Caffeine
4 sources
Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as Caffeine, coffeePW
For the coffee plant, see Coffea (botany). Summary sheet: CaffeinePW
Insufflated
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 2.5 mg | 10–25 mg | 25–40 mg | 40–80 mg | 80 mg+ |
| Onset | 0.5–2 minutes |
|---|---|
| Come-up | 0.5–2 minutes |
| Peak | 0.5–1 hours |
| Offset | 6–10 hours |
| Total | 1–2.5 hours |
| After-effects | 6–24 hours |
Oral
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 10 mg | 20–50 mg | 50–150 mg | 150–500 mg | 500 mg+ |
| Onset | 5–10 minutes |
|---|---|
| Come-up | 10–60 minutes |
| Peak | 1–2 hours |
| Offset | 6–10 hours |
| Total | 2–5 hours |
| After-effects | 2–4 hours |
Smoked
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 25 mg | 25–75 mg | 75–125 mg | 125–175 mg | 175 mg+ |
| Onset | 2–5 minutes |
|---|---|
| Peak | 10–20 minutes |
| Offset | 30–45 minutes |
| Total | 45–70 minutes |
| After-effects | 2–4 hours |
🧬 Receptor activityPHDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Adenosine receptor A2a | — | Ki 2480 nM | CHEMBL | TargetAdenosine receptor A2a Action— AffinityKi 2480 nM SourceCHEMBL |
| Adenosine receptor A2b | — | Ki 10000 nM | CHEMBL | TargetAdenosine receptor A2b Action— AffinityKi 10000 nM SourceCHEMBL |
| Adenosine receptor A1 | — | Ki 10000 nM | CHEMBL | TargetAdenosine receptor A1 Action— AffinityKi 10000 nM SourceCHEMBL |
| Guanine deaminase | — | Ki 10200 nM | CHEMBL | TargetGuanine deaminase Action— AffinityKi 10200 nM SourceCHEMBL |
| Adenosine receptor A3 | — | Ki 12589.25 nM | CHEMBL | TargetAdenosine receptor A3 Action— AffinityKi 12589.25 nM SourceCHEMBL |
| Adenosine receptor | — | Ki 15000 nM | CHEMBL | TargetAdenosine receptor Action— AffinityKi 15000 nM SourceCHEMBL |
| Adenosine A2 receptor | — | Ki 27000 nM | CHEMBL | TargetAdenosine A2 receptor Action— AffinityKi 27000 nM SourceCHEMBL |
| Unchecked | — | Ki 50000 nM | CHEMBL | TargetUnchecked Action— AffinityKi 50000 nM SourceCHEMBL |
| GABA-A receptor; anion channel | — | Ki 100000 nM | CHEMBL | TargetGABA-A receptor; anion channel Action— AffinityKi 100000 nM SourceCHEMBL |
| Amine oxidase [flavin-containing] B | — | Ki 3600000 nM | CHEMBL | TargetAmine oxidase [flavin-containing] B Action— AffinityKi 3600000 nM SourceCHEMBL |
| Adenosine receptor A1 (ADORA1) | Antagonist | 4.97 Ki | DRUGCENTRAL | TargetAdenosine receptor A1 (ADORA1) ActionAntagonist Affinity4.97 Ki SourceDRUGCENTRAL |
| Adenosine receptor A2a (ADORA2A) | Antagonist | 5.61 Ki | DRUGCENTRAL | TargetAdenosine receptor A2a (ADORA2A) ActionAntagonist Affinity5.61 Ki SourceDRUGCENTRAL |
| Adenosine receptor A2b (ADORA2B) | Antagonist | 4.77 Ki | DRUGCENTRAL | TargetAdenosine receptor A2b (ADORA2B) ActionAntagonist Affinity4.77 Ki SourceDRUGCENTRAL |
| Adenosine receptor A3 (ADORA3) | Antagonist | 4.33 Ki | DRUGCENTRAL | TargetAdenosine receptor A3 (ADORA3) ActionAntagonist Affinity4.33 Ki SourceDRUGCENTRAL |
| Acetylcholinesterase (ACHE) | — | 5.14 IC50 | DRUGCENTRAL | TargetAcetylcholinesterase (ACHE) Action— Affinity5.14 IC50 SourceDRUGCENTRAL |
| Adenosine A2 receptor (Adora2b) | — | 4.57 Ki | DRUGCENTRAL | TargetAdenosine A2 receptor (Adora2b) Action— Affinity4.57 Ki SourceDRUGCENTRAL |
| Adenosine A2a receptor (ADORA2A) | — | 4.1 Ki | DRUGCENTRAL | TargetAdenosine A2a receptor (ADORA2A) Action— Affinity4.1 Ki SourceDRUGCENTRAL |
| Adenosine receptor (Adora1) | — | 4.22 Ki | DRUGCENTRAL | TargetAdenosine receptor (Adora1) Action— Affinity4.22 Ki SourceDRUGCENTRAL |
| Adenosine receptor A1 (Adora1) | — | 4.77 Ki | DRUGCENTRAL | TargetAdenosine receptor A1 (Adora1) Action— Affinity4.77 Ki SourceDRUGCENTRAL |
| Adenosine receptor A2a (Adora2a) | — | 5.03 Ki | DRUGCENTRAL | TargetAdenosine receptor A2a (Adora2a) Action— Affinity5.03 Ki SourceDRUGCENTRAL |
| Glycogen phosphorylase, muscle form (PYGM) | — | 4.13 IC50 | DRUGCENTRAL | TargetGlycogen phosphorylase, muscle form (PYGM) Action— Affinity4.13 IC50 SourceDRUGCENTRAL |
| Guanine deaminase (GDA) | — | 4.99 Ki | DRUGCENTRAL | TargetGuanine deaminase (GDA) Action— Affinity4.99 Ki SourceDRUGCENTRAL |
| Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD) | — | 4.12 IC50 | DRUGCENTRAL | TargetPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD) Action— Affinity4.12 IC50 SourceDRUGCENTRAL |
| Potassium voltage-gated channel subfamily H member 2 (KCNH2) | — | 5.31 IC50 | DRUGCENTRAL | TargetPotassium voltage-gated channel subfamily H member 2 (KCNH2) Action— Affinity5.31 IC50 SourceDRUGCENTRAL |
Mechanism of actionPH
The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: **General and cellular actions** Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. **Respiratory** The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. **Central nervous system** Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. **Renal system** Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. **Cardiovascular system** Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain.
Caffeine competitively inhibits phosphodiesterase, the enzyme that degrades cyclic 3',5'-adenosine monophosphate (AMP). Increased levels of intracellular cyclic AMP mediate most of caffeine's pharmacologic actions.
Caffeine stimulates all levels of the CNS... Caffeine's cortical effects are milder and of shorter duration than those of amphetamines. In slightly larger doses, caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate.
Caffeine constricts cerebral vasculature. In contrast, the drug directly dilates peripheral blood vessels...
PharmacodynamicsPH
Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic.
Pharmacokinetics
Half-lifePH
In an average-sized adult or child above the age of 9, the half-life of caffeine is approximately 5 hours. Various characteristics and conditions can alter caffeine half-life. It can be reduced by up to 50% in smokers. Pregnant women show an increased half-life of 15 hours or higher, especially in the third trimester. The half-life in newborns is prolonged to about 8 hours at full-term and 100 hours in premature infants, likely due to reduced ability to metabolize it. Liver disease or drugs that inhibit CYP1A2 can increase caffeine half-life.
Elimination 1/2 life in adults = 2.5-4.5 hours; [Reference #1]
Caffeine has a plasma half-life (t1/2) of 3 to 5 hours in adults. In one study, when administered to pregnant women prior to delivery, caffeine had a prolonged mean half-life of 80 hours in neonates after delivery.
Mean half-life /T 1/2/ and fraction excreted unchanged in urine of caffeine in infants have been shown to be inversely related to gestational/postconceptual age. In neonates, the /T 1/2/ is approximately 3-4 days...
The half-time for caffeine is 0.7-1.0 hr in rats and mice, 1-1.6 hr in rabbits, 3-5 hr in monkeys, 4-4.3 hr in dogs and 11-12 hr in baboons.
/The authors/ studied 17 preterm infants receiving caffeine, and measured their plasma levels of caffeine and the theophylline metabolite by high-pressure liquid chromatography. The half-life was calculated by computer analysis using the least-square method. The mean gestational age of our patients was 29.7 +/- 1.9 weeks (mean +/- SD) and they were studied at 20.7 +/- 6.6 days (mean +/- SD) postnatal age. The caffeine half-life was 52.03 +/- 23.87 hr (means +/- SD) and the theophylline half-life was 77.04 +/- 65.01 hr (mean +/- SD).
AbsorptionPH
Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults.
The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules.
Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population.
The clearance of caffeine varies, but on average, is about 0.078 L/kg/h (1.3 mL/min/kg).
World-wide, many fetuses and infants are exposed to methylxanthines via maternal consumption of coffee and other beverages containing these substances. Methylxanthines (caffeine, theophylline and aminophylline) are also commonly used as a medication for apnea of prematurity. ... Methylxanthines readily passes the placenta barrier and enters all tissues and thus may affect the fetus/newborn at any time during pregnancy or postnatal life, given that the effector systems are mature. ...
Caffeine and citrated caffeine are well absorbed following oral administration. Absorption of caffeine following oral administration may be more rapid than that following IM injection of caffeine and sodium benzoate. Absorption following rectal administration of caffeine in suppositories may be slow and erratic. ... Following oral administration of 100 mg of caffeine (as coffee), peak plasma concentrations of about 1.5-1.8 ug/mL are reached after 50-75 minutes.
MetabolismPH
Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2) also participate in the metabolism of caffeine.
Caffeine is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by isoenzyme 1A2. Therefore, caffeine has the potential to interact with drugs that are metabolized by CYP1A2 or with drugs that induce or inhibit this isoenzyme.
In adults, the drug is rapidly metabolized in the liver to 1-methyluric acid, 1-methylxanthine, and 7-methylxanthine.
Interconversion between caffeine and theophylline has been reported in preterm neonates...
In-vivo and in-vitro experiments showed a progressive increase in the activity of the hepatic microsomal enzymes that metabolize caffeine during neonatal development. In beagle puppies, change in caffeine clearance was determined by the rate of maturation of caffeine-7-demethylase. Caffeine is eliminated in animals by biotransformation in the liver to dimethylxanthines, dimethyl- and monomethyluric acids and uracil derivatives; important quantitative differences have been demonstrated in the formation and elimination of metabolites in rats, mice and Chinese hamsters. These differences are even more important in monkeys, where caffeine is almost completely metabolized to theophylline. ... Some species-dependent metabolites have been identified. Trimethylallantoin was first reported in rats. A ... derivative of paraxanthine was found in mice and identified as the 3-beta-D-glucuronide of paraxanthine. Methylated ureas and sulfur-containing derivatives found in urine in trace amounts are produced by the intestinal flora. In contrast, the acetylated uracil derivative, 5-acetylamino-6-formylamino-3-methyluracil, one of the most important caffeine metabolites in humans, has not been identified in rodents or other animal species. Other uracil derivatives produced from caffeine, theobromine and paraxanthine in rats were found in human urine. In rats, the hepatic demethylation of caffeine shows an age-related decline, resulting in a greatly increased elimination half-time in older adult rats.
Caffeine metabolism is qualitatively relatively similar in animals and humans ... . The main metabolic pathways are: demethylation and hydroxylation of the 8-position leading to the formation of the respective uracil and uric acid derivatives. There are, however, some quantitative differences in the metabolic profile. Humans are characterized by the importance of 3-methyl demethylation leading to the formation of paraxanthine and especially metabolites thereof through subsequent metabolic steps. The main urinary metabolites in humans are 1-methyluric acid, 1-methylxanthine, 5-acetylamino-6-formylamino-3- methyluracil (not found in rats and mice), 1,7-dimethyluric acid and paraxanthin. In rats and mice, the metabolism of caffeine is predominantly via theobromine and theophylline. The main urinary metabolites are 1,3-dimethyluracil, paraxanthine, trimethyluric acid, theophylline, and theobromine. Caffeine metabolism decreases during pregnancy, resulting in higher serum concentrations.
Protein bindingPH
Plasma protein binding of caffeine has not been determined for neonates or infants. In vitro studies indicate a protein binding of about 10%-36%. Caffeine is reversibly bound to plasma proteins.
Plan a dose of Caffeine
Loading the fact-sheet…
Logging a dose needs somewhere to keep it. Start a free session — no signup; it and everything in it expire in 7 days.
External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.