4-Fluoromethylphenidate

Authors:

Ewelina Sujkowska, Rafał R Jaeschke

Findings:

Methylphenidate (MPH) exhibits a multimodal mechanism of action, primarily as a dopamine and noradrenaline reuptake inhibitor, and also protects the dopaminergic system. In placebo-controlled trials reviewed, MPH was moderately effective against core ADHD symptoms (SMD, 0.49) and accompanying emotion regulation deficits (SMD, 0.34) in adults. The most common adverse events with long-term MPH treatment include decreased appetite (~20%), dry mouth (15%), heart palpitations (13%), gastrointestinal infections (~10%), and agitation/feeling restless (~10%). The review concludes there is substantial evidence suggesting MPH is an effective and safe treatment option for adults with ADHD.

Participants:

Adult patients with attention-deficit/hyperactivity disorder (ADHD). The review focuses on the population of adults diagnosed with ADHD.

Dosage:

The review details various MPH formulations (e.g., Ritalin® immediate-release tablets 5, 10, 20 mg; Concerta® extended-release tablets 18, 27, 36, 54 mg; Adhansia XR® extended-release capsules 25-85 mg) and their pharmacokinetic profiles. Titration is described as a trial-and-error process, with a recommendation to start MPH-IR at 5 mg twice daily (or equivalent for MPH-ER/OROS), followed by increases. A provisional maximum dose of 150 mg/day is mentioned, though optimal dosage is not definitively established; doses around 1 mg/kg body mass are suggested to correlate with better efficacy. Dosing strategies include using long-acting MPH twice daily (e.g., around 8 a.m. and 3 p.m.) with possible short-acting formulations as add-ons.

Study Quality Assessment:

Narrative review. Applied structured search strategies covering MEDLINE and Cochrane Central Register of Controlled Trials, and performed handsearching of reference lists of relevant papers. The review focused primarily on high-quality systematic reviews, treatment guidelines, randomized controlled trials (RCTs), and observational studies for clinical data. Acknowledges that the evidence base on long-term outcomes of MPH treatment is 'too patchy to draw firm conclusions' and that optimal dosage regimens have 'not been determined yet'.

All Effects:

Findings:

This case report presents the first detection of 4-Fluoromethylphenidate (4F-MPH) in a decedent in the USA, and the first time it has been listed in the official cause of death of a decedent in Florida. 4F-MPH concentrations in femoral vein blood varied from 0.012 to 0.05 mg/L, and other substances including 3-methoxy-PCP, amphetamine, methamphetamine, 6-monoacetylmorphine, morphine, codeine, and tetrahydrocannabinol were also identified in the decedent. An additional peak suggested a possible structural isomer of 4F-MPH.

Participants:

A single decedent.

Dosage:

4F-MPH concentrations in femoral vein blood varied from 0.012 to 0.05 mg/L.

Study Quality Assessment:

Case report. Post-mortem specimens were screened using gas chromatography mass spectrometry (GC-MS) and liquid chromatography ion trap mass spectrometry (LC-Ion Trap-MSn). A validated method for the quantification of 4F-MPH was developed using liquid chromatography-tandem mass spectrometry (LC-MS-MS), with a linear range of 0.01-0.500 mg/L and acceptable validation criteria including precision, bias, carry-over, linearity and endogenous/exogenous interferences.

All Effects:

Findings:

Efficacy and safety evaluation are the main objectives of clinical trials. However, phase III clinical trials focus more on efficacy than safety, partly due to the low number of patients recruited, which makes it difficult to detect rare adverse drug reactions. The author argues that post-marketing (phase IV) trials and surveillance should become commoner practices to ensure ongoing evaluation of drug safety after market approval.

Study Quality Assessment:

Clinical trials use rigorous scientific methodology to compare the efficacy of new drugs with standard drugs or placebo. The design of clinical trials in phase III is described as more centered on the study of efficacy than safety. A limitation mentioned is the low number of patients recruited for phase III, which affects the detection of most type B adverse drug reactions (incidence usually of the order of 1:10^-4). Post-marketing (phase IV) trials and surveillance are suggested as practices for permanent evaluation of drug safety.

All Effects:

Findings:

The study reports intoxication by 4-Fluoromethylphenidate, an analog of methylphenidate.

Study Quality Assessment:

The intoxication was analytically confirmed.

Findings:

User reports for 4F-MPH tend to focus on the 'removal' of traditional side effects that are common with other MPH analogs, including anxiety and paranoia.

Study Quality Assessment:

Based on user reports.