Methamphetamine dependence

Summary

Methamphetamine dependence (MONDO:0005419) is a disease with 3 cohort genes (3 GWAS associations across 2 studies) and 83 clinical trials. Top therapeutic interventions include modafinil, methamphetamine, and aripiprazole.

At a glance

• Cohort genes: 3
• GWAS associations: 3
• Clinical trials: 83

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	methamphetamine dependence
Mondo ID	MONDO:0005419
EFO	EFO:0004701
UMLS	C1533217
MedGen	735816
Is cancer (heuristic)	no

Data availability: 3 GWAS associations (2 studies).

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › substance-related disorder › substance dependence › drug dependence › methamphetamine dependence

Related subtypes (9): barbiturate dependence, hallucinogen dependence, cocaine dependence, alcohol and nicotine codependence, opiate dependence, cannabis dependence, phencyclidine abuse, alcohol dependence, nicotine dependence

Genetics & variants

GWAS landscape

3 GWAS associations across 2 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs147247472	3e-12	AGBL4-IT1, AGBL4	A	0.35
rs2133896	4e-09	ANKS1B	T	0.1
rs10196867	5e-09	CTNNA2	C	0.24

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST008645	Sun Y	2019	521	2,859	Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence.
GCST000156	Uhl GR	2008	240	0	Genome-wide association for methamphetamine dependence: convergent results from 2 samples.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	3

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	3

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs147247472	1	49441901	G>A	0.017	intron_variant	AGBL4-IT1, AGBL4	3e-12	Tier 4: intronic/intergenic
rs2133896	12	99455122	G>T	0.222	intron_variant	ANKS1B	4e-09	Tier 4: intronic/intergenic
rs10196867	2	79751234	C>A,G,T	0.03	intron_variant	CTNNA2	5e-09	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANKS1B	HGNC:24600	ENSG00000185046	Q7Z6G8	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	gwas
CTNNA2	HGNC:2510	ENSG00000066032	P26232	Catenin alpha-2	gwas
AGBL4	HGNC:25892	ENSG00000186094	Q5VU57	Cytosolic carboxypeptidase 6	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANKS1B	Ankyrin repeat and sterile alpha motif domain-containing protein 1B	Isoform 2 may participate in the regulation of nucleoplasmic coilin protein interactions in neuronal and transformed cells.
CTNNA2	Catenin alpha-2	May function as a linker between cadherin adhesion receptors and the cytoskeleton to regulate cell-cell adhesion and differentiation in the nervous system.
AGBL4	Cytosolic carboxypeptidase 6	Metallocarboxypeptidase that mediates protein deglutamylation of tubulin and non-tubulin target proteins.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	12.2×	0.239
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKS1B	Scaffold/PPI	no		SAM, Ankyrin_rpt, PTB/PI_dom
CTNNA2	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
AGBL4	Protease	yes		Peptidase_M14, Pepdidase_M14_N, Cytosolic_carboxypeptidase

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
inferior vagus X ganglion	1
primary visual cortex	1
Brodmann (1909) area 46	1
frontal pole	1
superior frontal gyrus	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKS1B	210	broad	marker	Brodmann (1909) area 23, inferior vagus X ganglion, primary visual cortex
CTNNA2	200	broad	marker	frontal pole, Brodmann (1909) area 46, superior frontal gyrus
AGBL4	149	broad	marker	buccal mucosa cell, tendon of biceps brachii, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANKS1B	2,428
CTNNA2	2,385
AGBL4	704

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANKS1B	Q7Z6G8	4
CTNNA2	P26232	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
AGBL4	Q5VU57	87.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Myogenesis	1	190.3×	0.017	CTNNA2
Carboxyterminal post-translational modifications of tubulin	1	119.0×	0.017	AGBL4
Post-translational protein modification	1	9.6×	0.135	AGBL4
Metabolism of proteins	1	6.2×	0.155	AGBL4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
anterograde axonal transport of mitochondrion	1	2808.7×	0.002	AGBL4
radial glia guided migration of Purkinje cell	1	1872.4×	0.002	CTNNA2
protein deglutamylation	1	1872.4×	0.002	AGBL4
retrograde axonal transport of mitochondrion	1	1872.4×	0.002	AGBL4
C-terminal protein deglutamylation	1	1404.3×	0.002	AGBL4
regulation of synapse structural plasticity	1	1404.3×	0.002	CTNNA2
regulation of blastocyst development	1	1404.3×	0.002	AGBL4
protein side chain deglutamylation	1	936.2×	0.003	AGBL4
negative regulation of Arp2/3 complex-mediated actin nucleation	1	802.5×	0.003	CTNNA2
modification of postsynaptic actin cytoskeleton	1	468.1×	0.005	CTNNA2
prepulse inhibition	1	374.5×	0.006	CTNNA2
central nervous system neuron development	1	267.5×	0.007	AGBL4
brain morphogenesis	1	244.2×	0.008	CTNNA2
regulation of neuron migration	1	208.1×	0.008	CTNNA2
positive regulation of ubiquitin-dependent protein catabolic process	1	187.2×	0.009	AGBL4
regulation of neuron projection development	1	144.0×	0.010	CTNNA2
dendrite morphogenesis	1	144.0×	0.010	CTNNA2
ephrin receptor signaling pathway	1	114.6×	0.012	ANKS1B
axonogenesis	1	53.5×	0.023	CTNNA2
cell-cell adhesion	1	33.8×	0.035	CTNNA2
defense response to virus	1	23.1×	0.049	AGBL4
cell migration	1	20.5×	0.052	CTNNA2
negative regulation of cell population proliferation	1	14.0×	0.073	AGBL4
proteolysis	1	11.4×	0.085	AGBL4

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Citicoline	Phase 3 (in late-stage trials)
Naltrexone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcysteine, Buprenorphine, Bupropion, Dextroamphetamine, Haloperidol, Ibudilast, Lorazepam, Methamphetamine, Methylphenidate, Mirtazapine, Modafinil, Ondansetron, Prazosin, Risperidone, Topiramate, Varenicline, Vigabatrin.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ANKS1B	0	0
CTNNA2	0	0
AGBL4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AGBL4	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	AGBL4
E	Difficult family or no structure, no drug	2	ANKS1B, CTNNA2

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ANKS1B	0	—
CTNNA2	0	—
AGBL4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 83.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	25
Not specified	24
PHASE1	15
PHASE4	7
PHASE3	5
EARLY_PHASE1	4
PHASE1/PHASE2	3

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00728312	PHASE4	WITHDRAWN	Aripiprazole for Methamphetamine Dependence: Double Blind Placebo Trial
NCT00751023	PHASE4	COMPLETED	Effects of Modafinil in Methamphetamine Dependence
NCT01813643	PHASE4	TERMINATED	A Comparison of Risperidone and Aripiprazole for Treatment of Patirnts With Methamphetamine-Associated Psychosis
NCT01813656	PHASE4	TERMINATED	An Study of Aripiprazole in the Treatment of Methamphetamine Dependence
NCT01822730	PHASE4	COMPLETED	A Comparison of Paliperidone and Risperidone for Treatment of Patirnts With Methamphetamine-Associated Psychosis
NCT03825536	PHASE4	COMPLETED	Effect of Methamphetamine on Residual Latent HIV Disease Study
NCT03973489	PHASE4	COMPLETED	Effects of Genotype on Resting State Connectivity During Methamphetamine Administration
NCT02568878	PHASE3	RECRUITING	Creatine for Depressed Male and Female Methamphetamine Users
NCT06233799	PHASE3	RECRUITING	Trial of Naltrexone/Bupropion for the Treatment of Methamphetamine Use Disorder
NCT00950352	PHASE3	COMPLETED	Citicoline Treatment of Methamphetamine Dependence
NCT01007539	PHASE3	COMPLETED	Efficacy and Safety of CDP-choline in Patients With Methamphetamine Dependence
NCT01077024	PHASE3	COMPLETED	Smoking-Cessation and Stimulant Treatment (S-CAST)
NCT05854667	PHASE2	RECRUITING	Clinical Trial of High Dose Lisdexamfetamine and Contingency Management in MA Users
NCT06434818	PHASE2	RECRUITING	Enhanced Digital-Chemosensory-Based Olfactory Training for Remote Management of Substance Use Disorders
NCT06788587	PHASE2	RECRUITING	Feasibility of Long-term, High-dose Stimulant for Methamphetamine Use Disorder
NCT07204249	PHASE2	NOT_YET_RECRUITING	Glutide for Ending Methamphetamine
NCT00284206	PHASE2	COMPLETED	A Trial of Long-Acting Injectable Risperidone in the Treatment of Methamphetamine Dependence
NCT00332605	PHASE2	COMPLETED	N-Acetyl Cysteine Plus Naltrexone in Methamphetamine Dependence
NCT00469508	PHASE2	COMPLETED	Modafinil vs Placebo for the Treatment of Methamphetamine Dependence
NCT00520286	PHASE2	COMPLETED	Phase 2, Multi-Center Trial of Modafinil for Methamphetamine Dependence
NCT00569374	PHASE2	COMPLETED	Safety and Tolerability of Modafinil for Methamphetamine Dependence
NCT00687713	PHASE2	COMPLETED	Phase 2, Double-Blind, Placebo-Controlled Trial of Bupropion for Methamphetamine Dependence
NCT00730522	PHASE2	TERMINATED	Safety and Efficacy Study of Vigabatrin to Treat Methamphetamine Dependence
NCT00731133	PHASE1/PHASE2	COMPLETED	Open-Label Disulfiram for Methamphetamine Dependence
NCT00833443	PHASE2	COMPLETED	Study of Medical Treatment for Methamphetamine Addiction
NCT00859573	PHASE2	TERMINATED	Modafinil for Methamphetamine Dependence
NCT00984360	PHASE2	COMPLETED	Study of Naltrexone for Methamphetamine Addiction
NCT01011829	PHASE2	COMPLETED	Varenicline vs Placebo for the Treatment of Methamphetamine Dependence
NCT01044238	PHASE2	UNKNOWN	Methylphenidate to Treat Methamphetamine Dependence
NCT01071356	PHASE2	COMPLETED	Intensive Motivational Interviewing for Methamphetamine Dependence
NCT01215929	PHASE2	COMPLETED	Studying Amphetamine Withdrawal in Humans
NCT01354470	PHASE2	COMPLETED	A Randomized, Placebo-Controlled Trial of Modafinil for Methamphetamine Dependence
NCT01365819	PHASE2	COMPLETED	Varenicline for Methamphetamine Dependence
NCT01377662	PHASE2	COMPLETED	PHASE IIA: Trial of a Novel Ondansetron Formulation (OND-PR002) and Immediate-Release Methylphenidate (Ritalin®)(OND003IND)
NCT01557569	PHASE1/PHASE2	COMPLETED	Clinical Efficacy of Atomoxetine for Methamphetamine Dependence
NCT01860807	PHASE2	COMPLETED	Trial of Ibudilast for Methamphetamine Dependence
NCT03336866	PHASE1/PHASE2	COMPLETED	Study of Antibody for Methamphetamine Outpatient Therapy
NCT03341078	PHASE2	COMPLETED	Pilot Study of the Effect of Ibudilast on Neuroinflammation in Methamphetamine Users
NCT05034874	PHASE2	TERMINATED	Multiple-Dose Study to Evaluate the Safety and Efficacy of IXT-m200
NCT05283304	PHASE2	TERMINATED	Monthly Injectable BUP for MA Use Disorder (MURB) Trial

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MODAFINIL	4	6
METHAMPHETAMINE	4	5
ARIPIPRAZOLE	4	3
IBUDILAST	4	3
PERINDOPRIL	4	3
RIVASTIGMINE	4	3
ATOMOXETINE	4	2
PALIPERIDONE	4	2
DEXTROAMPHETAMINE	4	1
DISULFIRAM	4	1
ENTACAPONE	4	1
LEVAMFETAMINE	4	1
LISDEXAMFETAMINE	4	1
RISPERIDONE	4	1
VIGABATRIN	4	1
CITICOLINE	3	3
CANDESARTAN	3	1
LOBELINE	2	4
DEVEXTINETUG	2	2
RTI-336	1	1
CHEMBL508	0	4
CHEMBL4204890	0	3
CHEMBL4789770	0	2
CHEMBL4203446	0	2
CHEMBL5275950	0	1
CHEMBL5417591	0	1
CHEMBL3770406	0	1
CHEMBL4102982	0	1