Phytomelatonin: the next frontier of sleep medicine?

Melatonin (N-acetyl-5-methoxytryptamine) is a widely consumed supplement in the US but is a more tightly controlled substance in the UK and Europe.  

Primarily used to promote the correct circadian behaviour and function as an internal synchroniser of the circadian sleep-wake cycle, melatonin is widely used to treat insomnia, jet lag from trans-oceanic flights, night shift-work sleep disorder, delayed sleep phase syndrome, seasonal affective disorder, and sleep disorders in the blind and aging. 

The consumption of melatonin supplements has increased in recent years in part to improve sleep but other reasons have risen up the agenda, including for antioxidant, anti-aging and hunger regulation benefits. Studies in the last decade have shown melatonin has antioxidant, anti-cancer, hypoglycaemic and hypercholesterolemic properties that potentially make the supplement more valuable than just a ‘sleep’ medication. It is also now being used for treating neurodegenerative diseases such as Alzheimer’s and Parkinsons. 

Despite its increased use and the fact it can be bought over the counter in many countries as a supplement, there is still some scepticism about the safety of synthetic melatonin. The synthesis of melatonin has continued to improve over the years but there are still concerns over the formation of several by-products in the reaction that can become contaminants.  

The study of phytomelatonin – i.e., naturally occurring melatonin – has increased significantly in the last decade and is now seen as a potential natural alternative. However, it is difficult to extract and plants don’t often contain that much melatonin, which has led to new extraction methods being introduced to better harness melatonin as a natural supplement. Nevertheless, despite the potential benefits of phytomelatonin, not all are convinced it’s needed.

Phytomelatonin is the term for melatonin that has come from a plant, i.e., naturally occurring melatonin. First discovered in plants in 1995, the actual amount of melatonin in a plant varies significantly on the plant and the part of the plant being harvested – but it is usually between picogram and microgram levels. 

As a general rule of thumb, aromatic and medicinal plants have the highest levels of phytomelatonin and the highest concentrations within a plant can be found in the seeds, flowers (from the reproductive organs) and leaves. Mustard, alfalfa, fenugreek and sunflower seeds are known to have high concentrations of phytomelatonin.

Fruits are known to have the lowest concentrations of phytomelatonin but that doesn’t mean they are not useful. Tomato extract can be used as a natural way of delivering both sleep support and antioxidant benefits based on the natural properties of the fruit. Other fruits known to contain sufficient levels of phytomelatonin include kiwi, cucumber, banana, apple and strawberries. 

Alongside the plants themselves, the natural variation of phytomelatonin within plants also stems from growth conditions. It’s been discovered plants exposed to physical and chemical stressors – ranging from high temperatures to high UV radiation, highly saline water, heavy metals and herbicides – have elevated phytomelatonin levels. Phytomelatonin is used as a protective molecule in plants to protect the plant against different stress situations, so it might be possible to grow plants with higher phytomelatonin levels by altering their growth environment, i.e. growing them under a higher stress.

The rising use of melatonin has prompted interest into how people can obtain more natural versions. For some countries, like the UK and many parts of Europe, its use is restricted to patients who can obtain a prescription. In the US, however, the Food and Drug Administration classes it as a food supplement, as do some European countries. This means that in more regulated markets, melatonin is classed as a drug, not a supplement, so its use in some countries is limited to specific doses.  

In lesser regulated countries, the lack of oversight means melatonin supplements available today can contain a range of by-products. While not in all products, there have cases where a molecule called peak E (1,1-ethylidenebis-(tryptophan)) has been found. The molecule has been closely related to Eosinophilia Myalgia Syndrome (EMS)—an incurable and fatal disease. Some studies have also quoted that some synthetic processes could create melatonin isomers and derivatives that are harmful but not separable from the intended melatonin product using standard purification methods. There have also been reports of melatonin products containing CBD. The lack of regulation means that there is often no information about the right dosage either. 

There have also been academic studies that have looked directly at commercial melatonin food supplement products in the US to see if what is being advertised is true. A study published by the American Medical Association in 2023 assessed 25 different melatonin gummy products and found the actual amount of melatonin in them range from 74-347% of their stated quantity and found 88% of the products were incorrectly labelled.

The same study highlighted these gummies present an issue for children, in particular potentially the wrong dosage and the presence of CBD, with US hospitals from 2012 to 2021 experiencing 4,097 hospitalizations, 287 intensive care unit admissions and two deaths for children who took melatonin supplements. 

While many of the serious issues are only likely to occur in very rare cases (as many academic studies do only look down very specific lenses), for those involved with natural health and nutraceuticals it has been enough reason to investigate natural alternatives where any potential by-products are not being ingested. The issue around synthetic melatonin arises in the food supplement versus prescribed drug debate and many of the issues with labelling, dosage and purity are primarily focused on the supplement market, not prescription drugs.  

Melatonin prepared as a pharmaceutical and given out as a prescription is almost always going to have a high purity, be free from contaminants and be at the correct dosage according to the needs of the patient, attributes that are not regulated for food supplements. This is one of the reasons why consumers turn to natural health supplements and it looks like the same could be true for natural melatonin (especially with its antioxidant and other beneficial properties) if it can be extracted in large enough volumes for mass markets.

Alongside the type of plant and where the phytomelatonin is being extracted from, the extraction method is also important for obtaining a therapeutically rich extract. Maceration has been one of the conventional wet chemistry techniques for extracting melatonin from plants, where the plant is soaked in a solvent (such as methanol, chloroform, or ethyl acetate) for days to break down the cell wall and extract it chemically using appropriate solvents.  

However, this takes a lot of time, is not scalable and has low yields, so a number of advanced extraction methods, such as ultrasonic-assisted extraction (UAE), microwave-assisted extraction (MAE) and pressurised liquid extraction (PLE) are being used to help improve the extraction efficiency of phytomelatonin.

UAE is a sonication method that uses ultrasound waves to effectively break down cell walls, meaning phytomelatonin can be extracted more efficiently using solvents. Ultrasonic cavitation bubbles release a lot of energy when they rupture and this leads to the phytomelatonin entering the intracellular matrix, where it can be extracted with less solvent. UAE is also a quick and scalable method as ultrasonic cavitation can be employed on large scales.

MAE is a technique that enhances conventional extraction methods and improves the extraction capabilities by extracting from the plant at higher temperatures. Microwaves are used to heat the solvents the plant is dissolved in without any direct contact. The rotation of the solvent molecules breaks the hydrogen bonds of the cell wall, leading the solvent entering the plant matrix. The higher temperature, from the absorption of microwaves, generates a high pressure inside the plant cells, which causes the phytomelatonin to flow out with the solvent, where it can be extracted. While it is based on more traditional extraction methods, using microwaves speeds up the process, uses less solvent and produces higher extraction yields.

PLE, also known as accelerated solve extraction (ASE), is a high-pressure solvent extraction method. This approach uses a solvent at a high pressure and temperature and, as the temperature rises, the solvents’ ability to dissolve phytomelatonin increases. The high temperature and pressure also lower the viscosity of the solvent, providing a higher diffusion rate that enables it to enter cells more easily. While all these approaches are involved with a more efficient extraction of phytomelatonin into a solvent, different purification methods still need to be performed to extract the phytomelatonin from the solvent it is dissolved in.

There is evidence phytomelatonin is used in some dietary supplements already but products formulated using the substance as the main ingredient are rare – and despite some packages claiming to be a phytomelatonin product, studies have shown that these are synthetic melatonin with a small amount of the added, natural phytomelatonin extract. 

While there is a lot of interest in developing natural melatonin supplements to ensure that they are free from potential contaminants, not all experts agree about the ways synthetic and natural melatonin are discussed. 

Russel Reiter, Professor of Cell Biology at UT Health San Antonio, claims a lot of the scientific literature is misinterpreted. “I’ve been working with melatonin for 60 years and the misinformation derives from individuals who are not familiar with the scientific literature and have never worked with melatonin,” he says. “For example, podcasters cherry pick information to support their view”. While there have been studies that have looked at the effects of melatonin, Reiter claims that “in science, there are always outliers that differ from the mainstream and they tend to use this information”, adding: “The overwhelming experimental and clinical data show that melatonin is a highly beneficial molecule.”

Reiter does go on to say he has no objection against natural melatonin itself and has more problems with the vilification of synthetic melatonin. “For natural melatonin, it is a problem of extraction. If they can show me the unmanipulated purity data regarding the product, I’ll accept it” he says. “I am always cautious about accepting so-called data from individuals who have a vested interest in the product they are promoting. I have no association with melatonin (patents, vested interest etc), other than as a scientist.

“Synthetic and natural melatonin are the same thing and both would be good but show me the data on the purity of extracted melatonin and its efficacy to confirm its purity.”

Reiter also believes there’s a chance “plant extracted melatonin will likely contain more impurities that that produced synthetically”.

Regarding synthetic melatonin, he adds: “There’s no psychological or physiological dependency in reference to melatonin. People intrinsically synthesise melatonin almost every day of their life and it neither kills them nor does it cause dependency.”

Aspirin, Reiter says, “kills 700 people annually in the US and ibuprofen causes extensive kidney damage and physicians still continue to recommend its use”.

“Virtually every over-the-counter medication that is sold is much more toxic than melatonin will ever be,” he adds.

It’s clear there are some who are worried about the use of synthetic melatonin but others in the industry are not as concerned. There is growing interest in using phytomelatonin as natural supplement that can improve sleep alongside providing other health benefits. That interest has sparked new methods to improve extraction and the purity of these natural supplements. How much natural melatonin will take off in the coming years remains to be seen.