Caffeine

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For the coffee plant, see Coffea (botany).
Summary sheet: Caffeine
Caffeine
Caffeine.svg
Chemical Nomenclature
Common names Caffeine
Substitutive name 1,3,7-Trimethylxanthine[1]
Systematic name 1,3,7-Trimethylpurine-2,6-dione[1]
Class Membership
Psychoactive class Stimulant
Chemical class Xanthine
Routes of Administration

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


⇣ Smoked
Dosage
Bioavailability Vaped (not effective when smoked).
Threshold 25 mg
Light 25 - 75 mg
Common 75 - 125 mg
Strong 125 - 175 mg
Heavy 175 mg +
Duration
Total 45 - 70 minutes
Onset 2 - 5 minutes
Peak 10 - 20 minutes
Offset 30 - 45 minutes
After effects 2 - 4 hours
⇣ Oral
Dosage
Bioavailability ~100%
Threshold 10 mg
Light 20 - 50 mg
Common 50 - 150 mg
Strong 150 - 500 mg
Heavy 500 mg +
Duration
Total 2 - 5 hours
Onset 5 - 10 minutes
Come up 10 - 60 minutes
Peak 1 - 2 hours
Offset 6 - 10 hours
After effects 2 - 4 hours



⇣ Insufflated
Dosage
Bioavailability Caffeine's poor water solubility significantly limits its absorption through nasal membranes.
Threshold 2.5 mg
Light 10 - 25 mg
Common 25 - 40 mg
Strong 40 - 80 mg
Heavy 80 mg +
Duration
Total 1 - 2.5 hours
Onset 0.5 - 2 minutes
Come up 0.5 - 2 minutes
Peak 0.5 - 1 hours
Offset 6 - 10 hours
After effects 6 - 24 hours






DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Interactions
DOx
25x-NBOMe
ΑMT
PCP
Amphetamines
MDMA
Cocaine

Caffeine (also known as 1,3,7-Trimethylxanthine) 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.[2][3][4] 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.[citation needed]

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.[5]

History and culture

The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears in the middle of the 15th century, in Yemen's Sufi monasteries.[6] The Sufi monks drank coffee as an aid to concentration and even spiritual intoxication when they chanted the name of God.[7]

Caffeine is found in tea leaves. Tea ceremonies are a tradition practiced throughout East Asia, particularly Japan, Korea, and other regions.

Chemistry

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.[8]

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.[9]

Pharmacology

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.[10]

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.[11]

Alongside this, caffeine also has effects on most of the other major neurotransmitters, including dopamine, acetylcholine, serotonin, and, in high doses, on norepinephrine,[12] and to a small extent epinephrine, glutamate, and cortisol. Caffeine increases norepinephrine by about 75%, dopamine by 100%, epinephrine by 207%, and glutamate by 100% in studies.[13][14]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.[15]

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.[16]

710px-Caffeine metabolites.svg.png

Metabolites

Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines,[17] 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.

Subjective effects

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 ☠.


Physical effects
Child.svg

    • 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.[18]
    • 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.[19] 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.[19]
    • 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 it having both vasoconstricting and vasodilating effects.
    • Increased blood pressure[20]
    • Increased heart rate[21]
    • Increased perspiration[citation needed]
    • 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[22] and Vasodilation[23] - Whilst caffeine acts as a mild vasoconstrictor, its metabolite theobromine is a vasodilator and these effects are thought to cancel each other out.

Cognitive effects
User.svg

After effects
Aftereffects (3).svg

Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

Additional experience reports can be found here:

Forms

NoDoz caffeine tablets containing 200 milligrams of caffeine each, distributed by Novartis Consumer Health, Inc.

Caffeine is not just encountered in coffee and tea, but also in readily available forms like pharmaceutical grade caffeine tablets (and sometimes caffeine patches), making it a widely accessible stimulant.

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.

Lethal dosage

Extreme overdose can result in death.[24][25] 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.[26] Though achieving lethal dose of caffeine would be difficult with regular coffee, it is easier to reach high doses with caffeine pills or dry scooping, 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.

Main symptoms of caffeine overdose.png

Anxiety disorder

Caffeine-induced anxiety disorder is a condition where excessive caffeine consumption triggers or exacerbates anxiety symptoms. High intake (>400mg) can lead to panic attacks, especially in susceptible individuals, and may worsen existing anxiety disorders.[27]

Sleep disorder

Caffeine-induced sleep disorder is a psychiatric disorder that results from overconsumption of the stimulant caffeine.

Dependence and abuse potential

Caffeine dependence can develop with regular consumption, leading to cravings and withdrawal effects upon sudden cessation, but has low abuse potential. While it has a low potential for abuse compared to other substances, habitual users may experience difficulty quitting due to these dependence-related effects.

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.

Caffenism

Caffeinism is a state of intoxication caused by excessive consumption of caffeine. This syndrome regularly happens when a person ingested large amounts of caffeine from any source (e.g., more than 400–500 mg at a time).

Withdrawal symptoms

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.[28] 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.[29] 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.

Psychosis

Main article: Stimulant psychosis

Caffeine-induced psychosis, though rare, may occur with high doses or chronic abuse. It can trigger psychosis in healthy individuals and worsen it in those with schizophrenia.[30][31] Caffeine has been shown to potentiate the effects of methamphetamine, which can also induce psychosis.[32][33]

Dangerous interactions

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.

Legal status

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.[34] unless they are listed as a dietary supplement.[35]

See also

External links

Literature

  • 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

References

  1. ↑ 1.0 1.1 PubChem, Caffeine 
  2. ↑ Ashihara, H. (2004). "Distribution and biosynthesis of caffeine in plants". Frontiers in Bioscience. 9 (1–3): 1864. doi:10.2741/1367. ISSN 1093-9946. 
  3. ↑ 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. 
  4. ↑ 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. 
  5. ↑ What's your poison? Caffeine | http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm
  6. ↑ Weinberg, Bennett Alan; Bealer, Bonnie K. (2001). The world of caffeine. Routledge. pp. 3–4. ISBN 978-0-415-92723-9. 
  7. ↑ McHugo, John (18 April 2013). "How a drink downed by Arab mystics went global". BBC News. 
  8. ↑ Keskineva N., Chemistry of Caffeine, East Stroudsburg University 
  9. ↑ Vallombroso, T. (2001). Organic chemistry: pearls of wisdom. Boston Medical Pub. ISBN 9781584090168. 
  10. ↑ "Caffeine". DrugBank. University of Alberta. 16 September 2013. Retrieved 8 August 2014.
  11. ↑ 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. 
  12. ↑ Caffeine & Neurotransmitters – WORLD OF CAFFINE 
  13. ↑ https://www.nejm.org/doi/full/10.1056/NEJM197801262980403
  14. ↑ https://www.jneurosci.org/content/22/15/6321
  15. ↑ 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. 
  16. ↑ 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. 
  17. ↑ The Pharmacogenetics and Pharmacogenomics Knowledge Base | https://www.pharmgkb.org/drug/PA448710#biotransformation
  18. ↑ 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. 
  19. ↑ 19.0 19.1 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. 
  20. ↑ 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. 
  21. ↑ 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. 
  22. ↑ 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. 
  23. ↑ 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. 
  24. ↑ 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. 
  25. ↑ 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. 
  26. ↑ 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. 
  27. ↑ Klevebrant, Lisa; Frick, Andreas (2022-01-01). "Effects of caffeine on anxiety and panic attacks in patients with panic disorder: A systematic review and meta-analysis". General Hospital Psychiatry (in English). 74: 22–31. doi:10.1016/j.genhosppsych.2021.11.005 Freely accessible. ISSN 0163-8343. PMID 34871964. 
  28. ↑ 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. 
  29. ↑ 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. 
  30. ↑ 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. 
  31. ↑ 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. 
  32. ↑ 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. 
  33. ↑ 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. 
  34. ↑ CFR - Code of Federal Regulations Title 21 
  35. ↑ Consumer Q&A: Caffeine-Containing Dietary Supplements | http://crnusa.org/caffeine/Q+A.html


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