[5][6][18] Side effects of methenamine are generally minor and include upset stomach, nausea, and headache, among others.

[3][8][9] Formaldehyde is a non-specific antiseptic and bactericide which works via denaturation of bacterial proteins and nucleic acids.

[2][3][8][9] Conversion of methenamine into formaldehyde only occurs in acidic environments and hence its actions show selectivity for tissues like the bladder and stomach.

[2][8][7][14][24] Larger and higher-quality clinical trials of methenamine for UTI prevention have started to be published in the 2020s and it may soon be recommended by more medical guidelines.

[26] Methenamine is used in the treatment and prevention of recurrent urinary tract infections (UTIs) requiring long-term therapy.

[12] On the other hand, methenamine was not effective in reducing the risk of symptomatic UTI or bacteriuria in people with known renal tract abnormalities or neurogenic bladder.

[12][13] A subsequent large randomized controlled trial (RCT), the "ALternatives To prophylactic Antibiotics for the treatment of Recurrent urinary tract infection in women" (ALTAR) trial, was conducted by the United Kingdom National Health Service (NHS).

[13][27] This study, published in 2022, reported that methenamine (hippurate) was non-inferior to daily low-dose antibiotics for prevention of UTIs.

[15] Besides effectiveness in terms of UTI prevention, methenamine demonstrated lower rates of bacterial resistance relative to antibiotic therapy in this trial and in other studies.

[2][14][15] A 2024 systematic review found that methenamine was non-inferior to antibiotic prophylaxis in the prevention of UTIs in two comparative prospective clinical studies, including the ALTAR trial.

[15] Methenamine is converted into formaldehyde only in acidic environments like the urinary bladder and hence is not expected to be effective in the eradicative treatment of pyelonephritis (kidney infection) or chronic bacterial prostatitis.

[34] Prophylactic low-dose methenamine combined with an ascorbic acid (vitamin C) supplement has been reported to be effective for this purpose based on clinical experience.

[34] Methenamine, in a topical cream or gel stick formulation sold under brand names like Antihydral and Dehydral, is used in the treatment of hyperhidrosis (excessive sweating) and has been reported to be clinically effective for this indication.

[14][11][20] On the other hand, the findings of animal studies of methenamine and carcinogenicity have also been questioned by some authors,[20] though this topic is controversial.

[14] However, more studies are needed to assess the influence of methenamine on the host microbiome, both in the urinary tract and elsewhere in the body.

[5][41] Doses of methenamine much higher than usual have been clinically studied and found to produce significant toxicity.

[7][8][4] Some of these side effects are thought to be due to high levels of formaldehyde in the bladder and consequent irritation.

[42] Toxic effects of such high doses included urinary tract and bladder irritation, frequent urination, strangury, and hematuria.

[42] Animal studies employing double the modern human dosage of methenamine for 6 to 12 months found no adverse effects.

[9][13][8] Formaldehyde has been found in vitro to react with hydrochloric acid to form the highly carcinogenic compound bis(chloromethyl) ether and it may be conceivable that this might likewise occur in the stomach.

[2][4] In addition, certain urea-splitting bacteria, such as Proteus and Pseudomonas species, can make the urine more alkaline, thereby potentially inhibiting the antibacterial effects of methenamine.

[2][3][8][4] Providencia and Morganella species are also urea-splitting and might likewise be resistant to methenamine, although this topic requires more research.

[2] In accordance with its presence in cerebrospinal fluid, methenamine is known to cross the blood–brain barrier and enter the central nervous system.

[3] In terms of metabolism, methenamine is hydrolyzed to form formaldehyde and ammonium in acidic urine (pH < 6).

[2] The hydrolysis of methenamine occurs slowly and gradually, with approximately 3 hours required for 90% decomposition into formaldehyde.

[37][46] The drug is a white or colorless and odorless crystalline compound with a sweet, sour, and/or metallic taste.

[21][22] The drug was described as rapidly sterilizing and thereby restoring putrid and pus-filled urine to a normal appearance and constitution.

[2] However, there has been another resurgence in interest in methenamine for recurrent UTI prevention since 2010 owing to increasing rates of bacterial resistance with antibiotics.

[46][51][29] Brand names of methenamine include Aminoform, Antihydral, Dehydral, Formamine, Formin, Hexamine, Hiprex, Hyophen, Mandelamine, Metenamine, Phosphasal, Urelle, Urex, Uribel, Urimar, Urin DS, Urogesic Blue, Urotropin, and Ustell, among numerous others.

[29] The topical form of methenamine for hyperhidrosis has been marketed only in certain countries, including Austria, Canada, Germany, Luxembourg, and Switzerland.