Selegiline

Description

Selegiline is a medication primarily used to manage the symptoms of Parkinson's disease. It belongs to a class of drugs known as monoamine oxidase type B (MAO-B) inhibitors, which work by increasing the amount of dopamine in the brain. This article provides a comprehensive, yet accessible overview of Selegiline, including its uses, dosage, side effects, and potential interactions.

Quick Overview: Selegiline At-a-Glance

Key Benefit: Primarily used to manage symptoms of Parkinson's disease.
Primary Mechanism: Selectively inhibits monoamine oxidase type B (MAO-B) in the brain, preventing the breakdown of dopamine.
Best For: Individuals with Parkinson's disease who need assistance managing their symptoms, often used in conjunction with levodopa.
Typical Dose Range: 5 mg twice daily or 1.25mg - 2.5 mg daily for oral disintegrating tablets.
Key Caution/Consideration: Potential for serious drug interactions, including risk of serotonin syndrome and hypertensive crisis.

Table of Contents

Categories & Effectiveness
Dosage & Side Effects
Benefits by Use Case
Mechanism of Action
Frequently Asked Questions
Summary & Expert Opinion
Research Studies

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Categories & Effectiveness

Brain Health

Dopamine Support

10/10

Strong evidence of effectiveness

Brain Antioxidant Shield

7/10

Strong evidence of effectiveness

Neuro-Repair Support

7/10

Strong evidence of effectiveness

Neurogenesis (BDNF/NGF)

7/10

Strong evidence of effectiveness

Mood & Stress

Mood Elevation

7/10

Strong evidence of effectiveness

Systemic Health

Cellular Repair

7/10

Strong evidence of effectiveness

Systemic Antioxidant

4/10

Moderate evidence of effectiveness

Dosage & Side Effects

Recommended Dosage

Selegiline dosage varies depending on the formulation. For tablets and capsules, the typical adult dose is 5 mg taken twice daily, once at breakfast and again at lunch. An alternative initial dose is 2.5 mg daily, which can be gradually increased as needed. For oral disintegrating tablets, the dosage is 1.25 mg to 2.5 mg daily, placed under the tongue. Avoid exceeding 10mg/day from tablets or capsules or 2.5mg/day from orally disintegrating tablets.

Those with renal impairment should use caution with tablets and capsules, and orally disintegrating tablets are not recommended for severe renal impairment. For hepatic impairment, reduce the dose of orally disintegrating tablets to 1.25 mg daily in mild to moderate cases; it's not recommended in severe cases.

Potential Side Effects

Potential side effects of Selegiline include both common and serious reactions. Common side effects, especially at higher doses, include nausea, vomiting, dry mouth, dizziness, headache, insomnia, constipation, and abdominal pain. Use cautiously if you have pre-existing mental health conditions.

Rarely, Selegiline may cause severe allergic reactions, hallucinations, depression, tremors, chest pain, trouble breathing, suicidal thoughts/behavior, irregular heartbeat, or severe headache. If you experience any of these serious side effects, seek immediate medical attention.

Bioavailability & Half-Life

Oral Selegiline is rapidly absorbed, but undergoes significant first-pass metabolism, resulting in low bioavailability (less than 10%). Formulations that bypass first-pass metabolism, such as orally disintegrating tablets and transdermal patches, have improved bioavailability. Selegiline is metabolized in the liver, primarily into L-methamphetamine and L-amphetamine. The elimination half-life of Selegiline is approximately 1.5 to 3 hours, while its metabolites have longer half-lives.

Interactions & Stacks

Avoid combining Selegiline with other MAO inhibitors due to the risk of severe hypertensive crisis. Use extreme caution when combining Selegiline with opioids, especially meperidine, tramadol, and methadone, due to the risk of serotonin syndrome. Avoid combining Selegiline with St. John's Wort, cyclobenzaprine, dextromethorphan, and certain antidepressants (SSRIs, SNRIs, tricyclics, tetracyclics, triazolopyridine) due to the risk of serotonin syndrome.

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Benefits by Use Case

Parkinson's Disease Symptom Management

Selegiline helps manage motor symptoms like tremors, rigidity, and bradykinesia by increasing dopamine levels in the brain. It is often used as an adjunct to levodopa to improve its effectiveness and reduce motor fluctuations. However, it does not cure Parkinson's disease or halt its progression.

Mood Elevation

Selegiline may improve mood and reduce depressive symptoms in some individuals. This effect is likely related to its ability to increase dopamine and other monoamine neurotransmitters in the brain. However, it is not a primary treatment for depression and should be used with caution due to the risk of serotonin syndrome.

Mechanism of Action

The primary mechanism of action of Selegiline is the selective inhibition of monoamine oxidase type B (MAO-B) in the brain. In simple terms, MAO-B is an enzyme that breaks down dopamine. By inhibiting MAO-B, Selegiline prevents the breakdown of dopamine, leading to increased dopamine levels in the brain. This increased dopamine helps to alleviate the motor symptoms associated with Parkinson's disease.

Frequently Asked Questions

What is Selegiline used for?

How does Selegiline work?

What are the common side effects of Selegiline?

What are the serious side effects of Selegiline?

What drugs interact with Selegiline?

Is Selegiline safe during pregnancy and breastfeeding?

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Summary & Expert Opinion

Selegiline is a medication primarily used to manage Parkinson's disease symptoms by increasing dopamine levels in the brain. It's often used alongside levodopa, but requires careful consideration due to potential side effects and drug interactions. While some research suggests neuroprotective properties, clinical evidence is still limited. It is also used to treat depression, but requires careful consideration due to potential side effects and drug interactions.

Key Strengths: Proven for Parkinson's symptom management, potential in atypical depression.
Key Weaknesses: Risk of significant drug interactions (serotonin syndrome, hypertensive crisis), potential for side effects.
Recommendation: Effective for managing Parkinson's symptoms as part of a comprehensive treatment plan; requires careful monitoring and awareness of potential interactions.

From a more technical perspective, Selegiline's action extends beyond simple MAO-B inhibition. While the primary mechanism involves preventing dopamine breakdown, it also appears to have antioxidant and anti-apoptotic effects in preclinical studies. The selective inhibition of MAO-B is dose-dependent; at higher doses, Selegiline can also inhibit MAO-A, increasing the risk of side effects. The metabolism of Selegiline is complex, producing L-methamphetamine and L-amphetamine, which may contribute to some of its stimulant-like side effects. The slow recovery of MAO-B after Selegiline withdrawal (around 40 days half-time) suggests that lower doses may be effective and could reduce side effects. The use of transdermal formulations aims to bypass first-pass metabolism, potentially improving bioavailability and reducing the formation of amphetamine metabolites. However, such formulations may also increase the risk of MAO-A inhibition. The exploration of multifunctional propargylamine derivatives represents an interesting avenue for developing more targeted and effective treatments for neurodegenerative diseases. These derivatives combine MAO inhibition with other beneficial activities, such as metal chelation and antioxidant effects.

Research Studies

Showing 5 of 10 studies

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations (2023)

ADHD atypical depression depression +3 more

Authors:

Alessandro Vellucci, Andrea Sobrino, Andrea de Bartolomeis, Carlo Ignazio Cattaneo, Claudio Caiazza, Felice Iasevoli, Flavia Rossano, Henricus G. Ruhé, Ken Gillman, Michele Fornaro, Niccolò Solini, Nicolas Zotti, Stephen Stahl, Tom K. Birkenhager, Vincent Van den Eynde

Findings:

Selegiline (oral and transdermal) significantly outperformed placebo in reducing depressive symptoms (SMD=-0.96) and improving depression response rates (RR=1.61), particularly for atypical depression (RR=2.23). However, it did not show significant efficacy over placebo for negative or positive symptoms of schizophrenia, ADHD symptoms reduction, or smoking abstinence rates. Selegiline showed comparable acceptability (all-cause discontinuation) to placebo but was associated with significantly higher rates of insomnia and application site reactions (transdermal) and xerostomia (oral).

Participants:

Systematic review (42 studies) and meta-analysis (23 studies) involving human participants (any age) with primary psychiatric disorders, including depression (MDD, atypical, bipolar; k=10, n=1308 for symptoms; k=9, n=1238 for response; k=3, n=136 for atypical response), schizophrenia (k=4, n=191 for negative symptoms), ADHD (children, adolescents, adults; k=2, n=68 vs methylphenidate; k=2, n=48 vs placebo), smoking addiction (k=4, n=402 for abstinence), cocaine addiction (1 study included in SR), and social phobia (1 study included in SR).

Dosage:

Systematic review covered various oral (e.g., 5mg BID/TID, 10-60mg/day) and transdermal (STS 6mg/24h, 6-12mg/24h, 10-20mg/24h) formulations and dosages. Oral doses ≥20 mg/day mentioned for non-selective MAOI activity. STS 6-12 mg/24h approved for MDD.

Study Quality Assessment:

Systematic review and meta-analysis following PRISMA guidelines (PROSPERO registered: CRD42022359815). Searched multiple databases (PubMed/MEDLINE/Cochrane-Central/WHO-ICTRP/Clarivate-WebOfScience, Chinese-Electronic-Journal Database) up to 10/26/2022. Included interventional controlled studies (randomized and non-randomized). Used random-effects meta-analyses, assessed heterogeneity (I², τ², Q-test, GOSH), publication bias (funnel plot, Egger's test), and risk of bias (RoB2 for RCTs, ROBINS-I for non-randomized studies). Conducted sensitivity, subgroup, and meta-regression analyses. Confidence assessed using GRADE. 21/23 meta-analyzed studies were RCTs (RoB: 13 low, 3 unclear, 5 high). Confidence rated low/very-low for most outcomes, moderate for transdermal selegiline in depression symptom reduction. Acknowledged limitations include high heterogeneity for specific outcomes.

All Effects:

ADHD atypical depression depression schizophrenia side effects smoking cessation

Neuroprotective Function of Rasagiline and Selegiline ... (2022)

apoptosis inhibition gene induction mitochondrial function +2 more

Authors:

M Naoi

Findings:

This review indicates preclinical studies show neuroprotective functions for MAO-B inhibitors rasagiline and selegiline, including preventing mitochondrial apoptosis, inducing anti-apoptotic (Bcl-2) and pro-survival neurotrophic factors (BDNF, GDNF), and mitigating α-synuclein toxicity. MAO-A is also implicated in rasagiline's neuroprotective signaling. Despite preclinical promise, clinical trials have largely failed to demonstrate clear disease-modifying effects in synucleinopathies, highlighting the need for improved clinical trial strategies.

Participants:

Review summarizing studies involving cellular models (e.g., SH-SY5Y, U118MG, iPSCs), animal models (rats, mice, non-human primates), healthy human subjects, and patients with synucleinopathies (Parkinson's disease (PD), dementia with Lewy body (DLB), multiple system atrophy (MSA)) or mild cognitive impairment (MCI).

Dosage:

Selegiline: 10 mg/day (oral trials/pharmacokinetics), 5 mg/day (CSF study), 6 mg/24h (transdermal). Rasagiline: 1 mg/day or 2 mg/day (oral trials/pharmacokinetics), 0.1-0.25 mg/day (non-human primate study), 1 mg/day (MSA trial). In vitro concentrations mentioned (e.g., rasagiline 10⁻⁷–10⁻¹⁰ M for GDNF induction, selegiline 10⁻⁷–10⁻⁹ M for BDNF induction).

Study Quality Assessment:

Review mentions preclinical studies and clinical trials. Specific trials cited include: DATATOP (double-blind placebo-controlled), ADAGIO (controlled, randomized, delayed-start), TEMPO (controlled trial), PRESTO, LARGO, PROUD (delayed-start), LEAP (delayed-start), a phase III selegiline trial (randomized double-blind placebo-controlled), a phase 2 ladostigil trial (randomized, double-blind, placebo-controlled), an MSA trial (randomized, placebo-controlled), depression trials (double-blind, placebo-controlled). Assessment methods mentioned: Unified Parkinson’s Disease Rating Scale (UPDRS), PET imaging (β-CIT SPECT, [18F]fluorodopa PET, [11C]clorgyline PET). Acknowledges limitations of clinical trials (difficulty differentiating disease-modifying vs symptomatic effects, need for better trial design/markers).

All Effects:

apoptosis inhibition gene induction mitochondrial function neuroprotection α-synuclein modulation

An explorative study regarding the effect of l-deprenyl on cognitive and functional recovery in patients after stroke (2015)

attention cognitive functioning executive functions +1 more

Authors:

Annarita Capone, Chiara Zucchella, Francesco Pierelli, Giorgio Sandrini, Michelangelo Bartolo

Findings:

Selegiline (10 mg/day for 6 weeks) significantly improved performance on most neuropsychological tests after 2 and 6 weeks compared to placebo in stroke patients. Attention and executive functions benefited most. Both groups showed significant functional status improvement, but there was no significant difference between the selegiline and placebo groups regarding functional status.

Participants:

N=47 patients enrolled within two weeks of first-ever ischaemic or haemorrhagic stroke, with MMSE score 10-23 and FIM score ≤ 60. Randomly assigned to Study Group (n=23) or Control Group (n=24).

Dosage:

Selegiline 10 mg/day once a day for six weeks.

Study Quality Assessment:

Randomized controlled study; placebo-controlled (matched placebo); N=47 (23 treatment, 24 control); specific inclusion/exclusion criteria detailed; statistical methods mentioned (Student's t-test, Mann–Whitney U-test, chi-square test, Friedman test); conflict of interest declared none; funding source mentioned (donation from CHIESI Farmaceutici S.p.a.); study design suggestions acknowledged.

All Effects:

attention cognitive functioning executive functions stroke recovery

... trials in Parkinson's disease: systematic review

Authors:

Hart

Participants:

Studies involving Parkinson's Disease (PD)

Study Quality Assessment:

Study type: Synthesis of studies (likely systematic review or meta-analysis)

Efficacy and safety of selegiline across different psychiatric disorders: A systematic review and meta-analysis of oral and transdermal formulations

ADHD atypical depression depression +2 more

Findings:

Selegiline (oral and transdermal) significantly outperformed placebo in reducing depressive symptoms (SMD = -0.96) and improving depression response rates (RR = 1.61), particularly for atypical depression (RR = 2.23). However, selegiline failed to show significant superiority over placebo for negative or positive symptoms of schizophrenia, ADHD symptom reduction, or smoking abstinence rates. Selegiline acceptability (all-cause discontinuation) did not significantly differ from placebo, but it was associated with higher rates of xerostomia (RR = 1.58), insomnia (RR = 1.61), and application-site reactions for the transdermal formulation (RR = 1.81).

Participants:

Systematic review included studies on humans (any age) with primary psychiatric disorders (depression, schizophrenia, ADHD, smoking addiction, cocaine addiction, social phobia). Meta-analysis included N=23 studies involving patients with depression (N=1308 for symptoms, N=1238 for response), schizophrenia (N=191), ADHD (N=68 vs methylphenidate, N=48 vs placebo), and smoking addiction (N=402 endpoint, N=572 follow-up). Specific studies included adults, adolescents (12-17y), and children (4-16y).

Dosage:

Oral formulations studied ranged from 5mg BID (twice daily) or TID (thrice daily) up to 60mg/day (with doses ≥20mg/day noted for non-selective MAOI activity). Transdermal Selegiline System (STS) doses studied included 6mg/24h, 6-12mg/24h, and up to 20mg/24h patches.

Study Quality Assessment:

Systematic review and meta-analysis following PRISMA guidelines (PROSPERO registered: CRD42022359815). Searched multiple databases (PubMed, MEDLINE, Cochrane Central, ClinicalTrials.gov, WHO-ICTRP, Chinese Electronic Journal Database, Clarivate WebOfScience) until October 26th, 2022. Included 42 studies (SR), 23 (MA) - randomized (parallel, crossover) and non-randomized controlled trials (placebo-controlled, active comparator). Used random-effects meta-analysis models, assessed heterogeneity (I², τ², GOSH plots), publication bias (funnel plots, Egger's test), and risk of bias (RoB2, ROBINS-I tools). Conducted sensitivity, subgroup, and meta-regression analyses. GRADE framework used for evidence confidence (rated low/very-low for most outcomes, moderate for transdermal depression symptom reduction). High heterogeneity noted for some outcomes (e.g., depressive symptoms I²=97.9%). Significant publication bias detected for depression outcomes via Egger's test.

All Effects:

ADHD atypical depression depression schizophrenia side effects

Evidence that formulations of the selective MAO-B ...

MAO-A inhibition PET imaging brain enzyme activity +2 more

Findings:

Zydis selegiline (10 mg/day for 28 days) significantly inhibited brain MAO-A (mean 36.9%) but not DAT in healthy men. Transdermal selegiline (Emsam patch, 6 mg/day) also inhibited MAO-A (mean 33.2%), though not significantly in the small sample tested (N=3). This provides the first direct evidence that selegiline formulations bypassing first-pass metabolism inhibit brain MAO-A in humans.

Participants:

18 healthy men; 3 subjects receiving the selegiline transdermal system.

Dosage:

Zydis selegiline (orally disintegrating formulation): 2.5, 5.0, or 10 mg/day for 28 days. Selegiline transdermal system (Emsam patch): 6 mg/day.

Study Quality Assessment:

Clinical Trial; Measured brain MAO-A using positron emission tomography (PET) and [(11)C]clorgyline radiotracer; Measured dopamine transporter (DAT) availability; Sample size N=18 for Zydis group, N=3 for Emsam group; Acknowledged limitation: small sample size for Emsam group analysis; Funding sources mentioned (NIH, Non-U.S. Gov't, U.S. Gov't Non-P.H.S.).

All Effects:

MAO-A inhibition PET imaging brain enzyme activity pharmacodynamics Selegiline

Neuroprotective actions of selegiline

anti-apoptosis antioxidant dopamine modulation +2 more

Authors:

Ebadi

Findings:

A retrospective analysis indicated increased survival in Parkinson's patients using selegiline plus L-dopa versus L-dopa alone. Selegiline exhibits neuroprotective effects against various neurotoxins affecting different neuron types. Its complex mechanism involves MAO-B inhibition, dopamine modulation (release enhancement, reuptake blockade), antioxidant actions (radical reduction, enzyme up-regulation, autooxidation suppression), and anti-apoptotic effects, many of which are independent of MAO-B inhibition.

Participants:

Patients with Parkinson's disease (mentioned in context of a retrospective analysis). The text also mentions effects on dopaminergic, adrenergic, cholinergic, and sertoninergic neurons, suggesting cellular or animal models were likely involved in mechanism studies, but doesn't explicitly state the subjects for those experiments.

Study Quality Assessment:

Mentions a 'retrospective analysis' of data from patients with Parkinson's disease.

All Effects:

anti-apoptosis antioxidant dopamine modulation neuroprotection survival increase (Parkinson's)

Pharmacological actions of l-deprenyl (selegiline) and other selective monoamine oxidase B inhibitors

Parkinson's disease adjuvant therapy antiParkinson action +1 more

Findings:

l-deprenyl (l-selegiline) is a useful adjuvant to L-dopa therapy and monotherapy for Parkinson's disease, although not all aspects of its antiParkinson action are fully understood.

Study Quality Assessment:

Mentions studies using brains obtained at autopsy.

All Effects:

Parkinson's disease adjuvant therapy antiParkinson action monotherapy

Selegiline (l-deprenyl) mitigated oxidative stress, …

Parkinson's disease treatment antiapoptotic neurotrophic

Slow recovery of human brain MAO B after L-deprenyl ...

L-deprenyl withdrawal MAO B recovery Parkinson's disease +2 more

Findings:

Following withdrawal from L-deprenyl (Selegeline), the half-time for human brain MAO B synthesis was measured to be 40 days in both Parkinson's disease patients and normal subjects. This slow recovery suggests the standard clinical dose may be excessive, warranting evaluation of reduced dosing. This study provided the first measurement of a specific protein synthesis rate in the living human brain.

Participants:

Humans, including individuals with Parkinson's disease and normal subjects. MeSH terms indicate participants included Aged, Middle Aged, Male, and Female individuals.

Dosage:

The standard clinical dose for Parkinson's disease is mentioned as 5 mg twice a day.

Study Quality Assessment:

Designated as a 'Clinical Trial'. Methods included Tomography, Emission-Computed (as per MeSH terms). Funding sources mentioned: Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.; NS 15638/NS/NINDS NIH HHS/United States.

All Effects:

L-deprenyl withdrawal MAO B recovery Parkinson's disease dosing enzyme synthesis

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