By: Rebecca Reagan, Neelam Sharma, and Hemant Joshi
Tara Innovation LLC - www.tara-marketing.com - [email protected]
Historical Background
When thinking about caffeine, the first thought that often comes to mind is the drink “coffee”, despite the fact that caffeine can be obtained from a variety of other sources. Coffee dominates modern drink consumption, but tea was the original popular caffeinated drink. Chinese tea cultivation began around 2700 B.C. and the beverage spread around the world when Buddhist monks brought tea seeds to Japan after visiting China. Similarly, tea arrived in Europe after missionaries and merchants visited China and brought back tea leaves. The marriage of the Portuguese princess Catherine of Braganza to King Charles II of England only amplified the spread in Europe as the countries grew more interconnected. While tea became more widespread, the Dutch began cultivation on the island of Java in Indonesia and tea smuggling began as the British increased taxes.
Coffee was said to be discovered thousands of years later in Ethiopia by a goat herder named Kaldi after he observed one of his goats highly energetic after consuming a coffee cherry. Historical evidence that the Galla tribe of Ethiopia consumed balls of animal fat and coffee cherries further supports the theory that coffee was originally discovered in Ethiopia. When coffee arrived in the Arabian Peninsula, it rapidly spread around the world as a result of the annual pilgrimages to Mecca. Some of the first coffee houses were established in the region. Despite the clergy’s original opposition to coffee in Europe, the Pope’s approval only sped up the spread of the caffeine drink. Taxes from the British on tea led to an increase in the popularity of coffee in the colonies. As demand for the beverage increased, the Dutch attempted to cultivate the plant in a variety of places, including India and Java. Despite the plantations in India being a failure, the Dutch found massive success in the cultivation of coffee in Java. Currently, Brazil, Vietnam, Columbia, and Indonesia are some of the top coffee-producing countries in the world while China, India, Kenya, and Sri Lanka are included in some of the top tea-producing countries.
The word “coffee” entered the English language in 1582 via the Dutch word koffie, which was borrowed from the Ottoman Turkish kahve, in turn borrowed from the Arabic qahwah.
Caffeine in Recent Times
The spread of caffeine plants thousands of years before the 20th century spurred the establishment of the caffeine-based culture around the world. Differing styles of coffee-making, involving the invention of a wide variety of pot types, evolved as coffee continued to spread and become an integral part of many world cultures. In Turkey, brewers use a cezve, a long-handled brass pot that is used to brew coffee from finely ground beans. Some other coffee pots of various parts of the world are: in Vietnam - a phin, in Mexico - an olla, in Ethiopia - a jebena, and in Italy - a moka.
Socializing is closely tied to coffee. Ethiopian brewers have traditional ceremonies with three stages of pouring - abol, tona, baraka. Brazil has a culture of coffee being distributed almost anywhere as the drink, which represents a gesture of hospitality.
Tea has similar traditions associated with it. In Japan, tea ceremonies are known as sado. In Morocco, mint tea is poured from a standing height during greetings. In England, there is afternoon and high tea that is served with sandwiches that promote socializing and relaxation. The U.S. is primarily dominated by coffee culture in which 64% of adults report consuming coffee every day. Tea also plays a prominent role, in which 23% of adults consume the drink daily. Some of the most popular world coffee chains have been established in the United States, including Dunkin Donuts (1950) and Starbucks (1971).
Caffeine Content in Marketed Drinks
Companies marketing coffee, tea, or caffeinated drinks report caffeine content. We obtained four coffee products and determined the caffeine content by High-Performance Liquid Chromatography (HPLC).
The Dark Roast Blend was found to have 222 mg of caffeine per cup, while the Decaf Pike had 76 mg per cup. In addition, Caffeinated Level Four blend had a total of 139 mg of caffeine per cup in comparison to the 28 mg of caffeine in the Decaf Level Three blend. Coffee can provide a substantial dose of caffeine. Even decaffeinated coffee contains a considerable amount of caffeine. Thus, the term “decaffeinated” does not necessarily mean the drink is free of caffeine, but rather that it has a smaller amount.
Caffeine and its Side Effects
Caffeine is an organic chemical with the formula C8H10N4O2 and is identifiable as being an odorless white powder, with a bitter taste, and needle-like appearance in its pure form under a microscope. Most notably, it is found in a variety of natural plants and beverages including green and black tea, cocoa, coffee, yerba mate, guarana, kola, yaupon holly, and kombucha. The chemical has a large presence in modern consumption as it appears in medicines, desserts, drinks, protein bars, cereal, and yogurt. Pure caffeine pills are also available in both prescription and over-the-counter formats at dosages of 100-200 mg.
Because caffeine plays a major role in society, the side effects of the drug are often overlooked in daily life. A typical serving of caffeine at 80 mg can increase blood pressure, act as a diuretic, and stimulate the nervous system. Increased wakefulness and decreased reaction time are key indicators of the stimulating effects of caffeine. With caffeine’s neural stimulatory effects, it is recommended not to consume caffeine for six hours before sleep as sleep time has been proven to be reduced when the time period after consumption and before sleep is reduced.1 When caffeine is over-consumed at amounts around 400mg, the user may find themselves restless, anxious, and irritable. Often when a person attempts to limit their caffeine intake, they pledge to quit caffeine “cold turkey”. However, this strategy is oftentimes accompanied by a constant headache, fatigue, and a depressed mood. Others will cut down their consumption of caffeine slowly, to limit withdrawal symptoms by allowing their body to adjust to their new caffeine-limited state.
Caffeine as a Medicine
Perhaps the most interesting aspect of caffeine is its use in modern medicine because of its effect on adenosine receptors. In the brain, adenosine receptors influence sleeping. When adenosine triphosphate, a source of energy for molecular processes, is broken down, adenosine is released, which can then bind to adenosine receptors and activate them. This process triggers the slowing down of neural activity. Caffeine shares a similar, but slightly different structure to adenosine. It can bind to adenosine receptors, but its altered structure both prevents the receptor’s activation and adenosine from binding. There are a limited number of adenosine receptors in the body, and when caffeine molecules bind to the adenosine receptors instead of adenosine, neural activity will not be triggered to slow down until the caffeine is broken down and exits the body.
Caffeine is used in Excedrin, Midol, and Fioricet. Although the exact reason why caffeine amplifies the pain-killing properties of analgesics is not known, it is understood that it likely ties back to the disruption of adenosine receptors as well as its inhibition of enzyme activity.2 There is also evidence of caffeine enhancing the drugs that it is paired with.
Caffeine has been shown to block adenosine receptors that, in addition to modulating neural activity, play a role in pain signaling. Caffeine can block adenosine receptors, causing vasoconstriction, which combats headaches that are caused by blood vessels widening. Caffeine has been an active component in several combination drug therapies and its unique properties make it an integral part of medicine.
We have seen that we can benefit from caffeine usage in many ways. Another good example is - caffeine and its metabolites are reliable biomarkers of early Parkinson disease (PD). In PD patients, lower levels of caffeine and its metabolite were observed.3
Caffeine Interactions
Caffeine has the ability to affect the pharmacokinetics of other drugs. Specifically, caffeine can alter the pH of the stomach through triggering taste type 2 bitter receptors and increasing hydrochloric acid secretion, thus impacting the absorption of other drugs by changing their dissolution profiles while possibly resulting in drug degradation in the digestive system. The amount of active midazolam decreases by 75% after coffee consumption as a result. In contrast, the rate of aspirin absorption increases when pH decreases because unionized aspirin mass increases and is more readily absorbed in the stomach compared to the ionized version. The enzymes that break down caffeine (CYP450, CYP1A2) are also responsible for the breakdown of other drugs like warfarin, clozapine, theophylline, and many others. Caffeine can saturate the enzymes, thus making the metabolism of the other drugs more difficult and increasing the plasma levels of the drugs, which keeps them active in the bloodstream for longer periods of time.4
Caffeine interacts with acidic drugs through dipole-dipole forces as well as hydrogen bonding and can form bonds that decrease or increase solubility. An anxiety and depression medication known as escitalopram oxalate’s dissolution decreases by these interactions. Beyond degradation and molecule interactions, caffeine can react with neuroleptic drugs like thioridazine and butyrophenone and form a precipitate that decreases the concentration of active drugs. Caffeine helps to maintain the junction protein expression levels (balance between transcription, translation, and degradation) in the blood-brain barrier. However, this activity can prevent the movement of drugs through the blood-brain barrier like memantine and donepezil that are used in Alzheimer treatments.4 Without a doubt, caffeine interacts with a variety of other drugs, making it critical to confirm the interaction between drugs before use. Over 80 drug-caffeine interactions have been reported. In some cases, the drug’s concentration and/or effect are either enhanced or reduced. In some cases, the drug enhances or reduces caffeine’s effects. For example, ciprofloxacin increases caffeine’s effect causing headache, high blood pressure, and nervousness. Caffeine may cause methotrexate to fail in its ability to relieve rheumatoid arthritis.
Regulation of Caffeine
The FDA regulates drinks and food containing caffeine. There is a presence of widespread usage of pure caffeine, which can be deadly in small doses. There have been reported instances of teenagers mixing caffeine into workout beverages as well as two reported deaths from caffeine overdose. Servings of pure caffeine from bulk bags have been reported as 1/16 of a teaspoon, which is incredibly difficult to measure. The FDA does report that bulk caffeine is illegal and has made efforts to remove the products from the market.
With energy drinks, companies can decide whether to label their drinks as beverages or dietary supplements. When labeled as a beverage, products have to include a nutrition facts panel to comply with the Nutrition Labeling and Education Act of 1990 (NLEA). In contrast, the FDA states that supplements have a supplement facts panel where the manufacturers have the ability to list ingredients that are not “permitted on beverage labels under the NLEA”.
5-Hour Energy, Monster, and Rockstar energy drinks are all listed as dietary supplements.5 Such drinks may contain additives that have not been approved by the FDA. Because the FDA does not require dietary supplements to be proven safe before they are put onto the market, manufacturers are responsible for ensuring the safety of their products before sales. In order to remove a supplement from the market, the FDA must prove that it is unsafe after the supplement has been reported for adverse effects or false claims.
With this understanding, it is important to consider the ingredients and the type of foods that we are consuming. Each food that we put into our body impacts us, and we must pay attention in order to fuel our body effectively and safely each day.
At this point, no clear-cut evidence of modification of genes due to caffeine was observed. But genes can affect our reactivity towards caffeine or in other words, the same dose of caffeine can have different effects in different people.
Caffeine Analogs
Caffeine, like many other drugs, is known to have analogs, which are chemicals with similar structures that differ by a component - oftentimes, altered small groups such as a methyl group. There are 22 known analogs of caffeine; many are more potent than caffeine. 1-methylxanthine, 7-methylxanthine, and 1,3-dimethylxanthine are all analogs of the common drug and many are being researched to evaluate their impact on illnesses. Caffeine’s clear impact on adenosine receptors make for a possible therapeutic in its analogs for Alzheimer’s, type 2 diabetes, and a variety of other illnesses.
Concluding Remarks
Scientists continue to investigate the impacts of short-term and long-term caffeine consumption on the body and biochemical interactions. The FDA recommends a maximum of 400 mg caffeine for adults and the American Academy of Pediatrics recommends “no more than 100 mg of caffeine per day” for adolescents between the ages of 10-19. With continued use, people can become reliant on caffeine to rise in the morning and remain awake throughout the day. Each year, the world consumes over 160 million 60-kg bags of coffee and over 270 billion liters of tea. These statistics do not encompass the caffeine consumed through drinks, snacks, and medicines. People consuming caffeinated drinks must keep in mind caffeine’s interaction with drug(s) the person may be consuming. Caffeine has dominated social culture for thousands of years, and it is without a doubt that the famous substance will continue to play a major role around the world for thousands of years more.
References
- Drake, C., et al. “Caffeine Effects on Sleep Taken 0, 3, or 6 Hours before Going to Bed.” Journal of Clinical Sleep Medicine, vol. 09, no. 11, 2013, pp. 1195–1200., doi:10.5664/jcsm.3170.
- Baratloo, A. et al. “The Role of Caffeine in Pain Management: A Brief Literature Review.” Anesthesiology and pain medicine vol. 6,3 e33193. 26 Mar. 2016, doi:10.5812/aapm.33193
- Fujimaki, M. et al. “Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease.” Neurology, 2018; 90(5): 404-411.
- Belayneh, A., and Fantahun M. “The Effect of Coffee on Pharmacokinetic Properties of Drugs: A Review.” BioMed Research International, vol. 2020, 2020, pp. 1–11.,doi:10.1155/2020/7909703.
- Generali, J. A. “Energy drinks: food, dietary supplement, or drug?” Hospital pharmac, 2013;48: 5-9. doi:10.1310/hpj4801-5.test
Author Biographies
Rebecca Reagan is a senior at the Academy for Biotechnology in Mountain Lakes, NJ and is currently interning at Tara Innovations. She will pursue a double major in Chemistry and Bioethics at the University of Rochester in Fall 2021.
Neelam Sharma is a Chemist at Tara Innovations Organization. In her role, she currently supports in formulation development, assay development, and data analysis. She also evaluates stability samples as per given guidelines, and writes the SOPs, technical and stability reports. Neelam holds a Bachelor’s degree in Biology and Master’s degree in Biotechnology.
Hemant Joshi is the Founder of Tara Innovations LLC. He holds Ph.D. in Pharmaceutical Chemistry from the University of Kansas and MBA from Fairleigh Dickinson University. He is involved in the formulation development and stability studies of pharmaceutical products. He is passionate about developing drug delivery systems. He has developed a proprietary “Joshi Capsule” drug delivery system (www.joshicapsules.com).
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