The United States Food and Drug Administration (FDA) advisory committee rejected their claim in 2011, saying that the clinical trial results did not prove that rasagiline was neuroprotective.

[19] The effects of MAO-B inhibitors like rasagiline on fatigue, autonomic dysfunctions, apathy, and impulse control disorders in people with Parkinson's disease remain unknown.

[19] Rasagiline has been reported to significantly improve quality of life in people with Parkinson's disease, but the effect sizes were trivial to small and may not be clinically meaningful.

[2] The FDA label contains warnings that rasagiline may cause severe hypertension or hypotension, may make people sleepy, may make motor control worse in some people, may cause hallucinations and psychotic-like behavior, may cause impulse control disorders, may increase the risk of melanoma, and upon withdrawal, may cause high fever or confusion.

[2] Side effects when the drug is taken alone include flu-like symptoms, joint pain, depression, stomach upset, headache, dizziness, and insomnia.

[2] When taken with levodopa, side effects include increased movement problems, accidental injury, sudden drops in blood pressure, joint pain and swelling, dry mouth, rash, abnormal dreams and digestive problems including vomiting, loss of appetite, weight loss, abdominal pain, nausea, and constipation.

[2] When taken with Parkinson's drugs other than levodopa, side effects include peripheral edema, fall, joint pain, cough, and insomnia.

[2] Rarely, rasagiline has been reported to induce impulse control disorders,[24][25][26][27][28] obsessive–compulsive symptoms,[29] hypersexuality,[30][31][32][27] and spontaneous orgasm or ejaculation.

[33][34][35][36] Other rare adverse effects associated with rasagiline include pleurothotonus (Pisa syndrome),[37][38][39] livedo reticularis,[40] tendon rupture,[41] and hypoglycemia.

[52][53][54] However, in a dose-escalation study with concomitant levodopa therapy, a dosage of 10 mg/day rasagiline was associated with cardiovascular side effects including hypertension and orthostatic hypotension in some people.

[2] Rasagiline may have a risk of hypertensive crisis in combination with sympathomimetic agents such as amphetamines, ephedrine, epinephrine, isometheptene, and pseudoephedrine.

[1] However, based on widespread clinical experience with the related select I've MAO-B inhibitor selegiline, occasional use of over-the-counter sympathomimetics like pseudoephedrine appears to pose minimal risk of hypertensive crisis.

[1][2] In the case of Parkinson's disease, increased dopamine levels in the striatum are thought to be responsible for rasagiline's therapeutic effectiveness in treating the condition.

[1] The recommended dosing schedule of rasagiline in Parkinson's disease (1 mg/day) has been described as somewhat questionable and potentially excessive from a pharmacological standpoint.

[57][58] The clinical effectiveness of rasagiline in Parkinson's disease has been found to persist during a 6-week washout phase with discontinuation of the medication.

[10] Selective MAO-B inhibitors including rasagiline and selegiline have been found to increase dopamine levels in the striatum in rats in vivo.

[63][64][65] It has been theorized that this might be due to strong inhibition of the metabolism of β-phenylethylamine, which is an endogenous MAO-B substrate that has monoaminergic activity enhancer and norepinephrine–dopamine releasing agent actions.

[63][64][65][67] In 2021, it was discovered that MAO-A is solely or almost entirely responsible for striatal dopamine catabolism in the rodent brain and that MAO-B is not importantly involved.

[73][74][71][72] These findings may warrant a rethinking of the pharmacological actions of MAO-B inhibitors like selegiline and rasagiline in the treatment of Parkinson's disease.

[1][56] In addition, 1-aminoindan has been found to enhance striatal dopaminergic neurotransmission and improve motor function independent of MAO inhibition in animal models of Parkinson's disease.

[56] 2-Aminoindan, a closely related positional isomer of 1-aminoindan, is known to inhibit the reuptake and induce the release of dopamine and norepinephrine and to produce psychostimulant-like effects in rodents, albeit with lower potency than amphetamine, but rasagiline does not metabolize into this compound.

[8] Rasagiline has been found to bind reversibly to α-synuclein, a major protein involved in the pathophysiology of Parkinson's disease, and this action might be neuroprotective.

[2] As rasagiline acts as an irreversible inhibitor of MAO-B, its actions and duration of effect are not dependent on its half-life or sustained concentrations in the body.

[1][55] Both the hydrochloride and mesylate salts of rasagiline were studied and were found to have similar pharmacological, pharmacokinetic, and toxicological profiles.

[1] However, the mesylate salt of rasagiline was ultimately selected for its use as a pharmaceutical drug due to favorable chemical stability.

[1] The selectivity of rasagiline for MAO-B over MAO-A depends on the maintenance of a distance of no more than two carbon atoms between the aromatic ring and the N-propargyl group.

[11] Following its approval, rasagiline was described by some authors as a "me-too drug" that offered nothing new in terms of effectiveness and tolerability compared to selegiline.

[101][8] Conversely, others have maintained that rasagiline may be less efficacious than selegiline due to its lack of catecholaminergic activity enhancer actions.

[107] Rasagiline was tested for efficacy in people with multiple system atrophy in a large randomized, placebo-controlled, double-blind disease-modification trial; the drug failed.

[115] MAO-B inhibitors have been found to reduce depressive symptoms in people with Parkinson's disease with a small effect size.