Theanine and Caffeine: the yin-yang of green tea and brain waves

Theanine was discovered in 1949 by the Japanese researcher Yajiro Sakato1, as a new amide in the water extract of the Japanese green tea Gyokuro (玉 露) – also called “precious dew” due to its dark green colour and high price in Japanese markets, because of its unique characteristic taste of sweetness and “umami”2.

The green tea leaves from specialized varieties of the tea plant Camellia sinensis (Ericales plants) have enormous amounts of theanine, which they absorb from the roots of the plant depending on the nitrogen supply of the soil3, 4. A soil that is rich in nitrogen will promote the biosynthesis of the non-protein aminoacid L-Theanine from Glutamic Acid and Ethylamine (by the enzyme theanine synthetase)2. Since the commercial price of green tea is almost directly proportional to its theanine content, to obtain theanine-rich, good quality green tea leaves, a large amount of nitrogen fertilizer must be supplied to the cultivated plants throughout the growth period (with problematic effects on the environment)2.

Theanine is then transported via the xylem fluid, from the roots to the young bushes leaves. And, because light is necessary to the conversion of theanine into cathechins in the leaves of the plant, when Camellia sinensis bushes are protected from direct sunlight for a couple of weeks just before harvest, they have a high theanineamino acid content2. Even though cathechins are polyphenols with known antioxidant properties, they are also responsible for the astringent flavour of green tea. So, for an optimum taste, cathechins must be balanced with theanines. With less sunlight, there is less photosynthesis and leaf senescence; and, less theanine being converted into catechin, keeping the unique sweet-umami flavor characteristic of Gyokuro green tea.

Theanine is also known as N5-ethyl-L-glutamine due to its structural similarities to L-glutamic acid, which is the most abundant excitatory neurotransmitter in our brains5. Researchers think that L-theanine mechanism of action might be mediated by glutamate receptors, and it might act as a partial agonist for the N-methyl-D-aspartate receptor6

Theanine has known relaxing and anxiolytic effects, via the induction of the slow alpha-brain waves in the occipital and parietal regions of the human brain7. Plus, it doesn’t have any additive or side effects that are usually associated with conventional sleep inducers. 

There is only one IF…. 

In addition to L-TheanineCamellia sinensis leaves grown in the shade also have a high level of caffeine8, which decreases slow brain activity and keeps us awake (by increasing beta-wave activity). This because, the buds and young leaves of Camellia plants contain more caffeine than mature leaves8. As such, besides a high level of theanineGyokuro or Matcha green tea powder (which goes through the same shade process before harvest), also have high levels of caffeine

What is interesting, is that this dual effect of L-Theanine and Caffeine in Gyokuro or Matcha green tea powder, seem to have a synergistic effect in decreasing mind wandering and enhancing our attention to target stimuli9, 10. This was shown in a very small randomized clinical trial, that used functional Magnetic Resonance Imaging (fMRI) to scan the brains of subjects, after they ingested L-Theanine and Caffeine supplements while performing a visual task. 

So, if we want to focus and stay awake: a cup of Gyokuro or Matcha, will keep our attention sharp as a Japanese sword. 

If, on the other hand, we are not feeling very calm, anxiety is setting in, or if sleep is taking too long because the news are only “so-so” at the moment: 200-400mg of L-theanine could help us keep the zen mood, and have a good night sleep11.

The discovery of Theanine


1.         Sakato Y. Studies on the Chemical Constituents of Tea

Part III. On a New Amide <b>Theanine</b>. Nippon Nōgeikagaku Kaishi. 1950;23:262-267.

2.         Ashihara H. Occurrence, biosynthesis and metabolism of theanine (γ-glutamyl-L-ethylamide) in plants: a comprehensive review. Nat Prod Commun. 2015;10:803-10.

3.         Ruan J, Haerdter R and Gerendás J. Impact of nitrogen supply on carbon/nitrogen allocation: a case study on amino acids and catechins in green tea [Camellia sinensis (L.) O. Kuntze] plants. Plant Biol (Stuttg). 2010;12:724-34.

4.         Huang H, Yao Q, Xia E and Gao L. Metabolomics and Transcriptomics Analyses Reveal Nitrogen Influences on the Accumulation of Flavonoids and Amino Acids in Young Shoots of Tea Plant ( Camellia sinensis L.) Associated with Tea Flavor. J Agric Food Chem. 2018;66:9828-9838.

5.         Unno K, Furushima D, Hamamoto S, Iguchi K, Yamada H, Morita A, Horie H and Nakamura Y. Stress-Reducing Function of Matcha Green Tea in Animal Experiments and Clinical Trials. Nutrients. 2018;10:1468.

6.         Sebih F, Rousset M, Bellahouel S, Rolland M, de Jesus Ferreira MC, Guiramand J, Cohen-Solal C, Barbanel G, Cens T, Abouazza M, Tassou A, Gratuze M, Meusnier C, Charnet P, Vignes M and Rolland V. Characterization of l-Theanine Excitatory Actions on Hippocampal Neurons: Toward the Generation of Novel N-Methyl-d-aspartate Receptor Modulators Based on Its Backbone. ACS Chem Neurosci. 2017;8:1724-1734.

7.         Kobayashi K, Nagato Y, Aoi N, Juneja LR, Kim M, Yamamoto T and Sugimoto S. Effects of L-Theanine on the Release of &alpha;-Brain Waves in Human Volunteers. Nippon Nōgeikagaku Kaishi. 1998;72:153-157.

8.         Ashihara H and Suzuki T. Distribution and biosynthesis of caffeine in plants. Front Biosci. 2004;9:1864-76.

9.         Kahathuduwa CN, Dhanasekara CS, Chin SH, Davis T, Weerasinghe VS, Dassanayake TL and Binks M. l-Theanine and caffeine improve target-specific attention to visual stimuli by decreasing mind wandering: a human functional magnetic resonance imaging study. Nutr Res. 2018;49:67-78.

10.       Hidese S, Ogawa S, Ota M, Ishida I, Yasukawa Z, Ozeki M and Kunugi H. Effects of L-Theanine Administration on Stress-Related Symptoms and Cognitive Functions in Healthy Adults: A Randomized Controlled Trial. Nutrients. 2019;11:2362.

11.       Williams JL, Everett JM, D’Cunha NM, Sergi D, Georgousopoulou EN, Keegan RJ, McKune AJ, Mellor DD, Anstice N and Naumovski N. The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review. Plant Foods Hum Nutr. 2020;75:12-23.

Feeling anxious or depressed? Might be your microglia…

A macrophage is a hungry immune cell that engulfs and eats all things that don’t have a good reputation in our body (e.g., cellular debris, pathogens…); and, microglia cells are the resident macrophage population of the Central Nervous System (CNS)1. They function as sentinels of local infection in the brain, backing both innate and adaptive immune responses, and account for 10-15% of all cells found in the brain and spinal cord2.

Microglia cells are also involved in the maintenance of brain homeostasis, contributing to mechanisms that underly learning and memory. They constantly survey their local microenvironment – like patrols – extending their motile processes, or hands/legs, to make a brief contact with neuronal synapses. This continuous synaptic plasticity, throughout our lifetime, is essential to control maladaptive learning and memory, such as addiction3. For example, the number of synapses in the brain regions of the nucleus accumbensamygdala and dorsomedial striatum increase when we expose our brains to addictive substances (such as alcohol, or opiates); and, decrease upon withdrawal due to the action of microglia cells4. As such, microglia cells help to modify and eliminate synaptic structures when they grow too much, or, are on the way to touch too many other neurons5 – because, neurons tend to be touchy and to enjoy a synaptic orgy. 

Whenever a neuron starts to freak out that it has too many synapses and it needs help regulating its neuronal “touchy” behaviour, then the synapse extends a greeting “hand” (filopodia) and “Hi5s” the neighbouring microglia cell, telling her that it needs help remodelling. Once “Hi5ed”, the microglia cell starts nibbling on the synapse6 – cutting all the excess – and, avoiding that that specific neuron gets assigned a bad “sexual” reputation. It’s like behaviour counselling, transforming and remodelling, but neuron-wise and with a microglia cell as the counsellor…

Even though microglia cells are essential and extremely helpful; like everything in life, they can also go haywire, ending up pruning too many synapses, and destroying healthy tissue. An uncontrolled activation of the microglia can be directly toxic to neurons, because they can release inflammatory cytokines (IL-1, TNF-alpha, IL-6, Nitric Oxide, Prostaglandine E2, and Superoxide)7, and lead to excessive pruning of neuronal synapses3.

The most recent research in the pathophysiology of depression and anxiety shows that abnormalities in microglia cells have a central role in the development of these diseases8. For example, a neuroimaging study in depressed patients, revealed that stronger depressive symptoms related with microglial activation in brain regions associated with mood regulation (the prefrontalanterior cingulate, and insular cortices of the brain)9. Additionally, post-mortem studies of depressed suicide victims showed microglial activation and macrophage accumulation within the anterior cingulate cortex brain region10

Persistent stress activates a chronic low-inflammatory state in our bodies that enhances our inflammatory response to challenges11. Social stress causes the release of inflammatory monocytes into the circulation8, which end up reaching the Blood Brain Barrier (BBB) and its endothelial cells. This low-systemic inflammation that travels through our vessels, encourages the migration of the brain resident microglia cells to the area of the cerebral vessels. In here, microglia cells make physical contact with endothelial cells of the BBB, and “sense” the inflammatory environment that is present in the blood (aka, inflammatory cytokines activate receptors in the microglia cells). If there is sustained inflammation, then some of the microglia cells can “become neurotic” and start nibbling the end-feet of healthy cells, making the BBB more permeable and, consequently, damaging the protective BBB shield function12. This is turn, leaks inflammatory cytokines from the blood into the brain tissue, further activating more microglia cells, that start cutting synapses from healthy neurons.

What this means is that a persistent low-grade inflammation can trigger microglia activation and change the functional connectivity of healthy neurons in major brain emotional centers13. Because our immune system can interact with the neurocircuitry that is involved in emotion regulation and behaviour, a chronic low-inflammation derived from stress can influence the development of various neuropsychiatric disorders, like depression and anxiety. 

But, what can we do to avoid falling in this trap?

Eat well, sleep well, do sports and have a good laugh with friends. All things that inhibit inflammation, and make us feel good. 

Microglia cell (green) “counselling” a synapse


1.         Ginhoux F, Lim S, Hoeffel G, Low D, Huber T. Origin and differentiation of microglia. Frontiers in Cellular Neuroscience. 2013;7

2.         Lawson LJ, Perry VH, Gordon S. Turnover of resident microglia in the normal adult mouse brain. Neuroscience. 1992;48:405-415

3.         Neniskyte U, Gross CT. Errant gardeners: Glial-cell-dependent synaptic pruning and neurodevelopmental disorders. Nat Rev Neurosci. 2017;18:658-670

4.         Spiga S, Talani G, Mulas G, Licheri V, Fois GR, Muggironi G, et al. Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats. Proc Natl Acad Sci U S A. 2014;111:E3745-3754

5.         Tremblay M-È, Lowery RL, Majewska AK. Microglial interactions with synapses are modulated by visual experience. PLOS Biology. 2010;8:e1000527

6.         Weinhard L, di Bartolomei G, Bolasco G, Machado P, Schieber NL, Neniskyte U, et al. Microglia remodel synapses by presynaptic trogocytosis and spine head filopodia induction. Nature Communications. 2018;9:1228

7.         Kim YS, Joh TH. Microglia, major player in the brain inflammation: Their roles in the pathogenesis of parkinson’s disease. Exp Mol Med. 2006;38:333-347

8.         McKim DB, Weber MD, Niraula A, Sawicki CM, Liu X, Jarrett BL, et al. Microglial recruitment of il-1β-producing monocytes to brain endothelium causes stress-induced anxiety. Mol Psychiatry. 2018;23:1421-1431

9.         Setiawan E, Wilson AA, Mizrahi R, Rusjan PM, Miler L, Rajkowska G, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA Psychiatry. 2015;72:268-275

10.       Suzuki H, Ohgidani M, Kuwano N, Chrétien F, Lorin de la Grandmaison G, Onaya M, et al. Suicide and microglia: Recent findings and future perspectives based on human studies. Frontiers in cellular neuroscience. 2019;13:31-31

11.       Miller GE, Rohleder N, Cole SW. Chronic interpersonal stress predicts activation of pro- and anti-inflammatory signaling pathways 6 months later. Psychosom Med. 2009;71:57-62

12.       Haruwaka K, Ikegami A, Tachibana Y, Ohno N, Konishi H, Hashimoto A, et al. Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nature communications. 2019;10:5816-5816

13.       Kim J, Yoon S, Lee S, Hong H, Ha E, Joo Y, et al. A double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms. Nature Communications. 2020;11:1898

Clogged Synapses: better call the mailman (or have a shut eye)

Sleep is fundamental for our brain.

Our ability to learn and memorize new things profits from sleep; and, sleep loss leads to cognitive impairment that can only be reversed by closing our eyes and sleeping1. The more time we spend awake, and the further we engage with learning activities, the more our brains will demand for sleep. 

The synapse is the structure that allows the neuron (or nerve cell) to pass an electrical or chemical signal to another neuron, or to the end effector cell that produces the action demanded from our brain. Synapses are the foundation of neuronal plasticity, and, in the adult brain, synapses can change their strength and size within minutes or hours in response to a new experience and learning1. Recent research has shown that the need for sleep and synaptic function are strongly linked together.

Sarah B. Noya and her colleagues2 from the Institute of Pharmacology and Toxicology of the University of Zürich (Switzerland) have recently shown that 70% of the synaptic transcripts change during our 24h circadian cycles. The transcripts and proteins related to synaptic signaling, accumulate before the active phase of the bodies and get further cleared out during the day.  In the meantime, proteins that are associated with the body metabolism and translation, accumulate in the synapses just before the resting phase or sleeping time. As such, just before we go to bed, the synapses get congested with protein information from our bodies daily function, that needs to be compartmentalized and processed.

We can imagine the synapses as a clerk’s room filling up with boxes and parcels that need to be deliver to the proper address.

But what is interesting, is the result that comes from another study published at the same time, from Franziska Brüning and her team3 at the Institute of Medical Psychology of the Ludwig Maximilian University of Munich (Germany). This research study shows that sleep deprivation abolishes nearly all of the compartmentalization of these accumulating proteins at the synapses (98%); which means that, without a proper shut eye, the synapses get completely clogged with accumulating “protein-parcels” that don’t get removed. When a chemical or electrical information wants to get through the synapses the next day, it can’t because there’s accumulating protein transcripts that haven’t been properly processed, or phosphorylated. The information gets stalled, due to the congestion at the synapses.

So, next time your brain feels fizzle in the morning, and throughout the day; promise yourself (and your brain) to go to bed early, and have a proper night’s rest!



1.         Cirelli C and Tononi G. Linking the need to sleep with synaptic function. Science. 2019;366:189-190.

2.         Noya SB, Colameo D, Bruning F, Spinnler A, Mircsof D, Opitz L, Mann M, Tyagarajan SK, Robles MS and Brown SA. The forebrain synaptic transcriptome is organized by clocks but its proteome is driven by sleep. Science. 2019;366.

3.         Bruning F, Noya SB, Bange T, Koutsouli S, Rudolph JD, Tyagarajan SK, Cox J, Mann M, Brown SA and Robles MS. Sleep-wake cycles drive daily dynamics of synaptic phosphorylation. Science. 2019;366.

Stroke or heart infarct?

According to a recent study by Daghlas and colleagues1, compared to sleeping 6 to 9 h/night, short sleepers have a 20% higher risk of having a heart attack; but, if you are a long sleeper (i.e., sleeping >9h/night), than your chances are even worse, because your risk increases to 34%. Even though the researchers don’t know the underlying cause for such susceptibilities, they claim sleeping too much or too little boosts inflammation in the body, which is associated with the development of heart disease. If you have a genetic predisposition for heart disease, this study found that sleeping between 6-9h, actually reduces your risk of having a heart attack by 18%, which is actually very good news, since not only diet and exercise can help you keep your heart healthy. More and more data, supports the evidence that we should consider sleep to be an adjustable and controllable risk factor for our good heath status2.

Speaking of diet, another study published recently in the Journal of the American Heart Association by Hyunju Kim and his team3, showed that healthy plant‐based diets, which are higher in whole grains, fruits, vegetables, nuts, legumes, tea, and coffee, and lower in animal foods, were associated with a lower risk of cardiovascular disease mortality and all‐cause mortality. Of course, they didn’t explore if the quality of plant foods (either healthy plant foods, or less-healthy plant foods) within the “framework of plant‐based diets” would be associated with cardiovascular disease and all‐cause mortality in the general population.

But, what is intriguing is that, another recent study by Tammy Tong and colleagues4, examined the associations of vegetarianism with risks of ischemic heart disease (i.e., coronary artery disease) and stroke. The results of this study showed that vegetarians had 20% higher rates of total stroke than meat eaters – which was equivalent to 3x more cases of stroke over 10 years; and, the associations for stroke did not soothe after adjustments to other disease risk factors. As the authors of the study say, vegetarian and vegan diets have become increasingly popular in recent years, partly due to perceived health benefits, as well as concerns about the environment and animal welfare; but, what the evidence suggests, is that vegetarians might have different disease risks compared with non-vegetarians. The study group of vegetarians and vegans in this cohort had lower circulating levels of several nutrients (e.g., vitamin B12, vitamin D, essential amino acids, and long chain n-3 polyunsaturated fatty acids), and differences in some of these nutritional factors could contribute to the increased stroke risk. Not only that, but a number of studies in Japan5, 6, showed that individuals with very low intake of animal products, also had an increased incidence and mortality from hemorrhagic and total stroke, implying that some factors connected with animal food intake might be protective for stroke. 

Its like Yin and Yang from ancient Chinese philosophy. Rather than opposing, or standing at the sides, our health and life is made of complementary forces that interact to form a dynamic system. It’s all about balance and balancing the sides (and diets).

All in life is balance
Balancing life’s way


1.         Daghlas I, Dashti HS, Lane J, Aragam KG, Rutter MK, Saxena R and Vetter C. Sleep Duration and Myocardial Infarction. Journal of the American College of Cardiology. 2019;74:1304-1314.

2.         Tobaldini E, Fiorelli EM, Solbiati M, Costantino G, Nobili L and Montano N. Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence. Nat Rev Cardiol. 2019;16:213-224.

3.         Kim H, Caulfield LE, Garcia-Larsen V, Steffen LM, Coresh J and Rebholz CM. Plant-Based Diets Are Associated With a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All-Cause Mortality in a General Population of Middle-Aged Adults. J Am Heart Assoc. 2019;8:e012865.

4.         Tong TYN, Appleby PN, Bradbury KE, Perez-Cornago A, Travis RC, Clarke R and Key TJ. Risks of ischaemic heart disease and stroke in meat eaters, fish eaters, and vegetarians over 18 years of follow-up: results from the prospective EPIC-Oxford study. BMJ. 2019;366:l4897.

5.         Kinjo Y, Beral V, Akiba S, Key T, Mizuno S, Appleby P, Yamaguchi N, Watanabe S and Doll R. Possible protective effect of milk, meat and fish for cerebrovascular disease mortality in Japan. J Epidemiol. 1999;9:268-74.

6.         Sauvaget C, Nagano J, Allen N, Grant EJ and Beral V. Intake of animal products and stroke mortality in the Hiroshima/Nagasaki Life Span Study. Int J Epidemiol. 2003;32:536-43.

Habenula, the Master of the Brain

The Habenula, is an area of our brains close to the pineal gland, that is involved in pain processing, reproductive behaviour, nutrition, sleep-wake cycles and stress responses, among other things1. A professor I used to know always said the Habenula was the Master of the Brain… and, indeed, recent research has provided evidence that this tiny bundle of nerves is able to produce Dimethyltryptamine (DMT), a psychedelic drug, “cousin” to the famous LySergic acid Diethylamide (LSD). 

DMT is internally bio-synthesized by the enzymes Aromatic-L-Amino acid DeCarboxylase (AADC) and Indolethylamine-N-Methyltransferase (INMT). Dean and colleagues2 were able to identify INMT messenger RNA in human tissues, by using a RNAscope in situ assay system; a highly sensitive technique, which proved for the first time a clear-cut identification of DMT and its enzymes in human brain. 

Outstanding, was the discovery that there was a significant increase of DMT levels in the rat brain after stimulation of experimental cardiac arrest; showing for the first time, that the brain is capable of synthesizing and releasing DMT under stress. 

This ultimately raises the possibility that this phenomenon may also occur in human brains, when we experience situations of extreme stress. The researchers attest that the cardiac arrest-induced increase of DMT may be related to “near-death experiences”, as reported by Timmermann and collegues3. This group recently reported that human subjects given exogenous DMT, experienced “near-death”-like mental states, including the subjective feeling of transcending one’s body and entering an alternative realm, perceiving and communicating with ‘entities’, and themes related to death and dying.

It’s unbelievable that the more we know about how our body and brain functions, the more I realize that our mind is a construction of our organic biological nature.

What we sometimes perceive as a mystical experience is probably just rooted in an organic mechanism that is tricking our minds into a “trip”.

Into the light


1.         Namboodiri VM, Rodriguez-Romaguera J and Stuber GD. The habenula. Curr Biol. 2016;26:R873-R877.

2.         Jon G. Dean TL, Sean Huff, Ben Sheler, Steven A. Barker, Rick J. Strassman, Michael M. Wang & Jimo Borjigin Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain. Scientific Reports. 2019;9.

3.         Timmermann C, Roseman L, Williams L, Erritzoe D, Martial C, Cassol H, Laureys S, Nutt D and Carhart-Harris R. DMT Models the Near-Death Experience. Front Psychol. 2018;9:1424.

Underwater banquet!

Cabal, is a term defined in the Merriam-Webster dictionary, as the contrived scheme of a group of persons secretly united in a plot (as to overturn a government, for example). 

But, if you talk in terms of Biology, cabals are also a series of synergistic venom peptides essential for the capture of prey. One animal venom can be a complex mixture of 10-200+ short chains of amino acids linked by bonds (peptides), working in a concerted mode to regulate physiological function, with very potent and precise molecular targets1.

For example, cone snails, a small venomous marine mollusk that hunts fish and worms, has ~850 species identified, with each expressing many thousands of unique peptides that selectively target a diverse range of voltage- and ligand-gated ion-channels, transporters and G-protein couple receptors2

These tiny wonders of nature have the ability to switch between predatory and defensive venom regimes. For example, if they just want to stunt a predator causing a flaccid paralysis, they will produce venom that has high levels of muscle blockers (motor cabal), and that inhibit sodium channels and nicotinic acetylcholine receptors. But, if in the mean time, they change their minds and intend to eat the prey, they use a combination of peptides that cause a rigid paralysis. This lightning-strike cabal has excitatory peptides that inhibit potassium channels and delay inactivation of sodium channels, causing the prey to lie “dead” until it is happily digested in an underwater banquet.

But, how does the cone snail decide whether it is fear or hunger that it’s “feeling” in that moment?

The simple neuronal circuit of the cone snail shifts from a contented state of inertia, to an active motion, stimulated by internal hunger and an appetite stimulus – just like us, slushing from the couch to the fridge looking for our night prey… The hunting activity of the Conus is then organized by a basic set of behavioral transitions. Once the cone snail detects a fish, through sensory signals, it becomes much more active and moves towards the fish extending its rostrum– a massive funnel formed by the muscular walls of the snail sheath; and, a long, thin trunk extends out in the open, where a harpoon-like tooth shoots out to pierce the skin of the fish3 – imagine if we could actually do the same to that bag of cookies that is lying in the shelve right next to the couch.

The active feeding of the cone snail tends to inhibit the avoidance, and the snail changes to a prevention mood once its appetite is satisfied4

Cone snail


1.         Angell Y, Holford M and Moos WH. Building on Success: A Bright Future for Peptide Therapeutics. Protein Pept Lett. 2018;25:1044-1050.

2.         Himaya SWA, Mari F and Lewis RJ. Accelerated proteomic visualization of individual predatory venoms of Conus purpurascens reveals separately evolved predation-evoked venom cabals. Sci Rep. 2018;8:330.

3.         Olivera BM, Seger J, Horvath MP and Fedosov AE. Prey-Capture Strategies of Fish-Hunting Cone Snails: Behavior, Neurobiology and Evolution. Brain Behav Evol. 2015;86:58-74.

4.         Gillette R and Brown JW. The Sea Slug, Pleurobranchaea californica: A Signpost Species in the Evolution of Complex Nervous Systems and Behavior. Integr Comp Biol. 2015;55:1058-69.

Alcohol or Melatonin?

In 1958, in the Yale laboratories, A.B. Lerner and colleagues isolated melatonin from the pineal gland of bovines1. They were surprised that after 40 years of research they had finally found the active component that lightened the frog skin color, inhibiting the darkening effect of the Melanocyte Stimulating Hormone (MSH); hence the name, Melatonin1. Disappointingly, the skin lightening properties of melatonin could not be further demonstrated and the project was abandoned2. In the 90’s, melatonin got back on the coolness charts of science, with Reppert and Weaver calling it “Madness” in a Cell article in 1995. During this time, it was discovered its function in regulating the seasonal and circadian rhythms3, the presence of its specific G-coupled receptors in different tissues4; and, its antioxidant properties5. Since then, melatonin has been widely studied and continues to wonder over its broad range of therapeutic effects. From helping on jet-lag relief6, with insomnia7, being an anti-aging agent8, neuro-protective9, and also, improving cardiovascular diseases10: melatonin-madness continues until today.

Melatonin is widely accepted as a nutritional supplement being prescribed for sleep regulation in jetlag and adult sleep disorders; but in 2011 the U.S.A Food and Drug Administration (FDA), issued a warning to a company selling “relaxation brownies”, stating that the synthetic melatonin used in them hasn’t been proved safe as a food additive. Most commercial products are offered at dosages of 1-3mg of melatonin, which causes a spike of melatonin in the blood, reaching much higher levels than those that are naturally produced in the body somewhere between 50 and 200 pg/mL.

But, why use synthetic melatonin when this molecule is present in appetizing plants, nuts, fruits, meats, beverages and other foods11? The levels of melatonin in foods are much lower than those given as a nutritional supplement; but it has been proven that eating such foods drastically increases the circulating melatonin levels in the range of physiological concentrations, which peak at nighttime12, 13.

Maldonado and colleagues have shown that different types of beers are rich in melatonin; and, the more melatonin they have got, the greater is their alcoholic degree14. No wonder some people claim that beer makes them sleepy. But, Molfino15and I have made the same question: if the volunteers were sleepy, was it because of the melatonin or an alcoholic-mediated effect? So far, there’s still no answer to that question.

But, Garcia-Moreno and Maldonado’s group have shown, that Barley, which is malted and grounded in the early brewing process, and Yeast, during the second fermentation, are the largest contributors to the enrichment of beer with melatonin16. From this, we can deduct that not only beer has melatonin, but whatever drink where fermentation occurs, will also be rich in it. Logically, wine was also found to be a rich source of the Madness-molecule. In fact, beer has around 0,09 ng/mL while wine is up to 129,5 ng/mL11. And again, Rodriguez-Naranjo and colleagues showed that melatonin is formed during the alcoholic fermentation, because it is absent in the grapes and musts17.



    1. Lerner ABC, J.D.; Takahashi, Y.; Lee, T.H.; Mori, W. Isolation of melatonin, a pineal factor that lightens melanocytes. J Am Chem Soc. 1958;80:2587.
    2. Jiki Z, Lecour S and Nduhirabandi F. Cardiovascular Benefits of Dietary Melatonin: A Myth or a Reality? Front Physiol. 2018;9:528.
    3. Arendt J. Melatonin and the pineal gland: influence on mammalian seasonal and circadian physiology. Rev Reprod. 1998;3:13-22.
    4. Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA and Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A. 1995;92:8734-8.
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Evolution and melatonin

Since life has emerged on Earth, 3.7. billion years ago, the rising and setting of the Sun has been a constant. Whether it was light or dark, it was day or night. Humans, and all other organisms, have evolved with this imposed biological rhythm; and, human physiology was determined by the light/dark cycle.

Every cell in our bodies exhibits a circadian rhythm, a 24h-cycle synchronized to a light/dark pattern. But, how do cells deep inside in our bodies know when it’s dark outside? The answer to that question is Melatonin (N-acetyl-5-methoxytryptamine), the messenger from our brain to communicate to our cells that it is dark. The master clock of the body, the Suprachiasmatic Nucleus (SCN) receives darkness information from the retina and sends it to the brain. From there it provides an input to the Pineal Gland, to produce melatonin. Melatonin secretion increases in the evening, and is stimulated by darkness; whereas light rapidly suppresses melatonin production.

Melatonin is not unique to humans. It is spread through out the animal kingdom, plants, bacteria, and even unicellular organisms have it. There’s no species that has been identified so far that does not contain Melatonin. This expresses the importance of this molecule to life.