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All about caffeine

Last updated on May 11, 2021

1,3,7-trimethylxanthine (also known as caffeine) is a naturally occurring stimulant substance belonging to the xanthine class. Notable effects include Stimulation, alertness, increased concentration and motivation. It is the am most consumed psychoactive substance in the world.

Caffeine is found in varying amounts in the seeds, leaves, and fruits of some plants, where it acts as a natural pesticide and improves the reward memory of pollinators. It is most commonly consumed by people in infusions made from the seeds of the coffee plant and the leaves of the tea bush, as well as in various foods and beverages that contain products made from the kola nut.

Unlike many other psychoactive drugs, caffeine is legal and unregulated in almost every part of the world. Caffeinated drinks such as coffee, tea, soft drinks and energy drinks are very popular. Caffeine is the most commonly consumed drug in the world. 90% of adults in North America consume caffeine on a daily basis. Worldwide caffeine consumption is estimated at 120,000 tons per year, making it the most popular psychoactive substance in the world. This equates to one serving of a caffeinated drink for each person per day.

Chemistry of caffeine

Caffeine, or 1,3,7-trimethylpurine-2,6-dione, is an alkaloid with a substituted xanthine core. Xanthine is a substituted purine that consists of two fused rings: a pyrimidine and an imidazole. Pryimidin is a six-membered ring with nitrogen components at R1 and R3; Imidazole is a five-membered ring with nitrogen substituents on R1 and R3. Xanthine contains oxygen groups that are doubly 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 substance.

The xanthine nucleus of caffeine contains two fused rings, a pyrimidinedione and an imidazole. The pyrimidinedione, in turn, contains two functional amide groups that are predominantly present in a zwitterionic resonance, i.e. at the point where the nitrogen atoms are doubly bonded to the neighboring amide carbon atoms. Thus all six atoms within the pyrimidinedione ring system are sp2-hybridized and planar. The fused 5,6-ring core of caffeine contains a total of ten pi-electrons and is therefore aromatic according to Hückel's rule.

Pure, anhydrous caffeine is a bitter-tasting, white, odorless powder with a melting point of 235-238 ° C. Caffeine is moderately soluble in water (2 g / 100 mL) at room temperature, 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 (conjugate acid pKa = ~ 0.6) and requires a strong acid to protonate it. Caffeine does not contain any stereogenic centers and is therefore classified as an achiral molecule.

Pharmacology of caffeine

In the absence of caffeine and when a person is awake and alert, little adenosine is present in (CNS) neurons. With continued wakefulness, over time, adenosine accumulates in the neuronal synapse, which in turn binds to and activates adenosine receptors located on specific CNS neurons; when these receptors are activated, they create a cellular response that ultimately increases drowsiness. When caffeine is consumed, it antagonizes the adenosine receptors; in other words, caffeine prevents adenine from activating the receptor by blocking the site on the receptor where adenosine attaches to it. As a result, caffeine temporarily prevents or relieves drowsiness, maintaining or restoring alertness.

The main mechanism of action of caffeine is as a non-selective antagonist at the adenosine A1 and A2A receptors. During the waking state, the level of the neurotransmitter adenosine in the brain rises steadily and triggers tiredness and sleepiness. The caffeine molecule is structurally similar to adenosine, which means that it can bind to adenosine receptors on the cell surface without activating them, and thus acts as a competitive inhibitor.

In addition, caffeine affects most of the other major neurotransmitters, including dopamine, acetylcholine, serotonin, and, in high doses, norepinephrine, and to a lesser extent epinephrine, glutamate, and cortisol. In high doses exceeding 500 milligrams, caffeine inhibits GABA neurotransmission. The GABA reduction explains why high doses of caffeine increase anxiety, insomnia, palpitations, and respiratory rate.

Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and distributed to all body tissues. The maximum blood concentration is reached within 1-2 hours. It is eliminated with first order kinetics. Caffeine can also be absorbed rectally, as evidenced by suppositories made from ergotamine tartrate and caffeine (to relieve migraines) and from chlorobutanol and caffeine (to treat hyperemesis). However, rectal absorption is less efficient than oral: the maximum concentration (Cmax) and the 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 the antagonism of the A2A receptor as being responsible for the wakefulness of caffeine. The antagonism of A2A receptors in the ventrolateral preoptic area (VLPO) reduces the inhibitory GABA neurotransmission to the nucleus tuberomammillaris, a histaminergic projection nucleus that promotes arousal depending on activation. This disinhibition of the tuberomammillary core is the downstream mechanism by which caffeine creates wakefulness-promoting effects. Caffeine is an antagonist of all four adenosine receptor subtypes (A1, A2A, A2B and A3), but with different potencies. The affinity values ​​(KD) of caffeine for the human adenosine receptors are 12 μM on A1, 2.4 μM on A2A, 13 μM on A2B and 80 μM on A3.

Metabolic products

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, specifically the CYP1A2 isoenzyme, into three dimethylxanthines, each of which has its own effect on the body:

  • Paraxanthin (84%): Increases lipolysis, which leads to increased glycerol and free fatty acid levels in the blood plasma.
  • Theobromine (12%): dilates blood vessels and increases urine volume. Theobromine is also the main alkaloid in cocoa beans and thus in chocolate.
  • Theophylline (4%): Relaxes the smooth muscles of the bronchi and is used to treat asthma. However, the therapeutic dose of theophylline is many times higher than the values ​​achieved through caffeine metabolism.

Physical effects of caffeine

  • Stimulation - Caffeine is described as being light to moderately energetic and stimulating, in ways that are significantly weaker than traditional recreational stimulants like amphetamine, MDMA, or cocaine. This encourages physical activities such as doing household chores and repetitive tasks that would otherwise be boring and strenuous physical activities. The particular kind of stimulation that caffeine provides can be described as forced. This means that at higher dosages it becomes difficult or impossible to hold still because of jaw clenching, involuntary body tremors, and vibrations, resulting in extreme entire body tremors, restlessness in the hands, and a general lack of motor control.
  • Appetite suppression
  • Bronchodilation - Caffeine is a powerful bronchodilator. Clinical tests on adults with asthma have shown that caffeine at relatively low doses (5mg / kg body weight) causes a small improvement in lung function.
  • Dizziness - This effect is not common except when doses are too high or when taken when you are tired or have low blood sugar.
  • Frequent Urination - If people who have not consumed caffeine in the days before are given a dose of caffeine equivalent to 2-3 cups of coffee, there will be a slight increase in urine output, but most people who consume caffeine put it on daily yourself. It has been shown that regular caffeine users develop a strong tolerance to the diuretic effects.
  • Headache and Headache Suppression - Caffeine can suppress headaches at light and usual dosages, but can cause headaches at higher dosages. This is likely due to its vasoconstricting and vasodilating effects.
  • High blood pressure
  • Increased heart rate
  • Increased perspiration
  • Nausea - Moderate to extreme nausea has been reported to occur, typically at higher dosages.
  • Increased Endurance - This effect is relatively mild compared to other stimulants such as amphetamines.
  • Tactile reinforcement
  • Teeth grinding - This effect does not occur as consistently as with other stimulants such as amphetamine or MDMA.
  • Vasoconstriction and Vasodilation - While caffeine acts as a mild vasoconstrictor, its metabolite theobromine is a vasodilator and these effects are believed to be mutually exclusive.

Cognitive effects of caffeine

Although negative side effects are usually mild with low to moderate dosages, they become increasingly likely with higher amounts or prolonged use. This is especially true during the withdrawal of the experience. In general, some of the best known of these cognitive effects include:

  • Reinforcement of the analysis
  • anxiety
  • Cognitive Euphoria - This effect, when it occurs, is generally mild compared to most psychoactive stimulants and usually only occurs in those with low tolerance levels.
  • Cognitive Dysphoria - This effect typically only occurs at high to extremely high dosages.
  • Compulsive re-dosing - This effect is less pronounced than with nicotine or cocaine.
  • Ego bloating
  • Concentration Boost - This component is most effective at low to moderate dosages, as anything higher will usually affect concentration.
  • Increased libido
  • Increased feeling for music - while caffeine is able to produce this effect, it does not do so as reliably as with traditional stimulants or entactogens.
  • irritability
  • Memory enhancement
  • Improvement of motivation
  • Speed ​​up thinking
  • alertness

Aftermath of caffeine

The effects that occur during the offset of a stimulant experience generally feel negative and uncomfortable compared to the effects that occurred during the peak. Caffeine blocks adenosine receptors, causing adenosine to build up during climax. During the offset experience, the adenosine built up activates the previously blocked receptors to a much greater degree than they normally would, 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 amphetamines and cocaine. The general effects include:

Oral dosage of caffeine

WARNING: Always start with lower doses due to the differences between individual body weight, tolerance, metabolism and personal sensitivity. See safer use.

Oral duration of action of caffeine

Nasally drawn dosage of caffeine

Nasally drawn duration of action of caffeine

Toxicity and potential harm (dangers) of caffeine

Caffeine is not known to cause brain damage, and its toxicity is extremely low in relation to the dose. There are relatively few physical side effects associated with caffeine exposure. Various studies have shown that at reasonable doses in a careful context it has no negative cognitive, psychiatric or toxic physical consequences of any kind.

Deadly dose

Extreme overdose can result in death. The median lethal dose (LD50) for oral administration is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans depends on the individual sensitivity, but is estimated to be around 150 to 200 milligrams per kilogram Body mass or something 80 to 100 cups of coffee estimated for the average adult. While reaching the lethal dose of caffeine with regular coffee would be difficult, it's easier to high doses of caffeine tablets and the lethal dose may be lower in individuals whose ability to metabolize caffeine is compromised.

It is strongly recommended that safer use practices be followed when using this substance.

Dependency and Abuse Potential

With chronic use, caffeine creates addiction and has a low potential for abuse. If addiction has developed, food cravings and withdrawal symptoms will occur if you suddenly stop using it.

With prolonged and repeated consumption, tolerance to many of the effects of caffeine develops. This results in the user having to administer larger and larger doses in order to achieve the same effect. After tolerance has developed, it takes about 3 to 7 days for tolerance to halve and 1 to 2 weeks for it to return to baseline without further consumption. Caffeine shows cross-tolerance with antagonists of the adenosine receptors, which means that after consuming caffeine, certain stimulants such as theacrine and theobromine have a decreased effect.

Withdrawal symptoms

Withdrawal symptoms - including headache, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints - can occur within 12 to 24 hours of stopping caffeine, peak after about 48 hours, and usually last 2 to 9 days. 21] Withdrawal headaches occur in 52% of people who have stopped using caffeine for two days after consuming an average of 235 mg of caffeine per day. Symptoms such as increased depression and anxiety, nausea, vomiting, physical pain, and intense cravings for beverages containing caffeine have also been reported in long-term caffeine users. Knowledge, support, and interaction with peers can facilitate withdrawal.


There is limited evidence that high doses or chronic abuse of caffeine can induce psychosis in normal people and worsen pre-existing psychosis in people diagnosed with schizophrenia. Caffeine has been shown to increase the effects of methamphetamine, which is also a Can trigger psychosis.

Dangerous interactions (mixed consumption)

While many psychoactive substances are reasonably safe on their own, when combined with other substances they can suddenly become dangerous or even life-threatening. The following list contains some known dangerous combinations (although it is guaranteed not to contain all of them). Independent research (e.g., Google, DuckDuckGo) should always be done to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions were taken from TripSit.

  • DOx - High doses of caffeine can cause anxiety states that are less manageable when tripping, and since both are stimulant, there may be some physical discomfort.
  • 25x-NBOMe - Caffeine can bring out the natural stimulation of psychedelic drugs to make them uncomfortable. High doses can cause anxiety that is difficult to manage when tripping.
  • ΑMT - High doses of caffeine can cause anxiety that is less manageable when tripping, and since both are stimulant, the combination can cause some physical discomfort.
  • PCP - The details of this combination aren't well understood, but PCP generally interacts in unpredictable ways.
  • Amphetamines - This combination of stimulants is generally not necessary and can increase the stress on the heart and possibly cause anxiety and greater physical discomfort.
  • MDMA - Caffeine is not absolutely necessary in combination with MDMA and increases the neurotoxic effects of MDMA.
  • Cocaine - Both stimulants, risk of tachycardia, high blood pressure and, in extreme cases, heart failure.

Legal situation of caffeine

Caffeine is legal in almost 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) limits the caffeine content of beverages to less than 0.02% unless they are listed as a dietary supplement.

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Large parts of this article are direct translations from the PsychonautsWiki.

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