Depression

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Summary: Agmatine is an amino acid that offers a wide of cognitive boosting benefits. It also has excellent effects on reducing neuropathic pain, as well as drug addiction habits. It is neuroprotectant and can reduce tolerance built to many medications like benzodiazepines, morphine, and other painkillers. It also synergizes with SSRI’s & cannabis.


Introduction

What is Agmatine Sulfate?

Agmatine is a form of amino acid that derives from L-Arginine. It has been shown to inhibit receptors for the neurotransmitter acetylcholine, which plays a major role in memory and reasoning.

Agmatine supplement also regulates levels of Nitric Oxide by the affecting nitric oxide synthase enzyme. It controls cellular energy levels by influencing polyamine metabolism and function.

In some studies, it has been shown to enhance the effects of both morphine and fentanyl to increase pain killing, reduce tolerance, and lower addiction, as well as working synergistically with marijuana.

It is also found naturally in every day foods, including beer, wine, coffee, and other fermented foods.

Because it is capable of targeting multiple receptors, agmatine may benefit a spectrum of complex diseases, including diabetes, Alzheimer’s disease, opioid addiction, mood disorders, and even cancer. Furthermore, agmatine may enhance cognitive function, stress resiliency, mood, and athletic performance. The highest levels of agmatine are found in the gut, where it is produced by the microbes living there. It is also found in dietary form, mainly in fermented foods, and in supplemental form like agmatine sulfate. Agmatine is also produced in small amounts within the body by the mitochondria in the liver.


Benefits & Effects

What Are the Benefits of Agmatine Sulfate?

  1. Reduces Pain Sensitivity
  2. Reduces Symptoms of Anxiety & Depression
  3. Neuroprotection & Longevity
  4. Improves Weight Loss & Prevents Weight Gain
  5. Supports Muscle Growth
  6. Helps Erectile Dysfunction & Infertility
  7. Help with Alzheimer’s Disease
  8. Helps Alcohol & Morphine Withdrawal

Agmatine sulfate benefits the body and mind in many different ways and depending on the method it is taken. Some of the most notable agmatine benefits are:

Reduces Pain Sensitivity

In research studies, Agmatine shows to be an effective way for pain relief. Especially in the case of thermal hyperalgesia, a condition where the body is sensitive to changes in temperatures. The body becomes hypersensitive to heat or cold.

Agmatine improves those pain sensations, which is a result of its pro-circulations effect.

In studies looking at pain reduction in neuropathic conditions or inflammatory pain, agmatine was not found to produce a statistically significant effect. However, anecdotal, first-hand reports show that it actually did work for neuropathic conditions. So in this specific situation, it seems to be subjective to each individual.

Reduces Symptoms of Anxiety & Depression

Agmatine exhibits antidepressant effects and promotes mood improvement as well as anxiety reduction and relief. It helps the brain and body manage and overcome stress by reducing anxiety and promoting a sense of well-being.

By increasing NRF2, agmatine prevents depressive behavior by protecting brain cells from high levels of stress hormone cortisol. [R]

Agmatine increases adenylate cyclase in the prefrontal cortex, and decreases levels of adenylate cyclase which associate with depression. [R, R].

Furthermore, it blocks the NMDA receptor, prevents calcium overloading, as well as reverses the decrease of monoamines such as norepinephrine, epinephrine, and dopamine. Depression often associates with a reduction of monoamines in the brain [R, R]

Studies & Research

A small pilot study on three patients suffering depression, Agmatine supplement caused a complete disappearance of depression symptoms in all patients. It most likely did so through NMDA receptor-blocking and not through serotonin pathways. [R]

Agmatine also reduced anxiety in rats when they were put in swimming and maze navigation tests. [R]

Neuroprotection & Longevity

Agmatine acts as an anti-oxidant and is continuously under more research for its anti-aging and longevity potential. It has been found to exhibit neuroprotective effects against oxidative damage and injuries to the Central Nervous System (CNS). It is also believed to limit the activity of glutamate receptors and thus, the over-excitation of neurons within the brain.

Additionally, by inhibiting iNOS and nNOS and increasing eNOS, Agmatine protects against brain damage from stroke. Increasing eNOS protects the brain by dilating the blood vessels to increase blood flow. This prevents damage during times of lack of oxygen from reduced blood flow to the brain (also known as ischemic stroke).

Agmatine decreases iNOS and nNOS, two enzymes that contribute to brain damage from stroke. [R]

A Study on Effects of Agmatine Sulfate on Nerve Injury:

OBJECTIVE:
Evaluate the effect of agmatine sulphate on facial nerve regeneration after facial nerve injury using electron and light microscopy.

METHODS:
The study was performed on 30 male Wistar albino rats split into: a control group, a sham-treated group, a study control group, an anastomosis group, and an anastomosis plus agmatine sulphate treatment group. The mandibular branch of the facial nerve was dissected, and a piece was removed for histological and electron microscopic examination.

RESULTS:
Regeneration was better in the anastomosis group than in the study control group. However, the best regeneration findings were seen in the agmatine sulphate treatment group. There was a significant difference between the agmatine group and the others in terms of median axon numbers (p < 0.004) and diameters (p < 0.004).

CONCLUSION:
Agmatine sulphate treatment with anastomosis in traumatic facial paralysis may enhance nerve regeneration. PMID: 28122652

Improves Weight Loss & Prevents Weight Gain

Individuals who struggle to gain weight can benefit from Agmatine supplements. In some studies, subjects increased food consumption rates by 44% to 54% in 24 hours.

Moreover, in the following studies, Agmatine shows an increase in fat burning, a decrease in fat composition, and an increase in muscle mass [R], which also contributes to the next benefit of Agmatine:

Supports Muscle Growth

Agmatine stimulates the production of luteinizing hormone (LH). Increasing these hormone levels lead to an increase in testosterone levels.

By increasing testosterone levels, Agmatine contributes to an optimal hormonal environment for muscle growth, enhances athletic performance, and fastens recovery. [R]

Agmatine also increases insulin sensitivity and the uptake of glucose into the muscle. Increasing insulin sensitivity results in more effective shuttling of amino acids as well as glucose into the tissues for growth and repair. [R] [R]

Helps Erectile Dysfunction & Infertility

Studies show that L-arginine is involved in the process of cell replication, in addition to enhancing blood circulation, so it can help improve both sperm production and motility.

Men dealing with cardiovascular issues due to low levels of NO in the blood are more prone to experience erectile dysfunction and fertility problems because an erection requires a relaxation of smooth muscles, which Nitric Oxide triggers.

Although it doesn’t apply to every person, a significant rate of male infertility cases (92%) is treatable with L-arginine supplements in combination with dilators, antioxidants and/or anti-inflammatories. [R]

Research suggests that high-stress levels lower L-arginine levels in the sperm production pathway. Therefore, men with chronic stress specifically can benefit from Agmatine supplement.

According to Dr. Axe, a combination of L-arginine, L-glutamate and yohimbine hydrochloride is a common way of treating erectile dysfunction. And it works better than L-arginine alone. [R]

“In fact,” he says, “many of the most frequently prescribed medications for ED work similarly to L-arginine: by increasing nitric oxide production.”

Furthermore, there’s research suggesting treatment with N-Acetyl Cysteine (NAC) and L-arginine together can help balance hormones naturally and restore normal sexual function in women with polycystic ovary syndrome and estrogen imbalances.

Other studies suggest that L-arginine with herbs such as chasteberry, green tea extract, and antioxidant supplements improve pregnancy rates in women struggling to conceive. [R]

Help with Alzheimer’s Disease

Insulin resistance could cause an increase of plaque and neurofibrillary tangles in the brain, which are the signs of Alzheimer’s disease. Agmatine prevents cognitive decline by rescuing insulin signaling and avoiding potential accumulation of those tangles. [R]

Helps Alcohol & Morphine Withdrawal

Agmatine reduces and to an extent, prevents, symptoms of alcohol withdrawal such as “wet dog shakes,” anxiety, flashes, and shakings. [R] [R]

Agmatine sulfate

Mechanism of Action

How Does Agmatine Sulfate Work?

Agmatine has several mechanisms. It can inhibit N-methyl-D-aspartate (NMDA) and nicotinic acetylcholine receptors, as well as activate imidazoline receptors. Agmatine can also inhibit nitric oxide synthase enzymes, which allows it to regulate elevated levels of nitric oxide. Agmatine can inhibit calcium channels and specific serotonin receptors as well. Further research is needed to determine the full extent of agmatine mechanisms. [R]

Agmatine was found to exert modulatory actions directly and indirectly at multiple key molecular targets underlying cellular control mechanisms of cardinal importance in health and disease. It is considered capable of exerting its modulatory actions simultaneously at multiple targets. The following outline indicates the categories of control mechanisms and identifies their molecular targets:

Neurotransmitter receptors and receptor ionophores. Nicotinic, imidazoline I1 and I2, α2-adrenergic, glutamate NMDAr, and serotonin 5-HT2A and 5HT-3 receptors. Ion channels. Including: ATP-sensitive K+ channels, voltage-gated Ca2+ channels, and acid-sensing ion channels (ASICs).

Membrane transporters. Agmatine specific-selective uptake sites, organic cation transporters (mostly OCT2 subtype), extraneuronal monoamine transporters (ENT), polyamine transporters, and mitochondrial agmatine specific-selective transport system. Nitric oxide (NO) synthesis modulation. Both differential inhibition and activation of NO synthase (NOS) isoforms is reported.

Polyamine metabolism. Agmatine is a precursor for polyamine synthesis, competitive inhibitor of polyamine transport, inducer of spermidine/spermine acetyltransferase (SSAT), and inducer of antizyme. Protein ADP-ribosylation. Inhibition of protein arginine ADP-ribosylation. Matrix metalloproteinases (MMPs). Indirect down-regulation of the enzymes MMP 2 and 9. Advanced glycation end product (AGE) formation. Direct blockade of AGEs formation. NADPH oxidase. Activation of the enzyme leading to H2O2 production. – Wikipedia


Dosage

How to Take Agmatine Sulfate?

There is currently no standard dosage for agmatine sulfate because there haven’t been enough human studies for determination. These numbers are rough estimates to give an idea of typical, experimental dosing:

  1. For treatment of neuropathic pain: 1,000 to 2,500 mg of agmatine (daily)
  2. For improving cognitive function: 200 to 500 mg of agmatine (daily)
  3. For vasodilation and enhanced recovery: 500 to 1000 mg of agmatine (30 minutes pre-workout)

Note: Agmatine is not absorbed well when taken with dietary protein, because it uses the same transporters as arginine

Quoting Examine:

“There are no standard dosages for agmatine because of the lack of human evidence for its effects. However, a single human study used 1,300-2,670mg of agmatine, daily for the treatment of neuropathic pain. The estimated human dose for improving cognition is 1.6-6.4mg/kg of agmatine, taken orally.

This is based off of the 10-40mg/kg dosage range for rats, and is equivalent to 217-435 mg for a 150lb person. Supplementation should not exceed 6.4mg/kg of bodyweight. Studies on agmatine use a daily dosing protocol.

Agmatine is not absorbed well when taken with dietary protein, because it uses the same transporters as arginine. Further research is needed to determine if oral agmatine supplementation provides the same benefits as were observed in animal studies.”

“The generally accepted daily dosage range for Agmatine Sulfate is between 250 mg and 2.5 grams. Avoid taking higher than necessary dosages to reduce the risk of side effects.”


Side Effects

What Are Agmatine Sulfate Side Effects?

According to studies conducted so far, it appears that Agmatine Sulfate is safe even in relatively high doses. While there have been few studies conducted thus far, they have not shown any side effects to be associated with this supplement.

If you follow the recommended Agmatine sulfate dosage protocol and do not have any pre-existing contraindications for use, the risk of serious adverse effects is very low. Minor side effects included nausea, diarrhea, and vomiting in a small percentage of participants, which cleared up after a few days of discontinuing use. [R]


User Experience

Agmatine Sulfate Reddit User Experience

“Not only does it have varied anti-addiction properties to Opioids, amphetamines, caffeine, nicotine & alcohol, but it also seems to make other drugs, and medicines more potent in their effects. It also shares the properties of Ketamine’s antidepressant effects, via the mTOR AMPA pathway. A small study found a robust antidepressant effect; all patients reported remission of depression. Considering that, shutting down Serotonin production via parachlorophenylalanine, did not reverse the antidepressant effects, shows how punchy this substance is. It’s also a painkiller. I’d recommend this be added to everyone’s stack, provided they aren’t too fond of Alcohol, as I noticed it definitely seems to blunt the good feelings of certain drugs.” Reddit user


Frequently Asked Questions

What is Agmatine Sulfate?

Agmatine Sulfate is a biogenic amine that is derived from the amino acid L-Arginine. This happens by a process called decarboxylation, which is better known as the removal of carboxylic acid group from the amino acid.

Is Agmatine safe?

Yes. And here is a 5 year-long, daily high dosage of Agmatine in order to measure and proof its safety:

Clinical follow-up consists of periodic physical examinations and laboratory blood and urine analyses. All measurements thus far remain within normal values and good general health status is sustained throughout the study period, up to 5 years. This case study shows for the first time that the recommended high dosage of agmatine may be consumed for at least 5 years without evidence of any adverse effects. [R]

How long does Agmatine take to work?

Agmatine starts working as soon as it enters the bloodstream, which is typically 15 – 30 minutes after consumption. Users can expect to experience an increase in muscle pumps, vascularity and muscular endurance within this timeframe. [R]

How much Agmatine should I take?

The generally accepted daily dosage range for Agmatine Sulfate is between 250 mg and 2.5 grams. Avoid taking higher than necessary dosages to reduce the risk of side effects.

Can you take Agmatine with creatine?

This is the reason creatine and protein work so well together, in a nutshell. Bodybuilders can cut out the creatine middle man by supplementing with agmatine sulfate directly. … You take creatine to improve the protein effects. You take nitric oxide to improve the creatine effects.

Further Readings & Related Pages

  1. Agmatine – Wikipedia
  2. Agmatine – Scientific Review – Examine

Summary: N-Acetyl Cysteine (NAC) is a prodrug for L-cysteine, a precursor to the antioxidant glutathione, an essential antioxidant in the body. NAC supports glutathione replenishment which has been found to bind to the glutamate recognition sites of the NMDA and AMPA receptors. It also promotes healthy inflammatory responses.


Introduction

What is N-Acetyl Cysteine?

N-Acetyl Cysteine (also known as Acetylcysteine or NAC) is a prodrug for L-cysteine, a precursor to the antioxidant glutathione, an essential antioxidant in the body. NAC supports glutathione replenishment which has been found to bind to the glutamate recognition sites of the NMDA and AMPA receptors. It also promotes healthy inflammatory responses. Acetylcysteine was initially patented in 1960 and licensed for use in 1968. It is on the World Health Organization’s List of Essential Medicines and is easily accessible for a very affordable price.

“Acetylcysteine, also known as N-acetylcysteine, is a medication that is used to treat paracetamol overdose, and to loosen thick mucus in individuals with cystic fibrosis or chronic obstructive pulmonary disease. It can be taken intravenously, by mouth, or inhaled as a mist. Some people use it as a dietary supplement.” Wikipedia


Benefits & Effects

What Are The Benefits of N-Acetyl Cysteine? (NAC)

  1. Improves Cognitive Function
  2. Reduces Symptoms of Depression
  3. Helps Symptoms of Bipolar Disorder and Mania
  4. Reduces Symptoms of OCD (Obsessive Compulsive Disorder)
  5. Improves Male Fertility
  6. Boosts Skin Health
  7. May Improve Autism
  8. Reduces Muscle Fatigue
  9. Reduces Antibiotic Side Effects
  10. Reliefs ADHD Symptoms
  11. Other Benefits

Supporting Research:

N-Acetyl Cysteine Improves Cognitive Function

Combinations of NAC with other antioxidants improve cognition in both healthy older people and those with mild cognitive impairment. (R) (R)

NAC has many studies on enhancing cognitive function in Alzheimer’s, Parkinson’s, and schizophrenia. Currently, it’s under research for boosting cognitive performance after general anesthesia. (R)


N-Acetyl Cysteine Reduces Symptoms of Depression

NAC helps people with depression by balancing glutamate levels within the brain. Doing so, it reduces inflammation and increases the growth of new brain cells. R

In a study of more than 500 participants, NAC shows an improvement in symptoms of depression and overall functionality. At 2000mg per day, it improves mood in people diagnosed with depression. (R), (R)

NAC Helps Symptoms of Bipolar Disorder and Mania

NAC improves chronic health issues such as heart disease and hormonal imbalance in people with Bipolar Disorder. In a 6-month study, NAC indirectly shows to affect overall health, antioxidant and inflammation levels, as well as mood. (R)

Another study on 17 subjects with bipolar disorder, NAC shows improvements in low moods and reduction in overall associating symptoms after six months of supplementation. (R)

In a study of 15 individuals suffering from mania, NAC also shows improvement after a six-month regime. The group receiving NAC had a reduction in symptoms versus the one receiving placebo. However, mood swings seem to worsen as a result. (R)

NAC Reduces Symptoms of OCD (Obsessive Compulsive Disorder)

NAC balances glutamate levels as well as increases antioxidants within the brain. In a study of 44 subjects with OCD, a NAC dose of 2000mg added to standard medication shows to improve symptoms, even in severe cases. R

Another study of 48 subjects who didn’t respond to typical treatment, NAC shows to improve symptoms after a 3-month period safely. (R)

NAC is useful for obsessive-compulsive disorders according to extensive research. It shows promising benefits and has very few side-effects. (R)

Improves Male Fertility

In addition to helping women with PCOS (Polycystic ovary syndrome), NAC may help increase fertility in men. Oxidative stress damages the sperm’s DNA, which results in reducing fertility. (R)

A study done on 120 infertile men receiving NAC, improvements were notable in semen quality and antioxidant status after a period of three months. (R)

Other studies look at the fertility benefits of NAC in combination with other antioxidants such as B vitamins, vitamin C and D. The combination improves the sperm count in those with low sperm count. (R)

In an extensive study of almost 500 infertile men, NAC with selenium show improvement in fertility after a six month period. (R)

Sub-fertility Conditions

Some men are sub-fertile — they are less fertile without an apparent reason. In 84 of subfertile men trying to conceive, NAC combination supplement called Condensyl (with vitamins, zinc, fig extract, and vitamin E) increased pregnancy rates. It raises the “fertility potential” of subfertile men increasing the rate of successful pregnancy. (R)

The typical NAC dose for improving fertility in those studies was 600 mg/day.

NAC Boosts Skin Health

Interestingly, NAC can be used as a cream or gel to improve skin health. It boosts glutathione in the skin protecting it from damage. Furthermore, NAC reduces skin inflammation and normalizes skin cell division. It’s used for eczema, skin irritation, radiation-induced skin damage, wound healing, and acne. In a study of 100 participants, a 5% NAC gel shows to reduce mild to moderate acne. (R)

Overall, NAC skin formulations are promising and very safe. Case reports and animal studies support this wide range of skin benefits of NAC.

NAC May Improve Autism

NAC seems to benefit children with autism. In a study of 33 autistic children, NAC (900-2,700 mg/day) shows to reduce irritability after three months period. (R)

In 2 different studies with 80 autistic children, those receiving NAC as an add-on to their medication (risperidone) show less irritability and hyperactivity after two months period. (R), (R)

NAC Reduces Muscle Fatigue

Overall, NAC tends to help muscles improve blood flow during intense training as well as recover faster after a workout.

It also seems to help older individuals in improving fitness and enhancing endurance in athletes on the short-term. However, long-term NAC with exercise may prevent muscle recovery.

NAC Reduces Antibiotic Side Effects

Antibiotic side effects arise from free radicals damage. As a potent antioxidant, NAC (1,200 mg/day) reduces side effects, prevents kidney and ear damage from several strong antibiotics in 2 studies of 100 people. (RR)

NAC also protects the liver from the harmful effects of anti-tuberculosis drugs as shown in a study of 60 participants. Those receiving NAC show intact liver after treatment, while 40% of those who didn’t take NAC suffer liver damage. (R)

Reliefs ADHD Symptoms

In a study of nearly 100 ADHD participants, NAC shows to reduce ADHD symptoms in patients with as well as improving cognition, impulsivity, and overall symptoms.

Participants were receiving up to 5g per day during this study. (R)

Other Benefits

According to Health Line, the following are the 9 top benefits of NAC:

  1. Essential for Making the Powerful Antioxidant Glutathione
  2. Helps With Detoxification to Prevent or Diminish Kidney and Liver Damage
  3. May Improve Psychiatric Disorders and Addictive Behavior
  4. Helps Relieve Symptoms of Respiratory Conditions
  5. Boosts Brain Health by Regulating Glutamate and Replenishing Glutathione
  6. May Improve Fertility in Both Men and Women
  7. May Stabilize Blood Sugar By Decreasing Inflammation in Fat Cell
  8. May Reduce Heart Disease Risk by Preventing Oxidative Damage
  9. Ability to Boost Glutathione Levels May Improve Immune Function

Side Effects

What Are The Side Effects of NAC?

N-Acetyl Cysteine is a safe substance with very few known side effects. Although occasionally, it can cause nausea, diarrhea, or constipation.

Large doses in a mouse model showed that acetylcysteine could potentially cause damage to the heart and lungs. They found that acetylcysteine was metabolized to S-nitroso-N acetylcysteine (SNOAC), which increased blood pressure in the lungs and right ventricle of the heart (pulmonary artery hypertension) in mice treated with acetylcysteine.

The effect was similar to that observed following a 3-week exposure to an oxygen-deprived environment (chronic hypoxia).

The authors also found that SNOAC induced a hypoxia-like response in the expression of several important genes both in vitro and in vivo.

Wikipedia


Dosage


How To Take N-Acetyl Cysteine (NAC)?

The typical dose for general wellness and gut health is 500mg per day taken in the morning on an empty stomach 800to2,400mg are the most common across clinical studies. However, for a chronic health condition, consider a higher dose. Studies concerning addiction and mental health issues use doses closer to 3000 mg/day.

Daily doses should be taken at 2-3 times a day.