Baclofen

證據等級: L5

預測適應症: 4 個

Baclofen: From Spasticity to Attention Deficit-Hyperactivity Disorder

One-Sentence Summary

Baclofen is a GABA-B receptor agonist established internationally for the treatment of muscle spasticity, though it currently holds no marketing authorisation in Denmark. The TxGNN model predicts it may be effective for Attention Deficit-Hyperactivity Disorder (ADHD), supported by 10 publications but no registered clinical trials directly evaluating this indication. A secondary prediction of Nicotine Dependence carries substantially stronger evidence, with 3 Phase 2 clinical trials and 20 publications, and merits parallel consideration.

Quick Overview

Item	Content
Original Indication	Not registered in Denmark; globally used for muscle spasticity (e.g., spinal cord injury, multiple sclerosis)
Predicted New Indication	Attention Deficit-Hyperactivity Disorder (ADHD)
TxGNN Prediction Score	99.32%
Evidence Level	L4
Denmark Market Status	Not marketed
Number of Marketing Authorisations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Baclofen acts as a selective agonist at GABA-B receptors, activating both presynaptic and postsynaptic receptor subtypes to reduce neuronal excitability. In its established role as a muscle relaxant, this mechanism suppresses excessive motor neuron firing in spasticity. The theoretical connection to ADHD rests on baclofen’s ability to modulate GABAergic tone in the prefrontal cortex — a region critically implicated in the attention dysregulation and impulse control deficits that define ADHD — where it may indirectly dampen aberrant dopaminergic and noradrenergic signalling.

Two lines of preclinical evidence provide some mechanistic plausibility. First, studies in the spontaneously hypertensive rat (SHR), the most widely accepted ADHD animal model, have demonstrated that GABAergic agonists alter cortical and hippocampal EEG activity in ways that parallel ADHD-relevant neurophysiology (PMID 21300040). Second, there is precedent for GABAergic modulation improving impulsive decision-making — a core ADHD symptom — through shared prefrontal circuitry (PMID 24062084). Clinically, baclofen has been used in children with Tourette syndrome (which carries a high rate of ADHD comorbidity), with one clinical series of 450 patients reporting symptom reduction as assessed by the Yale Global Tic Severity Scale (PMID 10342599).

However, the mechanistic link to ADHD remains indirect. Baclofen has not been formally studied in ADHD populations in registered clinical trials, and its effects on prefrontal dopaminergic systems are substantially less characterised than those of established ADHD pharmacotherapies (methylphenidate, atomoxetine, guanfacine). The TxGNN score of 99.32% reflects knowledge graph topology rather than established clinical efficacy.

Clinical Trial Evidence

ADHD indication: Currently no related clinical trials registered.

Secondary Prediction — Nicotine Dependence (TxGNN Score: 99.19%, Evidence Level: L2)

The TxGNN model’s second-ranked unique prediction, nicotine dependence, is supported by a mechanistically coherent rationale and three registered Phase 2 trials. Baclofen inhibits mesolimbic dopamine release via GABA-B receptors in the ventral tegmental area (VTA) → nucleus accumbens pathway — the same reward circuit that nicotine hijacks to maintain dependence. This mechanism mirrors baclofen’s established (and in France, approved) use in alcohol use disorder. The clinical trials below assess this indication directly.

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01821560	Phase 2	Completed	44	fMRI and behavioural assessment of baclofen’s effects on brain and behavioural responses to smoking cues in cigarette smokers; the only completed Phase 2 trial — provides proof-of-concept clinical data for this indication
NCT00257894	Phase 2	Terminated	41	Evaluated baclofen for reducing smoking urge, withdrawal, and reinforcement in moderate-to-heavy smokers; early termination reasons (funding vs. futility vs. safety) require confirmation before interpreting the data
NCT01228994	Phase 2	Terminated	6	Randomised placebo-controlled trial directly testing the GABAergic hypothesis of nicotine dependence; recruitment halted after only 6 participants — negligible statistical power, though the study design has conceptual validity

Literature Evidence

The following publications relate to the ADHD indication (predicted_indications[0]). Studies are ordered by study design strength and direct relevance to baclofen in ADHD-related conditions.

PMID	Year	Type	Journal	Key Findings
35345730	2022	Systematic Review / Meta-analysis	Cureus	Systematic review of behavioural interventions, antipsychotics, and alpha-agonists for tic disorders in Tourette’s syndrome; ADHD is a prevalent comorbidity in this population
10342599	1999	Review	Journal of Child Neurology	Clinical series of 450 patients with tics/Tourette’s treated with baclofen or botulinum toxin; tic severity rated by Yale Global Tic Severity Scale — the most direct existing clinical evidence for baclofen in a TS/ADHD-overlapping population
26366961	2015	Review	Clinical Neuropharmacology	Mood stabilisers in children and adolescents with autism spectrum disorders; covers attention and behavioural symptom management including ADHD comorbidity
24295630	2013	Review	International Review of Neurobiology	Emerging treatment strategies in Tourette syndrome; discusses ADHD comorbidity and the pharmacological pipeline for combined TS-ADHD management
11393328	2001	Review	Paediatric Drugs	Clinical characteristics and pharmacotherapy strategies in Tourette syndrome, including use of clonidine and mentions of baclofen for tic suppression
24062084	2014	Animal Study	Psychopharmacology	Noradrenergic α2A-receptor stimulation in the ventral hippocampus reduces impulsive decision-making in rats — mechanistic relevance to the impulsivity dimension of ADHD
21300040	2011	Animal Study	Brain Research	Cortical and hippocampal EEG effects of neurotransmitter agonists in SHR (validated ADHD model) vs. kainate-treated rats; GABAergic agonists alter EEG activity patterns in the ADHD model
24496320	2014	Animal Study	Neuropsychopharmacology	Dissociable contributions of anterior cingulate cortex and basolateral amygdala in cost-benefit effort decision-making; relevant to the motivational and cognitive-effort deficits seen in ADHD
30122296	2019	Review / Clinical Guidance	L’Encéphale	Supervised off-label prescribing of methylphenidate in adult ADHD; contextualises the regulatory and clinical landscape for off-label treatments in adult ADHD — relevant background for any baclofen repurposing pathway
24103016	2013	Animal Study	European Journal of Neuroscience	Habenular modulation of monoaminergic neurotransmission and social play behaviour in rats; indirect relevance to ADHD neurobiology and monoaminergic circuitry

Denmark Market Information

Baclofen currently holds no marketing authorisations with the Danish Medicines Agency (Laegemiddelstyrelsen) and is not marketed in Denmark.

Any clinical use in Denmark would require an individual patient exemption or a named-patient supply arrangement. For pharmacological reference, baclofen is nationally authorised in several EU member states (e.g., Germany, France, the United Kingdom pre-Brexit) for muscle spasticity, and France has additionally granted authorisation for alcohol use disorder at high doses (≥180 mg/day). No EMA centralised marketing authorisation exists for baclofen. Healthcare professionals in Denmark seeking to prescribe baclofen should consult the relevant national SmPC from an authorised country and follow Laegemiddelstyrelsen’s procedures for import of non-authorised medicinal products.

Safety Considerations

No Denmark-specific safety data is available in the current evidence pack.

Please refer to the approved Summary of Product Characteristics (SmPC) for safety information — in particular, the SmPC from a country where baclofen holds national authorisation (e.g., Germany or France). Key areas to review include CNS depression and sedation, risk of abrupt withdrawal (which can cause seizures and hallucinations), renal dose adjustment requirements, and interactions with other CNS depressants.

Conclusion and Next Steps

Decision: Hold (ADHD indication)

Rationale: All available evidence for baclofen in ADHD is indirect — derived from animal models, Tourette syndrome case series with ADHD comorbidity, and mechanistic inference — with no Phase 1 or Phase 2 clinical trial data in ADHD patients. An L4 evidence base is insufficient to support clinical use, off-label prescribing, or programme investment without foundational human data.

To proceed, the following is needed:

A dedicated Phase 2 proof-of-concept trial in an ADHD patient population (children or adults), evaluating standardised ADHD endpoints (e.g., ADHD Rating Scale, CAARS, CPT performance)
Pharmacodynamic characterisation of baclofen’s effects on prefrontal dopaminergic and noradrenergic activity in humans, to confirm or refute the theoretical mechanistic link
Comprehensive safety review using the SmPC from a relevant EU national authorisation, with particular attention to CNS sedation and withdrawal risk in a paediatric or adult ADHD population
A regulatory opinion from Laegemiddelstyrelsen on the pathway for clinical investigation or named-patient use in Denmark
Priority reassessment: the nicotine dependence indication (L2, one completed Phase 2 trial, mechanistically well-grounded) may represent a more immediately actionable repurposing opportunity and warrants a separate evaluation report

This report is intended for research and evaluation purposes only. Predictions from the TxGNN model require clinical validation before any therapeutic application. This document does not constitute medical advice.

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.