Details of the Drug Combination

General Information of Drug Combination (ID: DCL8XZP)

• Drug Combination Name: Dextroamphetamine + Amphetamine
• Indication: Attention Deficit Disorder With Hyperactivity; Status: Phase 1 [1]
• Component Drugs:
  Dextroamphetamine (DMMIHVP): Small molecular drug
  Amphetamine (DMSZQAK): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dextroamphetamine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[2]
Depression	6A70-6A7Z	Approved	[3]
Narcolepsy	7A20	Approved	[2]

Dextroamphetamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Trace amine-associated receptor-1 (TAAR1)	TTIU98M	TAAR1_HUMAN	Modulator	[5]

Dextroamphetamine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[6]

Dextroamphetamine Interacts with 8 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Bcl-2-like protein 11 (BCL2L11)	OTNQQWFJ	B2L11_HUMAN	Increases Expression	[7]
BH3-interacting domain death agonist (BID)	OTOSHSHU	BID_HUMAN	Increases Expression	[7]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Decreases Activity	[8]
Bcl-2-like protein 1 (BCL2L1)	OTRC5K9O	B2CL1_HUMAN	Decreases Expression	[7]
Bcl-2 homologous antagonist/killer (BAK1)	OTDP6ILW	BAK_HUMAN	Increases Expression	[7]
Bcl-2-binding component 3, isoforms 3/4 (BBC3)	OTUAXDAY	BBC3B_HUMAN	Increases Expression	[7]
Disrupted in schizophrenia 1 protein (DISC1)	OT43AW4H	DISC1_HUMAN	Increases Response To Substance	[9]
Sodium-dependent serotonin transporter (SLC6A4)	OT6FGDLW	SC6A4_HUMAN	Affects Response To Substance	[10]

Indication(s) of Amphetamine

Disease Entry	ICD 11	Status	REF
Attention deficit hyperactivity disorder	6A05.Z	Approved	[2]
Depression	6A70-6A7Z	Approved	[4]
Narcolepsy	7A20	Approved	[4]
Obesity	5B81	Approved	[4]

Amphetamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Trace amine-associated receptor-1 (TAAR1)	TTIU98M	TAAR1_HUMAN	Modulator	[5]

Amphetamine Interacts with 4 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[11]
Organic cation/carnitine transporter 2 (SLC22A5)	DT3HUVD	S22A5_HUMAN	Substrate	[12]
Sodium-dependent noradrenaline transporter (SLC6A2)	DT9JBVI	SC6A2_HUMAN	Substrate	[13]
Sodium-dependent dopamine transporter (SLC6A3)	DT3BA8L	SC6A3_HUMAN	Substrate	[13]

Amphetamine Interacts with 2 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Cytochrome P450 2D6 (CYP2D6)	DECB0K3	CP2D6_HUMAN	Metabolism	[6]
Tyramine oxidase (tynA)	DEB3TNR	AMO_ECOLI	Metabolism	[14]

Amphetamine Interacts with 13 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Decreases Response To Substance	[15]
Protein c-Fos (FOS)	OTJBUVWS	FOS_HUMAN	Increases Expression	[16]
Proenkephalin-A (PENK)	OT8P3HMP	PENK_HUMAN	Decreases Expression	[16]
Transcription factor Jun (JUN)	OTCYBO6X	JUN_HUMAN	Increases Expression	[16]
Glial fibrillary acidic protein (GFAP)	OTQ01ZAS	GFAP_HUMAN	Increases Expression	[16]
Transcription factor JunB (JUNB)	OTG2JXV5	JUNB_HUMAN	Decreases Expression	[16]
Transcription factor JunD (JUND)	OTNKACJD	JUND_HUMAN	Decreases Expression	[16]
Protein FosB (FOSB)	OTW6C05J	FOSB_HUMAN	Increases Expression	[16]
Fatty-acid amide hydrolase 1 (FAAH)	OT9DX3N1	FAAH1_HUMAN	Affects Response To Substance	[17]
D(2) dopamine receptor (DRD2)	OTBLXKEG	DRD2_HUMAN	Affects Response To Substance	[18]
Casein kinase I isoform epsilon (CSNK1E)	OTF0UXX6	KC1E_HUMAN	Increases Response To Substance	[19]
Cytochrome P450 2C19 (CYP2C19)	OTFMJYYE	CP2CJ_HUMAN	Decreases Methylation	[20]
Adenosine receptor A2a (ADORA2A)	OTVRBZ0I	AA2AR_HUMAN	Increases Response To Substance	[21]

References

• [1] ClinicalTrials.gov (NCT04132557) A Study on Suicidality, Psychosis or Substance Abuse With Methylphenidate, Atomoxetine, Amphetamine/Dextroamphetamine or Lisdexamfetamine
• [2] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [3] Dextroamphetamine FDA Label
• [4] Amphetamine FDA Label
• [5] Methamphetamine and HIV-1-induced neurotoxicity: role of trace amine associated receptor 1 cAMP signaling in astrocytes. Neuropharmacology. 2014 Oct;85:499-507.
• [6] Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives. Xenobiotica. 1999 Jul;29(7):719-32.
• [7] An insight into the hepatocellular death induced by amphetamines, individually and in combination: the involvement of necrosis and apoptosis. Arch Toxicol. 2013 Dec;87(12):2165-85. doi: 10.1007/s00204-013-1082-9. Epub 2013 Jul 3.
• [8] Pharmacological characterization of the aminorex analogs 4-MAR, 4,4'-DMAR, and 3,4-DMAR. Neurotoxicology. 2019 May;72:95-100. doi: 10.1016/j.neuro.2019.02.011. Epub 2019 Feb 15.
• [9] Misassembly of full-length Disrupted-in-Schizophrenia 1 protein is linked to altered dopamine homeostasis and behavioral deficits. Mol Psychiatry. 2016 Nov;21(11):1561-1572. doi: 10.1038/mp.2015.194. Epub 2016 Jan 12.
• [10] Serotonin transporter genotype and acute subjective response to amphetamine. Am J Addict. 2006 Sep-Oct;15(5):327-35. doi: 10.1080/10550490600859868.
• [11] Interaction of organic cation transporter 3 (SLC22A3) and amphetamine. J Neurochem. 2010 Jul;114(1):142-9.
• [12] Novel organic cation transporter 2-mediated carnitine uptake in placental choriocarcinoma (BeWo) cells. J Pharmacol Exp Ther. 2005 Jan;312(1):192-8.
• [13] Amphetamines, new psychoactive drugs and the monoamine transporter cycle. Trends Pharmacol Sci. 2015 Jan;36(1):41-50.
• [14] Mechanistic elucidation of amphetamine metabolism by tyramine oxidase from human gut microbiota using molecular dynamics simulations. J Cell Biochem. 2019 Jan 30.
• [15] Dopamine transporter gene associated with diminished subjective response to amphetamine. Neuropsychopharmacology. 2005 Mar;30(3):602-9. doi: 10.1038/sj.npp.1300637.
• [16] Effect of acute and chronic psychostimulant drugs on redox status, AP-1 activation and pro-enkephalin mRNA in the human astrocyte-like U373 MG cells. Neuropharmacology. 2005 Apr;48(5):673-84. doi: 10.1016/j.neuropharm.2004.12.010.
• [17] More aroused, less fatigued: fatty acid amide hydrolase gene polymorphisms influence acute response to amphetamine. Neuropsychopharmacology. 2010 Feb;35(3):613-22. doi: 10.1038/npp.2009.166. Epub 2009 Nov 4.
• [18] Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: an exploratory study with d-amphetamine in healthy participants. Exp Clin Psychopharmacol. 2009 Dec;17(6):374-83. doi: 10.1037/a0017840.
• [19] Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine. Neuropsychopharmacology. 2006 May;31(5):1056-63. doi: 10.1038/sj.npp.1300936.
• [20] Human cytochrome P450 kinetic studies on six N-2-methoxybenzyl (NBOMe)-derived new psychoactive substances using the substrate depletion approach. Toxicol Lett. 2018 Mar 15;285:1-8. doi: 10.1016/j.toxlet.2017.12.017. Epub 2017 Dec 23.
• [21] Interindividual variation in anxiety response to amphetamine: possible role for adenosine A2A receptor gene variants. Am J Med Genet B Neuropsychiatr Genet. 2005 Nov 5;139B(1):42-4. doi: 10.1002/ajmg.b.30228.