Pseudoephedrine

Pseudoephedrine

Systematic (IUPAC) name
(S,S)-2-methylamino-1-phenylpropan-1-ol
Clinical data
Trade names	Afrinol, Sudafed, Sinutab(UK)
AHFS/Drugs.com	monograph
MedlinePlus	a682619
Pregnancy cat.	B2(AU) C(US)
Legal status	Pharmacist Only (S3) (AU) ? (CA) P (UK) OTC (US)
Routes	oral
Pharmacokinetic data
Bioavailability	~100%[1]
Metabolism	hepatic (10–30%)
Half-life	4.3-8 hours[1]
Excretion	43-96% renal[1]
Identifiers
CAS number	90-82-4 Y
ATC code	R01BA02
PubChem	CID 7028
DrugBank	DB00852
ChemSpider	6761 Y
UNII	7CUC9DDI9F Y
KEGG	D08449 Y
ChEBI	CHEBI:51209 N
ChEMBL	CHEMBL1590 Y
Chemical data
Formula	C10H15NO
Mol. mass	165.23
SMILES	eMolecules & PubChem
InChI InChI=1S/C10H15NO/c1-8(11-2)10(12)9-6-4-3-5-7-9/h3-8,10-12H,1-2H3/t8-,10+/m0/s1 Y Key:KWGRBVOPPLSCSI-WCBMZHEXSA-N Y
N(what is this?)  (verify)

Pseudoephedrine ( /ˌsuːdoʊ.ɨˈfɛdrɪn/ or /ˌsuːdoʊˈɛfɨdriːn/; PSE) is a sympathomimetic drug of the phenethylamine and amphetamine chemical classes. It is used as a nasal/sinus decongestant and stimulant, or as a wakefulness-promoting agent. The salts pseudoephedrine hydrochloride and pseudoephedrine sulfate are found in many over-the-counter preparations either as a single ingredient or, more commonly, in combination with antihistamines, guaifenesin, dextromethorphan, paracetamol (acetaminophen), and/or NSAIDs (e.g., aspirin, ibuprofen, etc.).

Chemistry

Pseudoephedrine is a diastereomer of ephedrine and is readily reduced into methamphetamine or oxidized into methcathinone.

Two pairs of enantiomers: Ephedrine (top) and Pseudoephedrine (bottom)

Nomenclature

The dextrorotary (+)- or d- enantiomer is (1S,2S)-Pseudoephedrine, whereas the levorotating (−)- or l- form is (1R,2R)-Pseudoephedrine.

In the outdated d/l system (+)-Pseudoephedrine is also referred to as l-Pseudoephedrine and (−)-Pseudoephedrine as d-Pseudoephedrine (in the Fisher projection then the phenylring is drawn at bottom). ^{[2] [3]}

Often the d/l system (with small caps) and the d/l system (with lower-case) are confused. The result is that the dextrorotary d-Pseudoephedrine is wrongly named d-Pseudoephedrine and the levorotary l-Ephedrine (the diastereomer) wrongly l-Ephedrine.

The IUPAC names of the two enantiomers are (1S,2S)- respectively (1R,2R)-2-methylamino-1-phenylpropan-1-ol. Synonyms for both are psi-Ephedrine and threo-Ephedrine.

Pseudoephedrine is the International Nonproprietary Name (INN) of the (+)-form, when used as pharmaceutical substance. ^[4]

Synthesis

Although pseudoephedrine occurs naturally as an alkaloid in certain plant species (for example, as a constituent of extracts from the ephedra species, also known as Ma Huang, in which it occurs together with other isomers of ephedrine), the majority of pseudoephedrine produced for commercial use is derived from yeast fermentation of dextrose in the presence of benzaldehyde. In this process, specialized strains of yeast (typically a variety of Candida utilis or Saccharomyces cerevisiae) are added to large vats containing water, dextrose and the enzyme pyruvate decarboxylase (such as found in beets and other plants). After the yeast has begun fermenting the dextrose, the benzaldehyde is added to the vats, and in this environment the yeast converts the ingredients to the precursor l-phenylacetylcarbinol (L-PAC). L-PAC is then chemically converted to pseudoephedrine via reductive amination.^[5]

The bulk of pseudoephedrine is produced by commercial pharmaceutical manufacturers in India and China, where economic and industrial conditions favor the mass production of pseudoephedrine for export.^[6]

Mechanism of action

Pseudoephedrine is a sympathomimetic amine. Its principal mechanism of action relies on its indirect action on the adrenergic receptor system. The vasoconstriction that pseudoephedrine produces is believed to be principally an α-adrenergic receptor response. ^[7]

While it may have weak or no direct agonist activity at α- and β-adrenergic receptors, the principal mechanism is to cause the release of endogenous norepinephrine (noradrenaline) from storage vesicles in presynaptic neurons. The displaced noradrenaline is released into the neuronal synapse where it is free to activate the postsynaptic adrenergic receptors. These adrenergic receptors are located on the muscles lining the walls of blood vessels. When these receptors are activated by noradrenaline, the muscles contract, causing the blood vessels to constrict (vasoconstriction). The constricted blood vessels now allow less fluid to leave the blood vessels and enter the nose, throat and sinus linings, which results in decreased inflammation of nasal membranes as well as decreased mucus production. Thus, by constriction of blood vessels, mainly those located in the nasal passages, pseudoephedrine causes a decrease in the symptoms of nasal congestion.

Medical uses

Pseudoephedrine is a stimulant, but it is well known for shrinking swollen nasal mucous membranes; for this reason, it is often used as a decongestant. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. Other beneficial effects may include increasing the drainage of sinus secretions, and opening of obstructed Eustachian tubes. The same vasoconstriction action can also result in hypertension, which is a noted side effect of pseudoephedrine.

Pseudoephedrine can be used either as oral or as topical decongestant. The advantage of oral pseudoephedrine over topical nasal preparations, such as oxymetazoline, is that it does not cause rebound congestion (rhinitis medicamentosa). However, due to its stimulating qualities, it is more likely to cause adverse effects, including hypertension, sweating, insomnia, and anxiety.

Pseudoephedrine may be useful as antitussive drug (suppressing of cough). ^[8]

Indications

Pseudoephedrine is indicated for the treatment of:

• nasal congestion
• sinus congestion
• Eustachian tube congestion.^[9]

Pseudoephedrine is also indicated for vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis.^[9]

Pseudoephedrine is also used as first-line therapy of priapism^{[citation needed]}. Erection is largely a parasympathetic response, so the sympathetic action of pseudoephedrine may serve to relieve this condition.

Treatment for urinary incontinence is an off-label use (a.k.a. "unlabeled use") for these medications.^[10]

Adverse effects

Common adverse drug reactions (ADRs) associated with pseudoephedrine therapy include: CNS stimulation, insomnia, nervousness, excitability, dizziness and anxiety. Infrequent ADRs include: tachycardia and/or palpitations. Rarely, pseudoephedrine therapy may be associated with mydriasis (blurred vision), hallucinations, arrhythmias, hypertension, seizures and ischemic colitis;^[11] as well as severe skin reactions known as recurrent pseudo-scarlatina, systemic contact dermatitis, and nonpigmenting fixed drug eruption.^[12] Pseudoephedrine, particularly in high doses, may also cause episodes of paranoid psychosis.^[13] It has also been reported that pseudoephedrine, amongst other sympathomimetic agents, may be associated with the occurrence of stroke.^[14]

Precautions and contraindications

It is recommended that pseudoephedrine not be used in patients with: diabetes mellitus, cardiovascular disease, severe or uncontrolled hypertension, severe coronary artery disease, prostatic hypertrophy, hyperthyroidism, closed angle glaucoma, or pregnant women.^[11]

Patients who are prone to anxiety or panic attacks should use pseudoephedrine with caution, as anxiety and restlessness are common side effects, mostly due to the drug's stimulant properties.

Since nasal congestion is considered to be a relatively minor ailment, alternatives are preferred in patients with these conditions. Appropriate alternatives may include saline sprays/instillations, depending on the patient's condition. Topical decongestants should be used with caution and for no longer than three days to avoid Rhinitis medicamentosa.

People with bipolar disorder should use care when taking pseudoephedrine, as it can cause insomnia and thus trigger a manic episode.

Interactions

Concomitant or recent (previous fourteen days) monoamine oxidase inhibitor (MAOI) use can lead to hypertensive reactions, including hypertensive crises.^[11]

The antihypertensive effects of methyldopa, mecamylamine, reserpine and veratrum alkaloids may be reduced by sympathomimetics. Beta-adrenergic antagonists may also interact with sympathomimetics. Increase of ectopic pacemaker activity can occur when pseudoephedrine is used concomitantly with digitalis. Antacids increase the rate of pseudoephedrine absorption, kaolin decreases it.^{[citation needed]}

Common brand names

Sudafed is a trademark for a common brand that contains pseudoephedrine, although Sudafed PE does not contain it.

The following are some brand names of medications that previously contained pseudoephedrine, though some of them now contain phenylephrine instead.

• Allerclear-D Kirkland, contains Loratadine 10 mg, pseudoephedrine sulfate 240 mg
• Sudafed (Johnson & Johnson [formerly Pfizer])
• Codral Cold and Flu Tablets (Johnson & Johnson - contains pseudoephedrine, paracetemol and codeine phosphate. Only the original formula contains pseudoephedrine, with most brands now containing phenylephrine.
• Unifed (United Pharmaceutical Manufacturer-Jordan)
• Actifed (Burroughs Wellcome)
• Contac (GlaxoSmithKline) - contains pseudoephedrine HCL.
• Sinufed (Trima - Israel Pharmaceutical company) - contains 60 mg pseudoephedrine HCL.
• Claritin-D - contains Loratadine along with pseudoephedrine.
• Zyrtec-D 12 Hour - contains pseudoephedrine HCL as well as cetirizine HCL.
• MucinexD - contains 60 mg pseudoephedrine and 600 mg guaifenesin, an expectorant.
• Eltor (Sanofi Aventis)
• Allegra D (Sanofi Aventis) - contains fexofenadine along with pseudoephedrine.
• Nurofen Cold & Flu (Reckitt Benckiser) - contains 200 mg ibuprofen along with 30 mg pseudoephedrine HCL
• TheraFlu (NeoCitran) - contains 60 mg pseudoephedrine HCl
• Cirrus (UCB) - contains 120 mg pseudoephedrine hydrochloride and 5 mg cetirizine dihydrochloride
• Congestal - combined with paracetamol and antihistamine
• Aleve D

Other uses

There have been reports of off-label uses of pseudoephedrine for its stimulant properties. Long-distance truck drivers and sports athletes, for example, have reportedly used pseudoephedrine as a stimulant to increase their state of alertness/awareness.^{[citation needed]}

The similarity in chemical structure to the amphetamines has made pseudoephedrine a sought-after chemical precursor in the illicit manufacture of methamphetamine and methcathinone. As a result of the increasing regulatory restrictions on the sale and distribution of pseudoephedrine, many pharmaceutical firms have reformulated, or are in the process of reformulating medications to use alternative, but less effective,^[15] decongestants, such as phenylephrine.

Many retailers such as Target, Walgreens, CVS, Rite Aid, Boots and Winn-Dixie have created corporate policies restricting the sale of pseudoephedrine-containing products. Their policies restrict sales by limiting purchase quantities and requiring a minimum age with proper identification. These requirements are similar to and sometimes more stringent than existing law. Internationally, pseudoephedrine is listed as a Table I precursor under the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.^[16]

Sports

Pseudoephedrine was on the banned substances IOC list until 2004, when the WADA list replaced the IOC list. Although WADA initially only monitored pseudoephedrine, it is once again on the banned list starting January 1, 2010.^[17] Romanian gymnast Andreea Răducan was stripped of her gold medal at the 2000 Sydney Olympics after testing positive. She took two pills given to her by the team coach for a cold. Although she was stripped of the overall gold medal, she kept her other medals, and, unlike in most other doping cases, was not banned from competing again; only the team doctor was banned for a number of years. Ion Ţiriac, the president of the Romanian Olympic Committee, resigned over the scandal.^[18][19]

Detection of use

Pseudoephedrine may be quantitated in blood, plasma or urine to monitor any possible performance-enhancing use by athletes, confirm a diagnosis of poisoning or assist in a medicolegal death investigation. Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with pseudoephedrine, but chromatographic techniques can easily distinguish pseudoephedrine from other phenethylamine derivatives. Blood or plasma pseudoephedrine concentrations are typically in the 50-300 µg/L range in persons taking the drug therapeutically, 500-3000 µg/L in abusers or poisoned patients and 10–70 mg/L in cases of acute fatal overdosage.^[20][21]

National legislation

Australia

Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way pseudoephedrine products are regulated. As of 2006, all products containing pseudoephedrine have been rescheduled as either "Pharmacist Only Medicines" (Schedule 3) or "Prescription Only Medicines" (Schedule 4), depending on the amount of pseudoephedrine in the product. A Pharmacist Only Medicine may only be sold to the public if a pharmacist is directly involved in the transaction. These medicines must be kept behind the counter, away from public access.

Pharmacists are also encouraged (and in some states required) to log purchases with the online database Project STOP.^[22] This system aims to prevent individuals from purchasing small quantities of pseudoephedrine from many different pharmacies.

In areas of low socio-economic demographics pharmacies simply no longer stock "Sudafed" (the common brand of pseudoephedrine cold/sinus tablets), opting instead to sell "Sudafed PE", a phenylephrine product which most pharmacists will now readily admit is useless as a replacement for the original drug, for those who need it for legitimate purposes.^{[citation needed]}

Mexico

On November 23, 2007, the use and trade of Pseudoephedrine in Mexico was made illicit, as it was argued that pseudoephedrine was extremely popular as a precursor in the synthesis of methamphetamine.

New Zealand

In New Zealand, from 15 October 2004, as a result of large intercepts of pseudoephedrine and ephedrine, any product containing these substances e.g. cold and flu medicines were classified as Class C Part III (partially exempted) controlled drugs in the Misuse of Drugs Act 1975.^[23] New Zealand Customs and police officers are continuing to make large interceptions of precursor substances believed to be destined for methamphetamine production. On 9 October 2009 Prime Minister John Key announced that pseudoephedrine-based cold and flu tablets would become prescription-only drugs and reclassified as a class B2 drug.^[24] The Misuse of Drugs Amendment Bill 2010 has not yet been finalised.^[25]

United Kingdom

In the UK pseudoephedrine is available over the counter under the supervision of a qualified pharmacist, or on prescription. In 2007 the MHRA reacted to concerns over diversion of ephedrine and pseudoephedrine for the illicit manufacture of methamphetamine by introducing voluntary restrictions limiting over the counter sales to one box containing no more than 720 mg of pseudoephedrine in total per transaction. These restrictions became law in April, 2008.^[26] However no form of ID is required.

United States

The United States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine. In 2005, the Committee on Education and the Workforce heard testimony concerning education programs and state legislation designed to curb this illegal practice.

Attempts to control the sale of the drug date back to 1986, when federal officials at the Drug Enforcement Administration (DEA) first drafted legislation, later proposed by Senator Bob Dole, R-KS, that would have placed a number of chemicals used in the manufacture of illicit drugs under the Controlled Substances Act. The bill would have required each transaction involving pseudoephedrine to be reported to the government, and federal approval of all imports and exports. Fearing this would limit legitimate use of the drug, lobbyists from over the counter drug manufacturing associations sought to stop this legislation from moving forward, and were successful in exempting from the regulations created by the bill, all chemicals that had been turned into a legal final product, such as Sudafed.^[27]

Prior to the passage of the Combat Methamphetamine Act of 2005, sales of the drug became increasingly regulated as DEA regulators and pharmaceutical companies continued to fight for their respective positions. The DEA continued to make greater progress in their attempts to control pseudoephedrine as methamphetamine production skyrocketed, becoming a serious problem in the Western United States. When purity dropped, so did the number of people in rehab, and people admitted to emergency rooms with methamphetamine in their systems. However, this reduction in purity was usually short lived as methamphetamine producers eventually found a way around the new regulations.^[28]

Congress passed the Combat Methamphetamine Epidemic Act of 2005 ("CMEA") as an amendment to the renewal of the USA PATRIOT Act. Signed into law by president George W. Bush on March 6, 2006, the act amended 21 U.S.C. § 830, concerning the sale of pseudoephedrine-containing products. The law mandated two phases, the first needing to be implemented by April 8, 2006 and the second phase to be completed by September 30, 2006. The first phase dealt primarily with implementing the new buying restrictions based on amount, while the second phase encompassed the requirements of storage, employee training, and record keeping.^[29] Though the law was mainly directed at pseudoephedrine products it also applies to all over the counter products containing:ephedrine, pseudoephedrine, and phenylpropanolamine, their salts, optical isomers, and salts of optical isomers.^[29] Pseudoephedrine was defined as a "scheduled listed chemical product" under 21 U.S.C. § 802(45(A)). The act included the following requirements for merchants ("regulated sellers") who sell such products:

• Required a retrievable record of all purchases, identifying the name and address of each party, to be kept for two years
• Required verification of proof of identity of all purchasers
• Required protection and disclosure methods in the collection of personal information
• Required reports to the Attorney General of any suspicious payments or disappearances of the regulated products
• Required training of employees with regard to the requirements of the CMEA. Retailers must self-certify as to training and compliance.
• The non-liquid dose form of regulated products may only be sold in unit dose blister packs
• Regulated products must be stored behind the counter or in a locked cabinet in such a way as to restrict public access
• Sales limits (per customer):
  • Daily sales limit—must not exceed 3.6 grams of pseudoephedrine base without regard to the number of transactions
  • 30-day (not monthly) sales limit—must not exceed 7.5 grams of pseudoephedrine base if sold by mail order or "mobile retail vendor"
  • 30-day purchase limit—must not exceed 9 grams of pseudoephedrine base. (A misdemeanor possession offense under 21 U.S.C. § 844a for the person who buys it.)

In regards to the identification that may be used by an individual buying pseudoephedrine products the following constitute acceptable forms of identification:

• US passport
• Alien registration or permanent resident card
• Unexpired foreign passport with temporary I-551 stamp
• Unexpired Employment Authorization Document
• Driver's License or Government issued identification card (including Canadian driver's license)
• School ID with picture
• Voter's Registration card
• US Military Card
• Native American tribal documents

^[29]

Forty-one states also have laws regulating pseudoephedrine.

Alabama, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawai'i (as of May 1, 2009) Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009) Maryland, Massachusetts, Michigan, Minnesota, Missouri, Montana, Nevada, New Hampshire, New Jersey, New York, North Carolina, Ohio, Oklahoma, Pennsylvania, Rhode Island, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter" and to collect personal information from purchasers.

Oregon and Mississippi require a prescription for the purchase of products containing pseudoephedrine,^[30] which has contributed to "the steepest decline in crime rates in the 50 states" in Oregon, and "the number of meth labs in [Mississippi] has fallen by 65 percent."^[31] Oregon also has had tremendous success in reducing the number of methamphetamine lab seizures from 467 in 2004, (the final full year before implementation of the prescription only law),^[32] to a new low of 12 in 2009.^[33] Some municipalities in Missouri have enacted similar ordinances, including Washington,^[34] Union,^[35] New Haven,^[36] and Cape Girardeau.^[37] Certain pharmacies in Terre Haute, Indiana do so as well.^[38]

Another popular approach to controlling the drug on the state level is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine. Several states that have implemented tracking systems are: Tennessee, Kentucky, and Oklahoma.^[39] These states have had mixed results in reducing the number of methamphetamine laboratory seizures in their states. Prior to implementation of the system in Tennessee in 2005, methamphetamine laboratory seizures totaled 1,497 in 2004, but were reduced to 955 in 2005, and 589 in 2009.^[33] Kentucky’s program was implemented statewide in 2008, but since statewide implementation, the number of laboratory seizures has actually increased.^[33] Oklahoma initially experienced success with their tracking system after implementation in 2006, as the number of seizures dropped in that year and again in 2007. However in 2008, seizures began rising again, and have continued to rise in 2009.^[33]

See also

• Ephedrine
• Phenylpropanolamine
• Amphetamine
• Methamphetamine
• Phenylephrine
• Sudafed

References

1. ^ ^{a b c} Laurence L Brunton, ed (2006). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill Medical Publishing Division. ISBN 0-07-142280-3. 
2. ^ Popat N. Patil, A. Tye and J.B. LaPidus A pharmacological study of the ephedrine isomers JPET May 1965 vol. 148, no. 2, pp. 158-168. PDF
3. ^ Martindale (1989). Edited by Reynolds JEF. ed. Martindale: The complete drug reference (29th ed.). London: Pharmaceutical Press. ISBN 0-85369-210-6. 
4. ^ Proposed International Non-Proprietary Names (Prop. I.N.N.): List 11 WHO Chronicle, Vol. 15, No. 8, August 1961, pp. 314-320
5. ^ Oliver AL, Anderson BN, Roddick FA (1999). "Factors affecting the production of L-phenylacetylcarbinol by yeast: a case study". Adv. Microb. Physiol.. Advances in Microbial Physiology 41: 1–45. doi:10.1016/S0065-2911(08)60164-2. ISBN 9780120277414. PMID 10500843. 
6. ^ Suo, Steve. Clamp down on shipments of raw ingredients. The Oregonian; 6 October 2004. From a version reprinted on a U.S. congressional caucus website.
7. ^ Drew, et al. Comparison of the effects of D-(-)-ephedrine and L-(+)-pseudoephedrine on the cardiovascular and respiratory systems in man. Br J Clin Pharmacol. 1978; 6, p 225; PDF
8. ^ Kiyoshi Minamizawa, et al. Effect of d-Pseudoephedrine on Cough Reflex and Its Mode of Action in Guinea Pigs Journal of Pharmacological Sciences, Vol. 102 (2006), No. 1 pp.136-142. PDF
9. ^ ^{a b} Bicopoulos D, editor. AusDI: Drug information for the healthcare professional, 2nd edition. Castle Hill: Pharmaceutical Care Information Services; 2002.
10. ^ http://www.aafp.org/afp/2005/0115/p315.html
11. ^ ^{a b c} Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
12. ^ Vidal C, Prieto A, Pérez-Carral C, Armisén M (April 1998). "Nonpigmenting fixed drug eruption due to pseudoephedrine". Ann. Allergy Asthma Immunol. 80 (4): 309–10. doi:10.1016/S1081-1206(10)62974-2. PMID 9564979. 
13. ^ Adco-Tussend
14. ^ Cantu C, Arauz A, Murillo-Bonilla LM, López M, Barinagarrementeria F (July 2003). "Stroke associated with sympathomimetics contained in over-the-counter cough and cold drugs". Stroke 34 (7): 1667–72. doi:10.1161/01.STR.0000075293.45936.FA. PMID 12791938. 
15. ^ Hatton RC, Winterstein AG, McKelvey RP, Shuster J, Hendeles L (March 2007). "Efficacy and safety of oral phenylephrine: systematic review and meta-analysis". Ann Pharmacother 41 (3): 381–90. doi:10.1345/aph.1H679. PMID 17264159. 
16. ^ Microsoft Word - RedListE2007.doc
17. ^ http://www.wada-ama.org/en/News-Center/Articles/WADA-2010-Prohibited-List-Now-Published/
18. ^ http://assets.espn.go.com/oly/summer00/news/2000/0925/776388.html
19. ^ http://web.archive.org/web/20010715112418/http://www.intlgymnast.com/news2000/oct3.html
20. ^ Boland DM, Rein J, Lew EO, Hearn WL. Fatal cold medication intoxication in an infant. J. Anal. Toxicol. 27: 523-526, 2003.
21. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 1344-1346.
22. ^ http://www.projectstop.com.au/
23. ^ "Ephedrine and Pseudoephedrine to Become Controlled Drugs"
24. ^ "Chemical Brothers", Listener
25. ^ Digest No. 1776
26. ^ "Drug Safety Update, March 2008" (pdf). The Medicines and Healthcare products Regulatory Agency and the Commission on Human Medicines. 2008-06-30. http://www.mhra.gov.uk/home/idcplg?IdcService=GET_FILE&dDocName=CON014095&RevisionSelectionMethod=LatestReleased. 
27. ^ http://www.oregonlive.com/special/oregonian/meth/stories/index.ssf?/oregonian/meth/1004_lobbyistsandloopholes.html
28. ^ http://www.oregonlive.com/special/oregonian/meth/pdfs/1004meth_purity.pdf
29. ^ ^{a b c} http://www.papharmacists.com/APhA%20Summary%20of%20Combat%20Meth%20Interim%20Final%20Rule.pdf
30. ^ "MS Senate passes bill to restrict pseudoephedrine sales". Associated Content (WLOX). February 2, 2010. http://www.wlox.com/Global/story.asp?S=11919990. Retrieved May 8, 2010. 
31. ^ "How to Kill the Meth Monster". The New York Times. November 15, 2010. http://www.nytimes.com/2010/11/16/opinion/16bovett.html. Retrieved November 16, 2010. 
32. ^ http://www.leg.state.or.us/cgi-bin/searchMeas.pl
33. ^ ^{a b c d} http://www.justice.gov/dea/concern/map_lab_seizures.html
34. ^ "Council Passes Law Restricting Pseudoephedrine". The Washington Missourian. July 7, 2009. http://www.emissourian.com/news/washington_news/article_6aec84e6-f67e-5535-a4d9-9d8be4452a22.html. Retrieved December 10, 2010. 
35. ^ "Union Board Approves Pseudoephedrine Ordinance". The Washington Missourian. October 13, 2009. http://www.emissourian.com/news/washington_news/article_6aec84e6-f67e-5535-a4d9-9d8be4452a22.html. Retrieved December 10, 2010. 
36. ^ "New Haven Passes Prescription Law". The Washington Missourian. November 11, 2010. http://www.emissourian.com/news/top_stories/article_776823c6-ee98-11df-b2bd-001cc4c03286.html. Retrieved December 10, 2010. 
37. ^ "Cape Girardeau City Council passes prescription requirement for pseudoephedrine". The Southeast Missourian. December 7, 2010. http://www.semissourian.com/story/1685849.html. Retrieved December 10, 2010. 
38. ^ "Four Valley pharmacies to require prescriptions for certain products to help fight meth problem". Terre Haute Tribune-Star. May 20, 2010. http://tribstar.com/news/x1414109043/Four-Valley-pharmacies-to-require-prescriptions-for-certain-products-to-help-fight-meth-problem. 
39. ^ http://www.namsdl.org/documents/2009CongressionalReportFinal.pdf