patients with schizophrenia [11].

 

In bipolar disorder (BD), an increase in cortisol secretion may be seen in the manic phase [20]. Another study showed that high cortisol awakening response (CAR) was present in both unipolar depression and bipolar disorder, but both conditions differed in the course of the changes in the daily curve of the hormone concentration, which was evidently influenced by manic symptoms [21]. Huang et al. examined hormone levels in patients during depression, mania, and partial remission against those of healthy control subjects [22]. Regardless of the patient’s condition, a weaker cortisol awakening response was observed, which confirms dysregulation of the HPA axis in BD subjects, although the course of the cortisol curve itself varied slightly depending on the phase of the disease.

 

2. Cortisol's implication in anhedonia, and its reversal by lowering CRH expression from the Amygdala.

 

Anhedonia following early-life adversity involves aberrant interaction of reward and anxiety circuits and is reversed by partial silencing of amygdala corticotropin-releasing hormone gene  

 

The reversal of anhedonia in individual rats upon partial silencing of ACe-Crh supports a causal role for amygdala CRF in the disruption of stress- and reward-related circuitry that results in anhedonia. Notably, the current experimental design could not definitively ascertain unilateral and regional specificity of ACe-CRF in CES-induced anhedonia.  Surprisingly, we found complete reversal of CES-induced anhedonia upon reduction of CRF levels unilaterally. For technical reasons, the reduction took place in left amygdala.

 

Abbreviations: corticotropin-releasing factor (CRF; encoded by the Crh gene), chronic early-life adversity/stress (CES)

 

acth.png

 

3. Omega 3 + Phosphatidylserine has been shown to correct and normalize cortisol levels. 

 

Phosphatidylserine – Protection from the Effects of Chronic Stress

 

Chronic PS supplementation has been found to promote a less stressed, more relaxed state and a subjective improvement in mood [4,5]. Some studies have combined PS with other nutritional supports, namely phosphatidic acid or omega-3 fatty acids, to good effect [6,7].

 

In the study’s lowest responders, treatment with omega-3 plus PS for 12 weeks seemed to restore the cortisol response to this challenge, and the researchers concluded that those with high chronic stress and/or a dysfunctional response of the HPA axis may benefit from omega-3 plus PS supplementation [6].

 

A similar effect was found for a soy-based PS/phosphatic acid complex (PA) at a dose of 400 mg PS and 400 mg PA per day in normalizing ACTH and salivary and serum cortisol in chronically high-stressed males, but not in low-stressed subjects, and there was no significant effect at a dose of 200 mg PS and 200 mg PA [7].

 

 

HDAC Possibility (I have no theory here how PS inhibiting HDAC would help bipolar specfically)

 

1. Phosphatidylserine inhibits HDAC

 

Phosphatidylserine improves axonal transport by inhibition of HDAC and has potential in treatment of neurodegenerative diseases

 

Familial dysautonomia (FD) is a rare children neurodegenerative disease caused due to a point mutation in the IKBKAP gene that results in decreased IKK complex-associated protein (IKAP) protein production. The disease affects mostly the dorsal root ganglion (DRG) and the sympathetic ganglion. Recently, we found that the molecular mechanisms underlying neurodegeneration in FD patients are defects in axonal transport of nerve growth factors and microtubule stability in the DRG. Neurons are highly polarized cells with very long axons. In order to survive and maintain proper function, neurons depend on transport of proteins and other cellular components from the neuronal body along the axons. We further demonstrated that IKAP is necessary for axon maintenance and showed that phosphatidylserine acts as an HDAC6 inhibitor to rescue neuronal function in FD cells. In this review, we will highlight our latest research findings

 

2. Bipolar & HDAC

 

HISTONE DEACETYLASES APPEAR TO HAVE PATHOPHYSIOLOGIC ROLE IN BIPOLAR DISORDER 

 

• Genetic, pharmacological and pathological studies have suggested roles for histone deacetylases (HDACs) in bipolar disorder (BD)  
 
• This study measured HDAC expression in 11 participants with BD and 11 age- and sex-matched healthy controls using an HDAC-specific radiotracer during simultaneous magnetic resonance–positron emission tomography neuroimaging  
 
• HDAC expression was significantly lower in the BD group than the control group in the right amygdala and a broader fronto-limbic distribution including the thalamus, orbitofrontal cortex and hippocampus  
 
• In the BD group, HDAC expression was associated with emotion regulation in the frontal and perisylvian regions and with attention in the temporal and fronto-parietal regions  
 
• These results suggest a potential role for HDACs in the fundamental pathophysiology of BD as well as in two of its hallmark clinical features

 

In vivo human brain expression of histone deacetylases in bipolar disorder

 

The etiology of bipolar disorder (BD) is unknown and the neurobiological underpinnings are not fully understood. Both genetic and environmental factors contribute to the risk of BD, which may be linked through epigenetic mechanisms, including those regulated by histone deacetylase (HDAC) enzymes. This study measures in vivo HDAC expression in individuals with BD for the first time using the HDAC-specific radiotracer [11C]Martinostat. Eleven participants with BD and 11 age- and sex-matched control participants (CON) completed a simultaneous magnetic resonance – positron emission tomography (MR-PET) scan with [11C]Martinostat. Lower [11C]Martinostat uptake was found in the right amygdala of BD compared to CON. We assessed uptake in the dorsolateral prefrontal cortex (DLPFC) to compare previous findings of lower uptake in the DLPFC in schizophrenia and found no group differences in BD. Exploratory whole-brain voxelwise analysis showed lower [11C]Martinostat uptake in the bilateral thalamus, orbitofrontal cortex, right hippocampus, and right amygdala in BD compared to CON. Furthermore, regional [11C]Martinostat uptake was associated with emotion regulation in BD in fronto-limbic areas, which aligns with findings from previous structural, functional, and molecular neuroimaging studies in BD. Regional [11C]Martinostat uptake was associated with attention in BD in fronto-parietal and temporal regions. These findings indicate a potential role of HDACs in BD pathophysiology. In particular, HDAC expression levels may modulate attention and emotion regulation, which represent two core clinical features of BD.  

 

3. HDAC inhibition & Fear Extinction

 

There's a few studies out there on HDAC inhibition and fear extinction, which probably is a reason my PTSD symptoms from severe hypomania from amygdala tickling improved/disappeared. But I cba to collaborate anymore studies I don't fully understand lol

 

4. Low DHA levels and bipolar and frontal lobes theory... written somewhere in this thread (with studies) previously

 

Regardless it's all good in the hood atm. Omega 3 + PS for the win! Enough said.


Edited by Mr Serendipity, 28 September 2022 - 05:28 PM.


#343 Mr Serendipity

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Posted 02 October 2022 - 03:21 PM

While I thought I wouldn't be able to come any closer to feeling any better with different supplements or stack, Phosphatidylserine being the last thing that would bring me as close as I could get to normality, it seems like good things seem to come all at once.

 

I took a chance on the methylation slow comt theory, while I don't really understand it, it has already worked miracles, instantly on the first day, and I'm only on the third day.

 

Basically I dropped anything from my stack that wasn't good for slow comt, these were:

 

Multivitamin

Methyl B9 & B12

Quercetin

Turmeric

 

I then added:

 

Magnesium Malate (1500mg providing 225mg elemental magnesium) (54%)

Glycine (1g)

Riboflavin B2 (100mg) (7143%)

Molybdenum (150mcg) (333%)

 

So basically I'm not taking any B vitamins anymore, except for B1 (Benfotiamine), and B2 (Riboflavin).  

 

An indigestion issue from nearly anything I ate that's been plaguing me regardless of whether I take my stack or take a long break from it, which I thought was SIBO or candida, has completely vanished! I can seem to eat greasy foods, yogurt, and even drink beer now without any issue, these previously caused me the worst indigestion. I can even seem to drink caffeinated beverages (only tested coke cola so far) without feeling sensitive to it, previously my max limit was 1 early in the morning if I decided to consume any.

 

I think I feel even calmer, I was already taking NAC for OCD and selenium for immune health (but selenium is also a cofactor of NAC). But I think adding the Molybdenum (the other cofactor) supercharged the NAC. The only time I was getting Molybdenum was 15-30mcg (depending if I took 1 or 2 of my multivitamin). In fact I've been feeling a bit too relaxed, probably my insomnia is cured now, though I've had beer the last couple of days, so can't tell yet.

 

Riboflavin Has Neuroprotective Potential: Focus on Parkinson's Disease and Migraine

 

Abstract
 
With the huge negative impact of neurological disorders on patient's life and society resources, the discovery of neuroprotective agents is critical and cost-effective. Neuroprotective agents can prevent and/or modify the course of neurological disorders. Despite being underestimated, riboflavin offers neuroprotective mechanisms. Significant pathogenesis-related mechanisms are shared by, but not restricted to, Parkinson's disease (PD) and migraine headache. Those pathogenesis-related mechanisms can be tackled through riboflavin proposed neuroprotective mechanisms. In fact, it has been found that riboflavin ameliorates oxidative stress, mitochondrial dysfunction, neuroinflammation, and glutamate excitotoxicity; all of which take part in the pathogenesis of PD, migraine headache, and other neurological disorders. In addition, riboflavin-dependent enzymes have essential roles in pyridoxine activation, tryptophan-kynurenine pathway, and homocysteine metabolism. Indeed, pyridoxal phosphate, the active form of pyridoxine, has been found to have independent neuroprotective potential. Also, the produced kynurenines influence glutamate receptors and its consequent excitotoxicity. In addition, methylenetetrahydrofolate reductase requires riboflavin to ensure normal folate cycle influencing the methylation cycle and consequently homocysteine levels which have its own negative neurovascular consequences if accumulated. In conclusion, riboflavin is a potential neuroprotective agent affecting a wide range of neurological disorders exemplified by PD, a disorder of neurodegeneration, and migraine headache, a disorder of pain. In this article, we will emphasize the role of riboflavin in neuroprotection elaborating on its proposed neuroprotective mechanisms in opposite to the pathogenesis-related mechanisms involved in two common neurological disorders, PD and migraine headache, as well as, we encourage the clinical evaluation of riboflavin in PD and migraine headache patients in the future.
 
Keywords: Parkinson’s disease; glutamate excitotoxicity; homocysteine; kynurenine; migraine; oxidative stress; pyridoxal phosphate; riboflavin.

 

 

 



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#344 Mr Serendipity

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Posted 04 December 2022 - 11:33 PM

Well here we are again, and another discovery made, in fact maybe the final one.

 

I’ve suffered from bad wound healing on my right ear over a year from skin fungal. It was like fighting a losing, I was continually adjusting my stack to help, but after over a year of no healing, i started a regime the last month of fungal cream, emu oil, and coconut oil. And even though this helped a little, it was still fighting a losing battle, as it would heal a bit, and then it would lesion again. Then this last week I tried megadosing vitamin c (10g a day), and dropped all ointments to see if it would heal better, and I had some positive results. Then since yesterday I’ve been taking zinc picolinate, the only zinc I used a decade ago where I saw major results before dropping it for zinc citrate with copper for years, and well I think now most of my issues stem from a serious zinc deficiency. I feel I probably had slight scurvy of the brain.

Even though my stack covers a lot, upping my vitamin c and zinc seem to be making a huge difference to my wound healing and calmness of mind, hypomania, and ocd. I’m the least hypomanic in the past 5 years it feels like.

 

I can only assume after years of taking NAC it ended up causing a zinc deficiency.

 

So what I’ve decided to do is drop the NAC, continue to take 10g of vitamin c a day, 5g in the morning stack and 5g with a later meal. 50mg of zinc picolinate in my morning stack. And another new edition; 4 beef liver tablets in an evening meal just to help with any possible copper deficiencies, or inducing one with my zinc intake.

 

 

Below is a quote of my current stack and thoughts on what supps to drop once I use them up, as long as the few new ones I’ve added (higher vit c, zinc picolinate, beef liver supps) work to fix my wound healing and mental issues:

 

 

Taken separately along with stack:

5 x Vitamin C (1g)

 

Purple:

3 x Magnesium Malate

2 x Multivitamin

2 x DHA-500

1 x Borage Oil (1g)

1 x Phosphatidylserine (300mg) *

1 x Lecithin (1360mg) *

1 x Taurine (1g) **

1 x Glycine (1g)

1 x DLPA (500mg)

 

* maybe use up and drop cause now taking beef liver supps, however can’t find much info on it in beef liver

** probably won’t need this after vitamin c and zinc kicks in for mental health 

 

Yellow:

2 x Zinc Picolinate (25mg)

2 x Candida Support *

1 x Benfotiamine (150mg)

1 x Boron 

1 x Vitamin D (1000 IU)

1 x Vitamin E (400 IU)

1 x Super K (K1 [1.5mg], K2 MK4 [1mg], K2 MK7 [0.1mg])

1 x Molybdenum (150mcg)

1 x Selenium (200mcg)

1 x CoQ10 (100mg) **

1 x Pycnogenol (40mg) ***

1 x Ginger (300mg/5% gingerols)

1 x Gingko Biloba (120mg 50:1 extract, Ginkgo flavone glycosides 24%, Terpene lactones (ginkgolides A, B, C & bilobalides 6%) ****

 

* use up and drop because megadosing vit c seems to be working for Candida/healing issues

** Use up and drop because of beef liver supps

*** Use up and drop because megadosing vitamin c cures allergies (unless I’m missing the fact it’s working in conjunction, but drop anyway and only add back if allergies come back)

**** Don’t really care about ginkgo, hoping vit c, zinc pico, & beef liver supps added to stack will be the answers I was looking for.

 

With a later meal away from stack:

4 x Beef Liver Capsules (750mg)

5 x Vitamin C (1g)

 

Note: This is so the copper and iron in the beef liver are away from the zinc supplementation to avoid competition.

 







Also tagged with one or more of these keywords: amygdala, visualization, frontal lobes, brain exercise

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