|Summary sheet: Caffeine|
|Routes of Administration|
1,3,7-Trimethylpurine-2,6-dione (commonly known as caffeine) is a naturally-occurring stimulant substance of the xanthine family. It is notable for having found widespread use in modern society for its ability to increase activity in the brain and induces temporary improvements including enhanced alertness, wakefulness, and locomotion.
Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants, 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.
- 1 Chemistry
- 2 Pharmacology
- 3 Subjective effects
- 4 Toxicity and harm potential
- 5 Legal status
- 6 See also
- 7 External links
- 8 References
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.
Caffeine acts through several mechanisms, but its most important effect is to counteract a substance called adenosine that naturally circulates at high levels throughout the body, and especially in the nervous system. In the brain, adenosine plays a generally protective role, part of which is to reduce neural activity levels.
The principal mechanism of action of caffeine is as a nonselective antagonist of adenosine receptors. The caffeine molecule is structurally similar to adenosine, and is thus capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.
Alongside this, caffeine also has profound 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. GABA reduction explains why caffeine increases anxiety, insomnia, rapid heart and respiration rate at high dosages.
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.
The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. The listed effects should be taken with a grain of salt and will rarely (if ever) occur all at once, but heavier doses will increase the chances and are more likely to induce a full range of effects. Likewise, adverse effects become much more likely on higher doses and may include serious 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.
- 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.
- 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.
- Bronchodilation - Caffeine is an effective bronchodilator. In clinical tests on adults with asthma, at fairly low doses (5mg/kg of body weight), caffeine has been shown to provide a small improvement in lung function.
- Appetite suppression
- Teeth grinding - This effect does not occur as consistently as it does on other stimulants such as amphetamine or MDMA.
- Dizziness - This effect is not common except at overly high doses or taken when fatigued or at low blood sugar.
- Increased blood pressure
- Increased heart rate
- Increased perspiration
- Nausea - Moderate to extreme nausea has been reported to occur, typically at higher dosages.
- Stamina enhancement
- Tactile enhancement
- 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.
The cognitive effects of caffeine can be broken down into several components which progressively intensify proportional to dosage. It contains a large number of typical stimulant cognitive effects. 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
- Compulsive redosing - This effect is less persistent than it is with nicotine or cocaine.
- Cognitive euphoria - This effect, when it occurs, is generally mild compared to the majority of psychoactive stimulants.
- Cognitive dysphoria - This effect typically only occurs at high to extremely high dosages.
- Focus enhancement - This component is most effective at low to moderate dosages as anything higher will usually impair concentration.
- Increased libido
- 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:
There are currently no anecdotal reports which describe the effects of this compound within our experience index. 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 drug.
Tolerance and addiction potential
As with other stimulants, the chronic use of caffeine can be considered moderately addictive with a high potential for abuse and is capable of causing psychological dependence among certain users. When addiction has developed, cravings and withdrawal effects may occur if a person suddenly stops their usage.
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 that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption).
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.
Caffeine is legal in nearly all parts of the world. Because caffeine is a psychoactive substance however, it is often regulated. 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.
- What's your poison? Caffeine | http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm
- Caffeine as a psychomotor stimulant: mechanism of action | http://link.springer.com/article/10.1007%2Fs00018-003-3269-3
- The Pharmacogenetics and Pharmacogenomics Knowledge Base | https://www.pharmgkb.org/drug/PA448710#biotransformation
- Caffeine ingestion and fluid balance: a review | http://onlinelibrary.wiley.com/doi/10.1046/j.1365-277X.2003.00477.x/abstract
- Caffeine ingestion and fluid balance: a review | http://onlinelibrary.wiley.com/doi/10.1046/j.1365-277X.2003.00477.x/abstract
- Caffeine for asthma | http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD001112.pub2/abstract
- Caffeine fatalities—four case reports | http://www.fsijournal.org/article/S0379-0738(03)00417-1/abstract
- Alstott RL, Miller AJ, Forney RB (1973). "Report of a human fatality due to caffeine". Journal of Forensic Science 18 (35).
- Factors Affecting Caffeine Toxicity: A Review of the Literature | http://onlinelibrary.wiley.com/doi/10.1002/j.1552-4604.1967.tb00034.x/abstract
- Actions of caffeine in the brain with special reference to factors that contribute to its widespread use (PubMed.gov / NCBI) | http://www.ncbi.nlm.nih.gov/pubmed/10049999
- A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features | http://webcitation.org/6533BsxXt
- Withdrawal Syndrome after the Double-Blind Cessation of Caffeine Consumption | http://www.nejm.org/doi/full/10.1056/NEJM199210153271601
- Caffeine-induced psychosis | https://www.ncbi.nlm.nih.gov/pubmed/19407709
- Psychosis Following Excessive Ingestion of Energy Drinks in a Patient With Schizophrenia | http://ajp.psychiatryonline.org/doi/abs/10.1176/appi.ajp.2009.09101456
- Caffeine enhances the stimulant effect of methamphetamine | http://www.ncbi.nlm.nih.gov/pubmed/7862940
- Interaction between caffeine and methamphetamine by means of ambulatory activity in mice. | http://www.ncbi.nlm.nih.gov/pubmed/2816095
- CFR - Code of Federal Regulations Title 21 | http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=182.1180&SearchTerm=caffeine
- Consumer Q&A: Caffeine-Containing Dietary Supplements | http://crnusa.org/caffeine/Q+A.html