Obesity is a major public health problem worldwide. It is a chronic and multifactorial disease characterized by increased body weight due to an excessive fat accumulation as a result of daily intake excess and inadequate calorie expenditure. Obesity represents a worldwide health problem in adults, as well as among children and adolescents, and significantly increases the risk of developing metabolic syndrome, type 2 diabetes mellitus, hypertension and cardiovascular and kidney diseases leading to high all-cause mortality. Given the multifactorial pathogenesis of obesity, its treatment involves an integrated approach between different intervention modalities. Personalized dietary regimens and physical activity are the cornerstones of anti-obesity therapy, which should be performed under medical supervision; however, this strategy is not easy to achieve as many patients show poor adherence and a low success rate. The pharmacological treatment should take place only after a poor effectiveness of diet and exercise in either inducing or maintaining weight-loss has been demonstrated. Currently not many pharmacological options are available and some of the drugs offer limited advantages over lifestyle intervention, and also the cost and side effects require that their use should be restricted to particular cases. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements.
This article examines the evidence surrounding the use of pseudoephedrine, a sympathomimetic drug commonly used as a decongestant, as a potential weight-loss aid.
What is Pseudoephedrine?
Pseudoephedrine is a sympathomimetic amine and precursor of amphetamine-like metabolites. It is well-known for shrinking swollen nasal mucous membranes, so 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. Pseudoephedrine can be used either as oral or as topical decongestant.
From a pharmacodynamics perspective, pseudoephedrine presents a sympathomimetic action both directly, by exerting agonist activity on β1, β2 and α1 adrenergic receptors, and indirectly, by inducing the release of norepinephrine from sympathetic neuron terminals, enhancing the effects of catecholamines. Ephedrine and pseudoephedrine additional action of depleting the endogenous catecholaminergic reserves may explain the onset of tachyphylaxis after repeated dosing. By virtue of their molecular structure, ephedrine and pseudoephedrine stimulate α adrenergic receptors at cavernous vein plexuses, determining its nasal decongestant effect. Pseudoephedrine increases hearth rate and contractility, induces constriction of bronchial and peripheral vessels smooth muscle, and affects the function of CNS.
Pseudoephedrine does not undergo hepatic first-pass metabolism and its gastrointestinal absorption is rapid and complete. The peak of plasma concentration is 500-900 µg/l and is reached about 2 h after oral administration of 180 mg pseudoephedrine. The plasma half-life is about 5-8 h, but the plasma concentrations vary considerably between individuals. Pseudoephedrine is resistant to the action of monoaminoxidase (MAO) and is excreted, mainly in an unmodified form, through the renal emunctories. Several pharmacokinetic studies have shown that at high urine pH, pseudoephedrine, as a weak base, is non-ionized, thus it is easily reabsorbed from the renal tubules, whereas at low urine pH, ephedrine is electrically charged and is cleared faster. Only a 1% fraction of pseudoephedrine is eliminated via the liver, by N-demethylation and formation of nor-pseudoephedrine (catine).
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The Proposed Mechanism for Weight Loss
As a sympathomimetic amine and precursor of amphetamine-like metabolites, pseudoephedrine owes its slimming properties to its anorectic action exerted through the inhibition of the activity of hypothalamic neurons of satiety, located in the hypothalamic paraventricular nucleus (PVN) and distinctively involved in the regulation of food intake, energy and sleep. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Furthermore, Vansal and Ferrel have proven that ephedrine isomers are able to interact with β3 adrenergic receptors involved in lipolysis and thermogenesis. Recent studies have shown that both ephedrine and pseudoephedrine are able to reduce fat accumulation by increasing the levels of down-regulators of the lipogenic transcriptional factors, such as sterol regulatory element-binding protein 1C (SREBP1C), peroxisome proliferator-activated receptor gamma (PPARγ), and CCAAT/enhancer-binding protein α (C/EBPα). Pseudoephedrine influences lipolysis and thermogenesis through interaction with β3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis.
Limited Clinical Data
Despite a comprehensive characterization of the mechanisms of action of pseudoephedrine, clinical data on the use of this compound in obesity are quite surprisingly limited. Only a single placebo-controlled weight-loss study of a slow-release formulation of pseudoephedrine (120 mg/day), conducted in 72 patients for 12 weeks, is available in the literature. The two groups in the study had similar anthropometric characteristics (baseline BMI 29.2 kg/m2 in the pseudoephedrine treatment group vs 28.5 in the placebo group). Weight loss at the end of the study overlapped in the two groups (4.6 kg pseudoephedrine vs. 4.5 kg placebo), with no statistical significance at any intermediate point of the study. Also, there was no difference in appetite reported by patients in the two subgroups. Controlled clinical studies aimed at verifying the effects of higher doses of pseudoephedrine are not available.
One study compared pseudoephedrine 120 mg/day and a placebo in a 12-week trial with 72 obese subjects. Pseudoephedrine was no different than placebo in inducing weight loss.
Adverse Events and Safety Concerns
However, several studies have been conducted to investigate the association between the consumption of food supplements and drugs containing ephedra compounds and the onset of adverse events. Between 1997 and 1999, the FDA received more than 140 reports of adverse events associated with the use of dietary supplements containing ephedra alkaloids. Among the 87 events that have been definitively, probably, or possibly related to the use of these food supplements, 10 resulted in death, 13 in permanent damage, while the remaining cases outcome to a full recovery.
Its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported.
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Because of these pharmacodynamic characteristics, patients under treatment or who recently discontinued therapy with monoaminoxidase inhibitors (MAOi), should not take pseudoephedrine for the increased risk of hypertensive episodes, such as paroxystic hypertension and malignant hyperthermia. Moreover, pseudoephedrine enhances the effects of other sympathomimetic drugs, thus increasing the risk of intense vasoconstriction and consequent possible hypertensive seizures; similarly, it is not recommended its use concomitantly with reversible inhibitors of monoaminoxidase A (RIMA) and ergot alkaloids, for the increased risk of vasoconstriction and/or hypertensive crises and severe arrhythmias.
Regulatory Landscape
After the first studies in the 1970s, the use of Ephedrine products was widespread in the following decades in Europe and in North America. Such exceeding consumption was promoted by the classification of these substances as nutritional supplements for slimming.
In the United States, federal laws control the sale of pseudoephedrine-containing products. Retailers in the US have created corporate policies restricting the sale of pseudoephedrine-containing products. Their policies restrict sales by limiting purchase quantities and requiring a minimum age and government issued photographic identification. These requirements are similar to and sometimes more stringent than existing law.
Illicit diversion of pseudoephedrine in Australia has caused significant changes to the way the 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.
Health Canada has investigated the risks and benefits of pseudoephedrine and ephedrine/Ephedra. Also, they warned that everyone should avoid taking ephedrine or pseudoephedrine with other stimulants like caffeine. Products whose only medicinal ingredient is pseudoephedrine must be kept behind the pharmacy counter. Pseudoephedrine-containing combination products were available over-the-counter from pharmacies, most commonly with paracetamol, under the brand names "Dolirhume","Actifed Rhyme Jour et Nuit" et al. Products combining pseudoephedrine and ibuprofen or certain antihistamines were also available (e.g. "Rhinadvil"). However, products containing pseudoephedrine as a single ingredient are not sold.
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In October 2023, the French health department officially warned against the usage of pseudoephedrine for patients with a cold.
Various pseudoephedrine-containing products in combination with ibuprofen, aspirin, or antihistamines can be obtained without a prescription upon request at a pharmacy. Common names include Aspirin Complex, Reactine Duo, and RhinoPront.
Pseudoephedrine, ephedrine, and any product containing these substances, e.g. cold and flu medicines, were first classified in October 2004 as Class C Part III (partially exempted) controlled drugs, due to being the principal ingredient in methamphetamine.
New Zealand Customs and police officers continued to make large interceptions of precursor substances believed to be destined for methamphetamine production.
Pseudoephedrine is available without a prescription in combination (with aspirin) under the brand name "Aspirin Complex".
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 the 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.
The United States Congress has recognized that pseudoephedrine is used in the illegal manufacture of methamphetamine.
Congress passed the Combat Methamphetamine Epidemic Act of 2005 (CMEA) as an amendment to the renewal of the USA Patriot Act.
The states of Alabama, Arizona, Arkansas, California, Colorado, Delaware, Florida, Georgia, Hawaii (as of May 1, 2009) Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana (as of August 15, 2009), Massachusetts, Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Jersey, North Carolina, Ohio, Oklahoma, Oregon, Pennsylvania, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia, Washington, West Virginia and Wisconsin have laws requiring pharmacies to sell pseudoephedrine "behind the counter".
The states of Oregon and Mississippi previously required a prescription for the purchase of products containing pseudoephedrine. However, as of 1 January 2022, these restrictions have been repealed.
Another approach to controlling the drug on the state level mandated by some state governments to control the purchases of their citizens is the use of electronic tracking systems, which require the electronic submission of specified purchaser information by all retailers who sell pseudoephedrine.
Thirty-two states now require the National Precursor Log Exchange (NPLEx) to be used for every pseudoephedrine and ephedrine OTC purchase, and ten of the eleven largest pharmacy chains in the US voluntarily contribute all of their similar transactions to NPLEx.
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