|Summary sheet: Caffeine|
|Routes of Administration|
1,3,7-Trimethylxanthine (also known as caffeine) is a naturally-occurring stimulant substance of the xanthine class. Notable effects include stimulation, wakefulness, enhanced focus and motivation. It is the most widely consumed psychoactive substance in the world.
Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants where it acts as a natural pesticide, as well as enhancing the reward memory of pollinators. It is most commonly consumed by humans in infusions extracted from the seed of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut.
Unlike many other psychoactive drugs, caffeine is legal and unregulated in nearly all parts of the world. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks, enjoy great popularity. Caffeine is the most commonly used drug in the world, with 90% of adults in North America consuming it on a daily basis. Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.
Caffeine, or 1,3,7-trimethylpurine-2,6-dione, is an alkaloid with a substituted xanthine core. Xanthine is a substituted purine comprised of two fused rings: a pyrimidine and an imidazole. Pryimidine is a six-membered ring with nitrogen constituents at R1 and R3; imidazole is a 5 membered ring with nitrogen substituents at R1 and R3. Xanthine contains oxygen groups double-bonded to R2 and R6. Caffeine contains additional methyl substitutions at R1, R3 and R7 of its structure. These are bound to the open nitrogen groups of the xanthine skeleton. It is an achiral aromatic compound.
The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominantly in a zwitterionic resonance the location from which the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2 hybridized and planar. Therefore, the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.
Pure anhydrous caffeine is a bitter-tasting, white, odorless powder with a melting point of 235–238 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL). It is weakly basic (pKa of conjugate acid = ~0.6) requiring strong acid to protonate it. Caffeine does not contain any stereogenic centers and hence is classified as an achiral molecule.
In the absence of caffeine and when a person is awake and alert, little adenosine is present in (CNS) neurons. With a continued wakeful state, over time adenosine accumulates in the neuronal synapse, in turn binding to and activating adenosine receptors found on certain CNS neurons; when activated, these receptors produce a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes adenosine receptors; in other words, caffeine prevents adenosine from activating the receptor by blocking the location on the receptor where adenosine binds to it. As a result, caffeine temporarily prevents or relieves drowsiness, and thus maintains or restores alertness.
The principal mechanism of action of caffeine is as a nonselective antagonist at the adenosine A1 and A2A receptors. During waking periods, the brain levels of the neurotransmitter adenosine steadily increase and trigger fatigue and sleepiness. The caffeine molecule is structurally similar to adenosine, which enables it to bind to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.
Alongside this, caffeine also has effects on most of the other major neurotransmitters, including dopamine, acetylcholine, serotonin, and, in high doses, on norepinephrine, and to a small extent epinephrine, glutamate, and cortisol. At high doses, exceeding 500 milligrams, caffeine inhibits GABA neurotransmission. Caffeine's GABA reduction results in an increase in anxiety, insomnia, heart rate and respiration rate at high dosages.
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed throughout all bodily tissues. Peak blood concentration is reached within 1–2 hours. It is eliminated by first-order kinetics. Caffeine can also be absorbed rectally, evidenced by suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and of chlorobutanol and caffeine (for the treatment of hyperemesis). However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and total amount absorbed (AUC) are both about 30% (i.e., 1/3.5) of the oral amounts.
Caffeine is an antagonist of adenosine A2A receptors, and knockout mouse studies have specifically implicated antagonism of the A2A receptor as responsible for the wakefulness-promoting effects of caffeine. Antagonism of A2A receptors in the ventrolateral preoptic area (VLPO) reduces inhibitory GABA neurotransmission to the tuberomammillary nucleus, a histaminergic projection nucleus that activation-dependently promotes arousal. This disinhibition of the tuberomammillary nucleus is the downstream mechanism by which caffeine produces wakefulness-promoting effects. Caffeine is an antagonist of all four adenosine receptor subtypes (A1, A2A, A2B, and A3), although with varying potencies. The affinity (KD) values of caffeine for the human adenosine receptors are 12 μM at A1, 2.4 μM at A2A, 13 μM at A2B, and 80 μM at A3.
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines, each of which has its own effects on the body:
- Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.
- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.
Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.
It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.
- Stimulation - Caffeine is reported to be mildly to moderately energetic and stimulating in a fashion that is considerably weaker in comparison to that of traditional recreational stimulants such as amphetamine, MDMA or cocaine. This encourages physical activities such as performing chores and repetitive tasks which would otherwise be boring and strenuous physical activities. The particular style of stimulation which caffeine presents can be described as forced. This means that at higher dosages, it becomes difficult or impossible to keep still as jaw clenching, involuntarily bodily shakes and vibrations become present, resulting in extreme shaking of the entire body, unsteadiness of the hands, and a general lack of motor control.
- Physical euphoria - Caffeine has been reported to produce very mild physical euphoria in non-tolerant users, especially when they are already well-rested.
- Appetite suppression
- Bronchodilation - Caffeine is an effective bronchodilator. In clinical tests on adults with asthma, at fairly low doses (less than 5mg/kg of body weight), caffeine has been shown to provide a small improvement in lung function.
- Dizziness - This effect is not common except at overly high doses or taken when fatigued or at low blood sugar.
- Frequent urination - When doses of caffeine equivalent to 2–3 cups of coffee are administered to people who have not consumed caffeine during prior days, they produce a mild increase in urinary output. Most people who consume caffeine, however, ingest it daily. Regular users of caffeine have been shown to develop a strong tolerance to the diuretic effect.
- Headaches and Headache suppression - Caffeine can suppress headaches at light and common dosages, but may cause headaches at higher ones. This is likely due to its vasoconstricting and a vasodilating effects.
- Increased blood pressure
- Increased heart rate
- Increased perspiration
- Nausea - Moderate to extreme nausea has been reported to occur, typically at higher dosages.
- Stamina enhancement - This effect is relatively mild compared to other stimulants such as amphetamine.
- Tactile enhancement
- Teeth grinding - This effect does not occur as consistently as it does on other stimulants such as amphetamine or MDMA.
- Vasoconstriction and Vasodilation - Whilst caffeine acts as a mild vasoconstrictor, its metabolite theobromine is a vasodilator and these effects are thought to cancel each other out.
Although negative side effects are usually mild at low to moderate dosages, they become increasingly likely to manifest themselves with higher amounts or extended usage. This particularly holds true during the offset of the experience.
The most prominent of these cognitive effects generally include:
- Analysis enhancement
- Cognitive euphoria - This effect, when it occurs, is generally mild compared to the majority of psychoactive stimulants, and usually only occurs in those with low tolerance.
- Cognitive dysphoria - This effect typically only occurs at high to extremely high dosages.
- Compulsive redosing - This effect is less persistent than it is with nicotine or cocaine.
- Ego inflation
- Focus enhancement - This component is most effective at low to moderate dosages as anything higher will usually impair concentration.
- Increased libido
- Increased music appreciation - While caffeine is capable of producing this effect, it does not do so as reliably as it does with traditional stimulants or entactogens.
- Memory enhancement
- Motivation enhancement
- Thought acceleration
- The effects which occur during the offset of a stimulant experience generally feel negative and uncomfortable in comparison to the effects which occurred during its peak. Caffeine blocks adenosine receptors, which causes a build up of adenosine during its peak. During the offset experience, the built up adenosine activates the previously blocked receptors with a much higher strength than they would normally, causing a number of unpleasant effects. This is often referred to as a "comedown". The comedown experienced with caffeine is usually less intense than the comedown experienced with dopaminergic stimulants such as amphetamine and cocaine. Its effects commonly include:
Anecdotal reports which describe the effects of this compound within our experience index include:
- Experience:Caffeine (~125 mg) + Nicotine (4.5 mg) - Essential performance boost
- Experience:Caffeine - very high dose
Additional experience reports can be found here:
Toxicity and harm potential
Caffeine is not known to cause brain damage, and has an extremely low toxicity relative to dose. There are relatively few physical side effects associated with caffeine exposure. Various studies have shown that in reasonable doses in a careful context, it presents no negative cognitive, psychiatric or toxic physical consequences of any sort.
Extreme overdose can result in death. The median lethal dose (LD50) given orally is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or roughly 80 to 100 cups of coffee for an average adult. Though achieving lethal dose of caffeine would be difficult with regular coffee, it is easier to reach high doses with caffeine pills, and the lethal dose can be lower in individuals whose ability to metabolize caffeine is impaired.
It is strongly recommended that one use harm reduction practices when using this substance.
Dependence and abuse potential
Caffeine produces dependence with chronic use and has a low abuse potential. When dependence has developed, cravings and withdrawal effects will occur if one suddenly stops their use.
Tolerance to many of the effects of caffeine develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After tolerance has developed, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to return to baseline in the absence of further consumption. Caffeine presents cross-tolerance with antagonists adenosine receptors, meaning that after the consumption of caffeine certain stimulants such as theacrine and theobromine will have a reduced effect.
Withdrawal symptoms – including headaches, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints –- may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days. Withdrawal headaches are experienced by 52% of people who stopped consuming caffeine for two days after an average of 235 mg caffeine per day prior to that. In prolonged caffeine drinkers, symptoms such as increased depression and anxiety, nausea, vomiting, physical pains and intense desire for caffeine containing beverages are also reported. Peer knowledge, support and interaction may aid withdrawal.
There is limited evidence that caffeine, in high doses or when chronically abused, may induce psychosis in normal individuals and worsen pre-existing psychosis in those diagnosed with schizophrenia. Caffeine has been shown to potentiate the effects of methamphetamine, which can also induce psychosis.
Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous and even life-threatening when combined with certain other substances. The following list provides some known dangerous interactions (although it is not guaranteed to include all of them).
Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.
- DOx - High doses of caffeine may cause anxiety which is less manageable when tripping, and since both are stimulating it may cause some physical discomfort.
- 25x-NBOMe - Caffeine can bring out the natural stimulation from psychedelic drugs to make it uncomfortable. High doses can cause anxiety which is hard to handle while tripping.
- ΑMT - High doses of caffeine may cause anxiety which is less manageable when tripping, and since both are stimulating the combination may cause some physical discomfort.
- PCP - Details of this combination are not well understood but PCP generally interacts in an unpredictable manner.
- Amphetamines - This combination of stimulants is not generally necessary and may increase strain on the heart, as well as potentially causing anxiety and greater physical discomfort.
- MDMA - Caffeine is not really necessary with MDMA and increases any neurotoxic effects from MDMA.
- Cocaine - Both stimulants, risk of tachycardia, hypertension, and in extreme cases heart failure.
Caffeine is legal in nearly all parts of the world. However, it is often regulated because it is a psychoactive substance. For example, in the United States, the Food and Drug Administration (FDA) restricts beverages to contain less than 0.02% caffeine. unless they are listed as a dietary supplement.
- Nehlig, A., Daval, J. L., & Debry, G. (1992). Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects. Brain Research Reviews, 17(2), 139-170. PMID: 1356551
- ↑ 1.0 1.1 PubChem, Caffeine
- ↑ Ashihara, H. (2004). "Distribution and biosynthesis of caffeine in plants". Frontiers in Bioscience. 9 (1–3): 1864. doi:10.2741/1367. ISSN 1093-9946.
- ↑ Nathanson, J. A. (12 October 1984). "Caffeine and Related Methylxanthines: Possible Naturally Occurring Pesticides". Science. 226 (4671): 184–187. doi:10.1126/science.6207592. ISSN 0036-8075.
- ↑ Wright, G. A., Baker, D. D., Palmer, M. J., Stabler, D., Mustard, J. A., Power, E. F., Borland, A. M., Stevenson, P. C. (8 March 2013). "Caffeine in Floral Nectar Enhances a Pollinator's Memory of Reward". Science. 339 (6124): 1202–1204. doi:10.1126/science.1228806. ISSN 0036-8075.
- ↑ What's your poison? Caffeine | http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm
- ↑ Keskineva N., Chemistry of Caffeine, East Stroudsburg University
- ↑ Vallombroso, T. (2001). Organic chemistry: pearls of wisdom. Boston Medical Pub. ISBN 9781584090168.
- ↑ "Caffeine". DrugBank. University of Alberta. 16 September 2013. Retrieved 8 August 2014.
- ↑ Fisone, G., Borgkvist, A., Usiello, A. (1 April 2004). "Caffeine as a psychomotor stimulant: mechanism of action". Cellular and Molecular Life Sciences CMLS. 61 (7): 857–872. doi:10.1007/s00018-003-3269-3. ISSN 1420-9071.
- ↑ Caffeine & Neurotransmitters – WORLD OF CAFFINE
- ↑ Teekachunhatean, S., Tosri, N., Rojanasthien, N., Srichairatanakool, S., Sangdee, C. (4 March 2013). "Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects". ISRN Pharmacology. 2013: 1–7. doi:10.1155/2013/147238. ISSN 2090-5173.
- ↑ Froestl, W., Muhs, A., Pfeifer, A. (14 November 2012). "Cognitive Enhancers (Nootropics). Part 1: Drugs Interacting with Receptors". Journal of Alzheimer’s Disease. 32 (4): 793–887. doi:10.3233/JAD-2012-121186. ISSN 1875-8908.
- ↑ The Pharmacogenetics and Pharmacogenomics Knowledge Base | https://www.pharmgkb.org/drug/PA448710#biotransformation
- ↑ Welsh, E. J., Bara, A., Barley, E., Cates, C. J. (20 January 2010). Cochrane Airways Group, ed. "Caffeine for asthma". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD001112.pub2. ISSN 1465-1858.
- ↑ 15.0 15.1 Maughan, R. J., Griffin, J. (December 2003). "Caffeine ingestion and fluid balance: a review". Journal of Human Nutrition and Dietetics. 16 (6): 411–420. doi:10.1046/j.1365-277X.2003.00477.x. ISSN 0952-3871.
- ↑ Nurminen, M. L., Niittynen, L., Korpela, R., Vapaatalo, H. (November 1999). "Coffee, caffeine and blood pressure: a critical review". European Journal of Clinical Nutrition. 53 (11): 831–839. doi:10.1038/sj.ejcn.1600899. ISSN 0954-3007.
- ↑ Green, P. J., Suls, J. (1 April 1996). "The effects of caffeine on ambulatory blood pressure, heart rate, and mood in coffee drinkers". Journal of Behavioral Medicine. 19 (2): 111–128. doi:10.1007/BF01857602. ISSN 1573-3521.
- ↑ Addicott, M. A., Yang, L. L., Peiffer, A. M., Burnett, L. R., Burdette, J. H., Chen, M. Y., Hayasaka, S., Kraft, R. A., Maldjian, J. A., Laurienti, P. J. (13 February 2009). "The effect of daily caffeine use on cerebral blood flow: How much caffeine can we tolerate?". Human Brain Mapping. 30 (10): 3102–3114. doi:10.1002/hbm.20732. ISSN 1065-9471.
- ↑ Bogaard, B. van den, Draijer, R., Westerhof, B. E., Meiracker, A. H. van den, Montfrans, G. A. van, Born, B.-J. H. van den (November 2010). "Effects on Peripheral and Central Blood Pressure of Cocoa With Natural or High-Dose Theobromine". Hypertension. 56 (5): 839–846. doi:10.1161/HYPERTENSIONAHA.110.158139.
- ↑ Holmgren, P., Nordén-Pettersson, L., Ahlner, J. (January 2004). "Caffeine fatalities—four case reports". Forensic Science International. 139 (1): 71–73. doi:10.1016/j.forsciint.2003.09.019. ISSN 0379-0738.
- ↑ Alstott, R. L., Miller, A. J., Forney, R. B. (April 1973). "Report of a human fatality due to caffeine". Journal of Forensic Sciences. 18 (2): 135–137. ISSN 0022-1198.
- ↑ Peters, J. M. (6 May 1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature". The Journal of Clinical Pharmacology and The Journal of New Drugs. 7 (3): 131–141. doi:10.1002/j.1552-4604.1967.tb00034.x. ISSN 0095-9863.
- ↑ Juliano, L. M., Griffiths, R. R. (October 2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features". Psychopharmacology. 176 (1): 1–29. doi:10.1007/s00213-004-2000-x. ISSN 0033-3158.
- ↑ Silverman, K., Evans, S. M., Strain, E. C., Griffiths, R. R. (15 October 1992). "Withdrawal Syndrome after the Double-Blind Cessation of Caffeine Consumption". New England Journal of Medicine. 327 (16): 1109–1114. doi:10.1056/NEJM199210153271601. ISSN 0028-4793.
- ↑ Hedges, D. W., Woon, F. L., Hoopes, S. P. (March 2009). "Caffeine-induced psychosis". CNS spectrums. 14 (3): 127–129. doi:10.1017/s1092852900020101. ISSN 1092-8529.
- ↑ Cerimele, J. M., Stern, A. P., Jutras-Aswad, D. (March 2010). "Psychosis Following Excessive Ingestion of Energy Drinks in a Patient With Schizophrenia". American Journal of Psychiatry. 167 (3): 353–353. doi:10.1176/appi.ajp.2009.09101456. ISSN 0002-953X.
- ↑ Kuribara, H. (October 1994). "Caffeine enhances the stimulant effect of methamphetamine, but may not affect induction of methamphetamine sensitization of ambulation in mice". Psychopharmacology. 116 (2): 125–129. doi:10.1007/BF02245053. ISSN 0033-3158.
- ↑ Fujii, W., Kuribara, H., Tadokoro, S. (June 1989). "Interaction between caffeine and methamphetamine by means of ambulatory activity in mice". Yakubutsu, Seishin, Kodo = Japanese Journal of Psychopharmacology. 9 (2): 225–231. ISSN 0285-5313.
- ↑ CFR - Code of Federal Regulations Title 21
- ↑ Consumer Q&A: Caffeine-Containing Dietary Supplements | http://crnusa.org/caffeine/Q+A.html