The SnackWell effect is a phenomenon whereby dieters will eat more low-calorie cookies, such as SnackWells, than they otherwise would for normal cookies.
Outline
Also known as moral license, it is also described as a term for the way people go overboard once they are given a free pass or the tendency of people to overconsume when eating more of low-fat food due to the belief that it is not fattening.
The term, which emerged as a reaction to dietary trends in the 1980s and 1990s, is also used for similar effects in other settings, such as energy consumption, where it is termed the “rebound effect”. For example, according to a 2008 study, people with energy-efficient washing machines wash more clothes. People with energy-efficient lights leave them on longer, and lose 5–12% of the expected energy savings of 80%.
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Creatine is a chemical found naturally in the body, and also in red meat and seafood. It is often used to improve exercise performance and muscle mass.
Creatine is involved in making energy for muscles, with approximately 95% of it being found in skeletal muscle. The majority of sports supplements in the US contain creatine. Individuals who have lower creatine levels when they start taking creatine seem to get more benefit than individuals who start with higher levels.
People commonly use creatine for improving exercise performance and increasing muscle mass, but it is also used for muscle cramps, fatigue, multiple sclerosis (MS), depression, and many other conditions – although there is no good scientific evidence to support most of these uses.
Creatine use is allowed by the International Olympic Committee (IOC) and the US National Collegiate Athletic Association (NCAA).
What is Creatine?
It is a combination of three different amino acids:
Glycine;
Arginine; and
Methionine.
Creatine is involved in a vast number of processes in the body. For example, it is a fundamental component in how your body creates its primary form of energy in muscle cells, the compound adenosine triphosphate (ATP). When muscles contract explosively, or for brief, intense work lasting no longer than 8-12 seconds, creatine (bonded with phosphoric acid as creatine phosphate) is how the muscle creates the energy necessary to do it.
It exists in a steady state with a similar compound named creatinine that can be measured in lab tests as a marker of kidney function.
It is passed out of your body in your urine.
This means your body must release stored creatine each day to keep normal levels, the amount depending on your muscle mass.
Although creatine is created naturally in your body, you must keep up your levels and do so through your daily diet.
What is the Role of Creatine?
Creatine is a fuel source.
Simply put, creatine helps to maintain a continuous supply of energy to working muscles by keep production up in working muscles.
Small amounts are also found in your heart, brain and other tissues.
The phosphate-bonded form of creatine is your body’s energy of first choice when performing anaerobic activity, for example lifting weights.
When your body is trying to create the compound that powers quick muscle contractions, ATP, it does so by ‘borrowing’ a phosphate molecule from phosphocreatine and combining it with another compound, adenosine diphosphate (ADP).
Only after a muscle has largely used up its store of phosphocreatine does it start to produce ATP from other sources, like glucose or fats.
A secondary function of creatine is to draw water into muscle cells, making them more hydrated.
What are our Sources of Creatine?
Most of the creatine in your body is created in the liver and kidneys, but the majority of it is stored in muscle tissue (approximately 95%).
As a healthy human body is capable of creating its own creatine – and it can also be easily obtained through a diet that contains animal products – it is not considered an ‘essential’ nutrient.
In a normal omnivorous /carnivorous diet, you consume one to two grams/day of creatine.
However, as dietary creatine generally comes from animal products, vegan and vegetarian fitness enthusiasts and professional athletes may not get as much creatine in their diet as those who eat dairy products, eggs, and/or meat.
This is one reason why creatine is often recommended as an important supplement for vegans and vegetarians.
What is it Used For?
Possibly Effective for:
Athletic Performance: Taking creatine by mouth seems to somewhat improve rowing, jumping, and soccer performance. It is not clear if it helps with sprinting, cycling, swimming, or tennis.
Disorders of Creatine Metabolism or Transport: Taking creatine by mouth daily can increase creatine levels in the brain in children and young adults with conditions called GAMT deficiency or AGAT deficiency. But taking creatine does not seem to improve brain creatine levels in children who have a disorder in which creatine is not transported properly.
Guanidinoacetate Methyltransferase (GMAT) deficiency is an inherited disorder that primarily affects the brain and muscles.
Arginine: Glycine Amidinotransferase (AGAT) deficiency is an inherited disorder that primarily affects the brain.
Muscle Strength: Taking creatine by mouth seems to somewhat improve muscle strength in both younger and older adults. It is not clear if applying creatine to the skin helps.
Sarcopenia (Age-Related Muscle Loss): Taking creatine by mouth for up to 12 weeks seems to improve muscle strength in older adults. It seems to work best when used along with exercise to build muscles.
Possibly Ineffective for:
Lou Gehrig Disease (Amyotrophic Lateral Sclerosis or ALS): Taking creatine by mouth does not seem to slow disease progression or improve survival in people with ALS.
An inherited brain disorder that affects movements, emotions, and thinking (Huntington Disease): Taking creatine by mouth does not improve symptoms in people with Huntington disease.
Osteopenia (Low Bone Mass): Taking creatine by mouth does not seem to slow or reduce bone loss in people with osteopenia.
There is interest in using creatine for a number of other purposes, but there is not enough reliable information to say whether it might be helpful.
What are the Side Effects?
When taken by mouth:
Creatine is likely safe for most people.
Doses up to 25 grams daily for up to 14 days have been safely used.
Lower doses up to 4-5 grams daily for up to 18 months have also been safely used.
Creatine is possibly safe when taken long-term.
Doses up to 10 grams daily for up to 5 years have been safely used.
Side effects might include dehydration, upset stomach, and muscle cramps.
When applied to the skin:
There is not enough reliable information to know if creatine is safe.
It might cause side effects such as redness and itching.
The majority of reported side effects (mild to moderate) are of weight gain, gastrointestinal distress, altered insulin production, inhibition of endogenous creatine synthesis, renal dysfunction, or dehydration in study participants.
Experts generally agree that there is sufficient evidence to be confident that 5 g/day of creatine is generally harmless to healthy adults, but there is not enough evidence to make an informed recommendation in favour or against doses higher than 5 g/day (Shao et al., 2006).
Are There Any Special Precautions or Warnings to Consider?
Pregnancy and breast-feeding:
Creatine is used as a dietary supplement to increase muscle mass and improve exercise performance.
Creatine is a normal component of human milk, supplying about 9% of the infant’s daily requirements.
Milk levels of creatine have not been measured after exogenous administration in humans.
Creatine is converted into creatinine in the mother’s and infant’s bodies.
It may increase the infant’s serum creatinine, which may alter estimations of the infant’s kidney function.
Some authors speculate that creatine supplementation of nursing mothers might help avoid creatine deficiency syndromes, but no studies are available that test this hypothesis.
Until more data are available, it is probably best to avoid creatine supplementation unless it is prescribed by a healthcare professional.
Children:
Creatine is possibly safe when taken by mouth, short-term.
Creatine 3-5 grams daily for 2-6 months has been taken safely in children 5-18 years of age.
Creatine 2 grams daily for 6 months has been taken safely in children 2-5 years of age.
Creatine 0.1-0.4 grams/kg daily for up to 6 months has been taken safely in both infants and children.
Creatine might make kidney disease worse in people who already have kidney disease.
If you have kidney disease, speak with a healthcare professional before using creatine.
Parkinson disease:
Caffeine and creatine taken together may make symptoms of Parkinson disease worse.
If you have Parkinson disease and take creatine, use caffeine with caution.
What about Dosage?
Creatine is found in foods such as meat and seafood. Creatine is also found in many different types of sports supplements.
In supplements (discussed below), creatine has most often been used by adults in a one-time loading dose of up to 20 grams by mouth daily for up to 7 days, followed by a maintenance dose of 2.25-10 grams daily for up to 16 weeks.
Speak with a healthcare provider to find out what type of product and dose might be best for a specific condition.
Interactions
A total of five (5) drugs are known to interact with creatine:
Minor:
Cimetidine.
Probenecid.
Trimethoprim.
These are all known to interfere with the kidney’s secretion of creatinine.
Moderate:
Entecavir: Using entecavir together with creatine may increase the blood levels of one or both medications.
Pemetrexed: Creatine may increase the blood levels of Pemetrexed. You may be more likely to develop serious side effects such as anaemia, bleeding problems, infections, and nerve damage when these medications are used together.
What about Creatine Monohydrate?
Creatine monohydrate, the most popular form of creatine supplements, is simply creatine with one molecule of water attached to it – hence the name monohydrate.
It is usually around 88-90% creatine by weight.
It is not a steroid, it is totally different and works in a different manner.
Its not a stimulant, although it is sometimes combined with stimulant ingredients (such as caffeine) in pre-workout formulas.
Supplementation and Fitness
More Work:
Supplementation with creatine serves to increase creatine stores and phosphocreatine availability in the body, resulting in faster ATP formation.
The understanding being that the more phosphocreatine you have, the more work you can accomplish before fatigue sets it.
Cell Hydration:
A secondary function of creatine is to draw water into muscle cells, making them more hydrated.
When muscle cells are hydrated a few things happen, the most notable being an increase in protein synthesis. Muscle protein synthesis (MPS) is the driving force behind adaptive responses to exercise and represents a widely adopted proxy for gauging chronic efficacy of acute interventions (i.e. exercise/nutrition).
This action of drawing water into the cell can make muscles look bigger or fuller (think weightlifters/bodybuilders).
Specifically, in an open-label clinical trial of creatine, Roitman et al. (2007) reported that two patients diagnosed with bipolar disorder exhibited hypomania or mania following daily supplementation with 3-5 g creatine.
In a clinical trial examining the effectiveness of creatine to enhance heavy resistance training, Volek et al. (2000) noted that two subjects reported feeling more aggressive and nervous after 1 week of creatine supplementation (25 g/day).
In rodents, Allen et al. (2010) observed increased depression-like behaviour in male rats supplemented with 4% creatine for five weeks, although this effect was not replicated in male rats in a follow-up study (Allen et al., in press).
Taken together, there remains the possibility that creatine can increase risk of mania or depression in susceptible individuals.
It is also possible that long-term high dosing of creatine alters creatine transporter function or creatine kinase activity in a manner that adversely affects emotional regulation.
Further research is required before definitive conclusions are drawn, but caution is warranted in at-risk individuals.
For a good outline of creatine metabolism and psychiatric disorders read Patricia Allen’s article here.
Have you ever wondered what coats your medications and vitamin/dietary/nutritional supplements? Well, it is an additive made from magnesium stearate.
“Magnesium stearate is widely used in the production of dietary supplement and pharmaceutical tablets, capsules and powders as well as many food products, including a variety of confectionery, spices and baking ingredients.” (Hobbs et al., 2017, p.554).
Magnesium stearate is a fine, light white powder that sticks to your skin and is greasy to the touch. It is a simple salt made up of two substances:
A saturated fat known stearic acid; and
The mineral magnesium.
Stearic acid can also be found in many foods, including:
Chicken;
Eggs;
Cheese;
Chocolate;
Walnuts;
Salmon;
Cotton seed oil;
Palm oil; and
Coconut oil.
Magnesium stearate is commonly added to many foods, pharmaceuticals, and cosmetics. In medications and vitamins, its primary purpose is to act as a lubricant. It may be derived from plants as well as animal sources.
What is it Used For?
It has been widely used for many decades in the food industry as an emulsifier, binder and thickener, as well as an anticaking, lubricant, release, and antifoaming agent.
It is present in many food supplements, confectionery, chewing gum, herbs and spices, and baking ingredients.
It is also commonly used as an inactive ingredient in the production of pharmaceutical tablets, capsules and powders.
It is useful because it has lubricating properties, preventing ingredients from sticking to manufacturing equipment during the compression of chemical powders into solid tablets; magnesium stearate is the most commonly used lubricant for tablets.
However, it might cause lower wettability and slower disintegration of the tablets and slower and even lower dissolution of the drug.
It can also be used efficiently in dry coating processes.
In the creation of pressed candies, magnesium stearate acts as a release agent and it is used to bind sugar in hard candies such as mints.
It is a common ingredient in baby formulas.
It is possible to create capsules without magnesium stearate, but it is more difficult to guarantee the consistency and quality of those capsules.
Other Names
Mangeniusm stearate has number of other names, approximately 45, including:
Magnesium Distearate.
Magnesium Octadecanoate.
Octadecanoic Acid, Magnesium Salt.
Dibasic Magnesium Stearate.
Stearic Acid, Magnesium Salt.
Magnesium Dioctadecanoate.
Synpro 90.
Petrac MG 20NF.
NS-M (Salt).
SM-P.
Synpro Magnesium Stearate 90.
HSDB 713.
Rashayan Magnesium Stearate.
How is it Manufactured/Made?
Molecular Formula: C36H70MgO4 or Mg(C18H35O2)2, it exists as a salt containing two stearate anions and a magnesium cation.
An anion has more electrons than protons, consequently giving it a net negative charge.
A cation has more protons than electrons, consequently giving it a net positive charge.
Magnesium stearate is produced by:
The reaction of sodium stearate (the sodium salt of stearic acid) with magnesium salts; or
Treating magnesium oxide with stearic acid.
Some nutritional supplements specify that the sodium stearate used in manufacturing magnesium stearate is produced from vegetable-derived stearic acid.
Magnesium stearate is a major component of bathtub rings. When produced by soap and hard water, magnesium stearate and calcium stearate both form a white solid insoluble in water, and are collectively known as soap scum.
What Does My Body Do With Magnesium?
Upon ingestion, magnesium stearate is dissolved into magnesium ion and stearic and palmitic acids.
Magnesium is absorbed primarily in the small intestine, and to a lesser extent, in the colon.
Magnesium is an essential mineral, serving as a cofactor for hundreds of enzymatic reactions and is essential for the synthesis of carbohydrates, lipids, nucleic acids and proteins, as well as neuromuscular and cardiovascular function.
The majority of magnesium content in the body is stored in bone and muscle.
A small amount (~1%) is present in serum and interstitial body fluid, mostly existing as a free cation while the remainder is bound to protein or exists as anion complexes.
The kidney is largely responsible for magnesium homeostasis and maintenance of serum concentration.
Excretion occurs primarily via the urine, but also occurs in sweat and breast milk.
Stearic and palmitic acids are products of the metabolism of edible oils and fats for which the metabolic fate has been well established.
These fatty acids undergo ß-oxidation to yield 2-carbon units which enter the tricarboxylic acid cycle (aka Krebs cycle and citric acid cycle, the second stage of cellular respiration) and the metabolic products are utilised and excreted.
How Much Can I Consume and What are the Risks?
The US Food and Drug Administration (FDA) has approved magnesium stearate for use as an additive in food and supplements, being classified (in the US) as generally recognised as safe (GRAS).
In the European Union (EU) and European Free Trade Agreement (EFTA) it is listed as food additive E470b.
In 1979, the FDA’s Subcommittee on GRAS Substances (SCOGS) reported, “There is no evidence in the available information on … magnesium stearate … that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when they are used at levels that are now current and in the manner now practiced, or which might reasonably be expected in the future.”
It is generally considered to have a “safe toxicity profile”. (Hobbs et al., 2017, p.554).
According to PubChem (a part of the The National Library of Medicine’s National Centre for Biotechnology Information), it is considered safe for consumption at amounts below 2,500 milligrams (mg) per kilogram per day. For a 150-pound (68 kg) adult, that equals 170,000 mg per day.
Capsule manufacturers typically use only small amounts of magnesium stearate in their products. When you take their products at the recommended dose, they do not contain enough magnesium stearate to cause negative side effects.
“Stearic acid typically ranges between 0.5-10 percent of the tablet weight while magnesium stearate typically represents 0.25-1.5 percent of the tablet weight. Therefore, in a 500 mg tablet, the amount of stearic acid would probably be about 25 mg, and magnesium stearate about 5 mg.” (Bruno, 2013, p.53).
What are the Health Risks of Magnesium Stearate?
Toxicology data from animal studies relevant to evaluation of magnesium stearate are lacking (e.g. doses that will not lead to a dietary imbalance, known composition of material tested, appropriate administration route, etc.).
There are also no human data related to magnesium stearate toxicity.
It has been noted that infants are particularly sensitive to the sedative effects of magnesium salts and that individuals with chronic renal impairment retained 15-30% of administered magnesium, which may cause toxicity.
Moreover, diarrhoea and other gastrointestinal effects have been observed with excessive magnesium intake resulting from use of various magnesium salts for pharmacological/medicinal purposes.
Many magnesium-containing food additives have been evaluated individually, but not collectively, for laxative effects.
With this in mind, it is important to understand what effect cumulative exposure to magnesium via food additives may have, although studies indicate a lack of genotoxic risk posed specifically by magnesium stearate consumed at current estimated dietary exposures.
PubChem also notes that it can be an irritant which may cause skin, eye, and respiratory irritation, as well as potentially causing long lasting harmful effects to aquatic life (although relates to the powder form and not capsule form).
Some people report having negative reactions to magnesium stearate and feel much better when they eliminate it. These people might have a sensitivity to it. It is possible to be allergic to magnesium stearate, and it can be difficult to avoid this food additive.
Alleged Health Risks Not Borne Out by the Science
Some people (mainly on the internet) claim that magnesium stearate suppresses your immune T-cell function and causes the cell membrane integrity in your helper T cells to collapse.
However, there is no scientific evidence to support those claims.
Generally, these claims have been made based on a single mouse study that was related to stearic acid, not magnesium stearate (Tebbey & Buttke, 1990).
Mice lack an enzyme in their T cells that humans have. This makes stearic acid safe for us to ingest. Human T-cells have the delta-9 desaturase enzyme required to convert stearic acid into oleic acid to avoid a toxic build-up.
Another factor to consider is that the study was conducted by bathing the mouse T-cells in stearic acid.
It is impossible to consume stearic acid in such humongous amounts through supplements.
Some people have also claimed that magnesium stearate might interfere with your body’s ability to absorb the contents of medication capsules.
Studies have found that although magnesium stearate may slow down dissolution and absorption in some cases, it does not affect the overall bioavailability of nutrients.
Gene Bruno (MS, MHS), writing in Vitamin Retailer in March 2013, gives a good outline on why the above two points are not borne out by the science.
Another claim is that magnesium stearate can form a biofilm in the intestines just as soaps containing calcium and magnesium stearates form soap scum in sinks and bathtubs.
The Human gut environment is completely different to that of a bathroom.
Human intestines have acids and enzymes that do not allow soap scum to accumulate.
And, soap scum is nothing like a biofilm – If anything, magnesium stearate can actually prevent the formation of biofilms.
What are the Alternatives to Magnesium Stearate?
Magnesium stearate and stearic acid are the most common lubricants used in pharmaceutical processes. However, there are other lubricants, including fatty acid esters, inorganic materials, and polymers.
Metallic Salts of Fatty Acids:
They are still the most dominant class of lubricants.
Magnesium stearate, calcium stearate, and zinc stearate are the three common metallic salts of fatty acids used.
Of these three lubricants, magnesium stearate is one of the most frequently used.
Fatty Acids:
These are also common lubricants, with stearic acid being the most popular one.
Chemically, stearic acid is a straight-chain saturated monobasic acid found in animal fats and in varying degrees in cotton seed, corn, and coco.
The commercial material of stearic acid has other minor fatty acid constituents such as myistic acid and palmitic acid.
Fatty Acid Esters:
Fatty acid esters, including glyceride esters (glyceryl monostearate, glyceryl tribehenate, and glyceryl dibehenate) and sugar esters (sorbitan monostearate and sucrose monopalmitate), are often used as lubricants in the preparation of solid dosage forms.
In particular, Compritol® 888 ATO is an effective lubricant to replace magnesium stearate when the latter causes delay of dissolution and other compatibility issues.
Inorganic Materials and Polymers:
Are used as lubricants when magnesium stearate is not appropriate.
In terms of inorganic materials, talc (a hydrated magnesium silicate (Mg3Si4O10(OH)2)), is often used as a lubricant or a glidant in formulations.
Similarly, polymers, such as PEG 4000, are occasionally used as lubricants in solid dosage forms when the use of magnesium stearate displays compression and chemical incompatibility issues.
Besides the conventional lubricants, manufacturers are also using natural-based lubricants (such as rice extract) or excipient premixes (such as cellulose/rice extract/oil/wax).
Summary
The benefits of using magnesium stearate in supplements far outweigh the potential risks. And, apart from ensuring a homogenous mixture of active ingredients and accurate, consistent dosage, magnesium stearate has several health benefits of its own. As an essential mineral, magnesium is crucial for more than 300 enzyme reactions occurring in the human body. Stearic acid is known to lower LDL cholesterol and improve heart function.
Hobbs, C.A., Saigo, K., Koyanagi, M. & Hayashi, S-M. (2017) Magnesium Stearate, A Widely-Used Food Additive, Exhibits a Lack of In Vitro and In Vivo Genotoxic Potential. Toxicology Reports. 4, pp.554-559. doi: 10.1016/j.toxrep.2017.10.003.
Li, J. & Wu, Y. (2014) Lubricants in Pharmaceutical Sold Dosage Forms. Lubricants. 2, pp.21-43. doi:10.3390/lubricants2010021.
gamma-Aminobutyric acid (or γ-aminobutyric acid or GABA), is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system.
GABA is sold as a dietary supplement in many countries. It has been traditionally thought that exogenous GABA (i.e. taken as a supplement) does not cross the blood-brain barrier, however data obtained from more current research indicates that it may be possible.
Brief History
In 1883, GABA was first synthesized, and it was first known only as a plant and microbe metabolic product.
In 1950, GABA was discovered as an integral part of the mammalian central nervous system.
In 1959, it was shown that at an inhibitory synapse on crayfish muscle fibres GABA acts like stimulation of the inhibitory nerve. Both inhibition by nerve stimulation and by applied GABA are blocked by picrotoxin.
GABAA in which the receptor is part of a ligand-gated ion channel complex; and
GABAB metabotropic receptors, which are G protein-coupled receptors that open or close ion channels via intermediaries (G proteins).
Neurons that produce GABA as their output are called GABAergic neurons, and have chiefly inhibitory action at receptors in the adult vertebrate. Medium spiny cells are a typical example of inhibitory central nervous system GABAergic cells. In contrast, GABA exhibits both excitatory and inhibitory actions in insects, mediating muscle activation at synapses between nerves and muscle cells, and also the stimulation of certain glands. In mammals, some GABAergic neurons, such as chandelier cells, are also able to excite their glutamatergic counterparts.
Release, Reuptake, and Metabolism Cycle of GABA.
GABAA receptors are ligand-activated chloride channels: when activated by GABA, they allow the flow of chloride ions across the membrane of the cell. Whether this chloride flow is depolarising (makes the voltage across the cell’s membrane less negative), shunting (has no effect on the cell’s membrane potential), or inhibitory/hyperpolarising (makes the cell’s membrane more negative) depends on the direction of the flow of chloride. When net chloride flows out of the cell, GABA is depolarising; when chloride flows into the cell, GABA is inhibitory or hyperpolarising. When the net flow of chloride is close to zero, the action of GABA is shunting. Shunting inhibition has no direct effect on the membrane potential of the cell; however, it reduces the effect of any coincident synaptic input by reducing the electrical resistance of the cell’s membrane. Shunting inhibition can “override” the excitatory effect of depolarising GABA, resulting in overall inhibition even if the membrane potential becomes less negative. It was thought that a developmental switch in the molecular machinery controlling the concentration of chloride inside the cell changes the functional role of GABA between neonatal and adult stages. As the brain develops into adulthood, GABA’s role changes from excitatory to inhibitory.
Brain Development
While GABA is an inhibitory transmitter in the mature brain, its actions were thought to be primarily excitatory in the developing brain. The gradient of chloride was reported to be reversed in immature neurons, with its reversal potential higher than the resting membrane potential of the cell; activation of a GABA-A receptor thus leads to efflux of Cl− ions from the cell (that is, a depolarising current). The differential gradient of chloride in immature neurons was shown to be primarily due to the higher concentration of NKCC1 co-transporters relative to KCC2 co-transporters in immature cells. GABAergic interneurons mature faster in the hippocampus and the GABA signalling machinery appears earlier than glutamatergic transmission. Thus, GABA is considered the major excitatory neurotransmitter in many regions of the brain before the maturation of glutamatergic synapses.
In the developmental stages preceding the formation of synaptic contacts, GABA is synthesized by neurons and acts both as an autocrine (acting on the same cell) and paracrine (acting on nearby cells) signalling mediator. The ganglionic eminences also contribute greatly to building up the GABAergic cortical cell population.
GABA regulates the proliferation of neural progenitor cells, the migration and differentiation the elongation of neurites and the formation of synapses.
GABA also regulates the growth of embryonic and neural stem cells. GABA can influence the development of neural progenitor cells via brain-derived neurotrophic factor (BDNF) expression. GABA activates the GABAA receptor, causing cell cycle arrest in the S-phase, limiting growth.
Beyond the Nervous System
Besides the nervous system, GABA is also produced at relatively high levels in the insulin-producing β-cells of the pancreas. The β-cells secrete GABA along with insulin and the GABA binds to GABA receptors on the neighbouring islet α-cells and inhibits them from secreting glucagon (which would counteract insulin’s effects).
GABA can promote the replication and survival of β-cells and also promote the conversion of α-cells to β-cells, which may lead to new treatments for diabetes.
Alongside GABAergic mechanisms, GABA has also been detected in other peripheral tissues including intestines, stomach, Fallopian tubes, uterus, ovaries, testes, kidneys, urinary bladder, the lungs and liver, albeit at much lower levels than in neurons or β-cells.
Experiments on mice have shown that hypothyroidism induced by fluoride poisoning can be halted by administering GABA. The test also found that the thyroid recovered naturally without further assistance after the Fluoride had been expelled by the GABA.
Immune cells express receptors for GABA and administration of GABA can suppress inflammatory immune responses and promote “regulatory” immune responses, such that GABA administration has been shown to inhibit autoimmune diseases in several animal models.
In 2018, GABA has shown to regulate secretion of a greater number of cytokines. In plasma of T1D patients, levels of 26 cytokines are increased and of those, 16 are inhibited by GABA in the cell assays.
In 2007, an excitatory GABAergic system was described in the airway epithelium. The system is activated by exposure to allergens and may participate in the mechanisms of asthma. GABAergic systems have also been found in the testis and in the eye lens.
GABA occurs in plants.
Structure and Conformation
GABA is found mostly as a zwitterion (i.e. with the carboxyl group deprotonated and the amino group protonated). Its conformation depends on its environment. In the gas phase, a highly folded conformation is strongly favoured due to the electrostatic attraction between the two functional groups. The stabilisation is about 50 kcal/mol, according to quantum chemistry calculations. In the solid state, an extended conformation is found, with a trans conformation at the amino end and a gauche conformation at the carboxyl end. This is due to the packing interactions with the neighbouring molecules. In solution, five different conformations, some folded and some extended, are found as a result of solvation effects. The conformational flexibility of GABA is important for its biological function, as it has been found to bind to different receptors with different conformations. Many GABA analogues with pharmaceutical applications have more rigid structures in order to control the binding better.
Biosynthesis
GABA is primarily synthesized from glutamate via the enzyme glutamate decarboxylase (GAD) with pyridoxal phosphate (the active form of vitamin B6) as a cofactor. This process converts glutamate (the principal excitatory neurotransmitter) into GABA (the principal inhibitory neurotransmitter).
GABA can also be synthesized from putrescine by diamine oxidase and aldehyde dehydrogenase.
Traditionally it was thought that exogenous GABA did not penetrate the blood–brain barrier, however more current research indicates that it may be possible, or that exogenous GABA (i.e. in the form of nutritional supplements) could exert GABAergic effects on the enteric nervous system which in turn stimulate endogenous GABA production. The direct involvement of GABA in the glutamate-glutamine cycle makes the question of whether GABA can penetrate the blood-brain barrier somewhat misleading, because both glutamate and glutamine can freely cross the barrier and convert to GABA within the brain.
Metabolism
GABA transaminase enzymes catalyse the conversion of 4-aminobutanoic acid (GABA) and 2-oxoglutarate (α-ketoglutarate) into succinic semialdehyde and glutamate. Succinic semialdehyde is then oxidized into succinic acid by succinic semialdehyde dehydrogenase and as such enters the citric acid cycle as a usable source of energy.
Pharmacology
Drugs that act as allosteric modulators of GABA receptors (known as GABA analogues or GABAergic drugs), or increase the available amount of GABA, typically have relaxing, anti-anxiety, and anti-convulsive effects. Many of the substances below are known to cause anterograde amnesia and retrograde amnesia.
In general, GABA does not cross the blood-brain barrier, although certain areas of the brain that have no effective blood–brain barrier, such as the periventricular nucleus, can be reached by drugs such as systemically injected GABA. At least one study suggests that orally administered GABA increases the amount of human growth hormone (HGH). GABA directly injected to the brain has been reported to have both stimulatory and inhibitory effects on the production of growth hormone, depending on the physiology of the individual. Certain pro-drugs of GABA (e.g. picamilon) have been developed to permeate the blood-brain barrier, then separate into GABA and the carrier molecule once inside the brain. Prodrugs allow for a direct increase of GABA levels throughout all areas of the brain, in a manner following the distribution pattern of the pro-drug prior to metabolism.
GABA enhanced the catabolism of serotonin into N-acetylserotonin (the precursor of melatonin) in rats. It is thus suspected that GABA is involved in the synthesis of melatonin and thus might exert regulatory effects on sleep and reproductive functions.
Chemistry
Although in chemical terms, GABA is an amino acid (as it has both a primary amine and a carboxylic acid functional group), it is rarely referred to as such in the professional, scientific, or medical community. By convention the term “amino acid”, when used without a qualifier, refers specifically to an alpha amino acid. GABA is not an alpha amino acid, meaning the amino group is not attached to the alpha carbon. Nor is it incorporated into proteins as are many alpha-amino acids.
GABAergic Drugs
GABAA receptor ligands are shown in the following table.
Neuroactive steroids (Pregnenolone sulfate), furosemide, oenanthotoxin, and amentoflavone.
Additionally, carisoprodol is an enhancer of GABAA activity. Ro15-4513 is a reducer of GABAA activity
GABAergic pro-drugs include chloral hydrate, which is metabolised to trichloroethanol, which then acts via the GABAA receptor.
Skullcap and valerian are plants containing GABAergic substances[citation needed]. Furthermore, the plant kava contains GABAergic compounds, including kavain, dihydrokavain, methysticin, dihydromethysticin and yangonin.
Other GABAergic modulators include:
GABAB receptor ligands.
Agonists: baclofen, propofol, GHB, and phenibut.
Antagonists: phaclofen and saclofen.
GABA reuptake inhibitors: deramciclane, hyperforin, and tiagabine.
GABA analogues: pregabalin, gabapentin, picamilon, and progabide.
In Plants
GABA is also found in plants. It is the most abundant amino acid in the apoplast of tomatoes. Evidence also suggests a role in cell signalling in plants.
Development and validation of a UPLC-MS/MS method for the simultaneous determination of gamma-aminobutyric acid and glutamic acid in human plasma.
Background
Gamma-aminobutyric acid (GABA) and its precursor glutamic acid are important neurotransmitters. Both are also present in peripheral tissues and the circulation, where abnormal plasma concentrations have been linked to specific mental disorders. In addition to endogenous synthesis, GABA and glutamic acid can be obtained from dietary sources.
An increasing number of studies suggest beneficial cardio-metabolic effects of GABA intake, and therefore GABA is being marketed as a food supplement.
The need for further research into their health effects merits accurate and sensitive methods to analyse GABA and glutamic acid in plasma.
Methods
To this end, an ultra-pressure liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of GABA and glutamic acid in human plasma.
Samples were prepared by a protein precipitation step and subsequent solid phase extraction using acetonitrile.
Results
Chromatographic separation was achieved on an Acquity UPLC HSS reversed phase C18 column using gradient elution. Analytes were detected using electrospray ionisation and selective reaction monitoring. Standard curve concentrations for GABA ranged from 3.4 to 2500 ng/mL and for glutamic acid from 30.9 ng/mL to 22,500 ng/mL. Within- and between-day accuracy and precision were <10% in quality control samples at low, medium and high concentrations for both GABA and glutamic acid. GABA and glutamic acid were found to be stable in plasma after freeze-thaw cycles and up to 12 months of storage. The validated method was applied to human plasma from 17 volunteers. The observed concentrations ranged between 11.5 and 20.0 ng/ml and 2269 and 7625 ng/ml for respectively GABA and glutamic acid.
Conclusions
The reported method is well suited for the measurement of plasma GABA and glutamic acid in pre-clinical or clinical studies.
Reference
de Bie, T.H., Witkamp, R.F., Jongsma, M.A. & Balvers, M.G.J. (2021) Development and validation of a UPLC-MS/MS method for the simultaneous determination of gamma-aminobutyric acid and glutamic acid in human plasma. Journal of Chromatography. doi: 10.1016/j.jchromb.2020.122519. Online ahead of print.
Linda Cowan is a counsellor/therapist; she has worked at her Private Practice for many years.
Linda has drawn on the experience she has learnt over the years to inspire her to write her new book, ‘Travel Light a Handbook for Mental Health’.
Linda acknowledges that not everyone has access to private therapy (this book is not a substitute for personal therapy) however, it will go a long way to help people understand themselves in a way they have never before. If you are: tormented by anxiety- doubts and self-critical thoughts- stressed and overwhelmed by unhealthy addictive behaviours – weighed down by the mental clutter of unforgiveness, anger and shame.
This book is for you; Whether you have a strong faith or no faith, this book will transform and revolutionise your life. You will learn to find peace in a frantic world.
Brain Changer: How diet can save your mental health – cutting-edge science from an expert.
Author(s): Felice Jacka.
Year: 2019.
Edition: First (1st).
Publisher: Yellow Kite.
Type(s): Paperback, Audiobook, and Kindle.
Synopsis:
A combination of Professor Felice Jacka’s love of food and her own experience of depression and anxiety as a young woman led her to question whether what we put in our mouths everyday affects more than our waistline. Felice set out on a journey of discovery to change the status quo and uncover the truth through rigorous science. Beginning her PhD in 2005, she examined the association between women’s diets and their mental health, focusing on depression and anxiety. She soon discovered – you feel how you eat. It is Professor Jacka’s ground-breaking research that has now changed the way we think about mental and brain health in relation to diet.
Brain Changer explains how and why we should consider our food as the basis of our mental and brain health throughout our lives. It includes a selection of recipes and meal plans featuring ingredients beneficial to mental health. It also includes the simple, practical solutions we can use to help prevent mental health problems in the first place and offers strategies for treating these problems if they do arise.
This is not a diet book to help you on the weight scales. This is a guide to good habits to save your brain and to optimise your mental health through what you eat at every stage of life.
The Effect of Nutrition on Mental Health: A Focus on Inflammatory Mechanisms.
Background
Neuropsychiatric disorders are closely associated with a persistent low-grade inflammatory state.
This suggests that the development of psychopathology is not only limited to the brain, but rather involves an additional systemic aspect, accounting for the large body of evidence demonstrating co-presentation of mental illness with chronic inflammatory conditions and metabolic syndromes.
Studies have shown that inflammatory processes underlie the development of neuropsychiatric symptoms, with recent studies revealing not only correlative, but causative relationships between the immune system and psychopathology.
Lifestyle factors such as diet and exercise may influence psychopathology, and this may occur via a bidirectional relationship.
Mental illness may prevent health-seeking behaviours such as failing to maintain a balanced diet, whilst adopting a ‘healthy’ diet rich in fruits, vegetables and fish alongside nutritional supplementation correlates with a reduction in psychiatric symptoms in patients.
Obesity and the gut microbiome have proven to be further factors which play an important role in inflammatory signalling and the development of psychiatric symptoms.
In a related paper the authors focus on the role of exercise (another significant lifestyle factor) on mental health (Venkatesh et al. 2020).
Conclusions
Lifestyle modifications which target diet and nutrition may prove therapeutically beneficial for many patients, especially in treatment-resistant subgroups.
The current evidence base provides equivocal evidence, however future studies will prove significant, as this is a highly attractive therapeutic avenue, due to its cost efficacy, low side effect profile and preventative potential.
By promoting lifestyle changes and addressing the limitations and barriers to adoption, these therapies may prove revolutionary for mental health conditions.
Reference
Edirappuli, S.D., Venkatesh, A. & Zaman, R. (2020) The Effect of Nutrition on Mental Health: A Focus on Inflammatory Mechanisms. Psychiatria Danubina. 32(Suppl 1), pp.114-120.
The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials.
Background
The role of nutrition in mental health is becoming increasingly acknowledged. Along with dietary intake, nutrition can also be obtained from “nutrient supplements”, such as polyunsaturated fatty acids (PUFAs), vitamins, minerals, antioxidants, amino acids and pre/probiotic supplements.
Recently, a large number of meta-analyses have emerged examining nutrient supplements in the treatment of mental disorders.
Methods
To produce a meta-review of this top-tier evidence, the researchers identified, synthesised and appraised all meta-analyses of randomised controlled trials (RCTs) reporting on the efficacy and safety of nutrient supplements in common and severe mental disorders.
Results
Their systematic search identified 33 meta-analyses of placebo-controlled RCTs, with primary analyses including outcome data from 10,951 individuals. The strongest evidence was found for PUFAs (particularly as eicosapentaenoic acid) as an adjunctive treatment for depression.
More nascent evidence suggested that PUFAs may also be beneficial for attention-deficit/hyperactivity disorder, whereas there was no evidence for schizophrenia.
Folate-based supplements were widely researched as adjunctive treatments for depression and schizophrenia, with positive effects from RCTs of high dose methylfolate in major depressive disorder.
There was emergent evidence for N-acetylcysteine as a useful adjunctive treatment in mood disorders and schizophrenia.
All nutrient supplements had good safety profiles, with no evidence of serious adverse effects or contraindications with psychiatric medications.
Conclusions
In conclusion, clinicians should be informed of the nutrient supplements with established efficacy for certain conditions (such as eicosapentaenoic acid in depression), but also made aware of those currently lacking evidentiary support.
Future research should aim to determine which individuals may benefit most from evidence-based supplements, to further elucidate the underlying mechanisms.
Reference
Firth, J., Teasdale, S.B., Allott, K., Siskind, D., Marz, W., Cotter, J., Veronese, N., Schuch, F., Smith, L., Solmi, M., Carvalho, A.F., Vancampfort, D., Berk, M., Stubbs, B> & Sarris, J. (2019) The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta-review of meta-analyses of randomized controlled trials. World Psychiatry. 18, pp.308-324.
Mental Health Matters 
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