Table 2.
Animal studies demonstrating evidence of cognitive dysfunction, neurotoxicity, or neuroinflammation induced by khat extract or synthetic cathinones.
| Species | Sex | Drue | Cognitive deficits | Toxicity | Inflammation | ΔTB | Reference |
|---|---|---|---|---|---|---|---|
| mouse | M | khat extract 120–360 mg/kg i.p. 1x daily for 5 d | ↑↓ MWM acq., probe trial, and reversal learning (Tx prior to testing) | ND | ND | ND | (Kimani and Nyongesa 2008) |
| np | khat extract 40–360 mg/kg i.p. 1x daily for 17 d | ↑↓ MWM acq., probe trial, and reversal learning (time relative to Tx not provided) | ND | ND | ND | (Kimani et al. 2016) | |
| M | khat extract 100–400 mg/kg i.g. 1x daily for 60 d | ↓ social interaction, ↓ MWM acq and probe trial (variable time relative to Tx) | ND | ND | ND | (Bogale et al. 2016) | |
| F | mephedrone 40 mg/kg i.p. 4x @ 2 hr intervals | ND | ↓ striatal DAT n.c. striatal GFAP |
n.c. striatal ILB4 | ↑ | (Angoa-Perez et al. 2012) | |
| F | mephedrone 40 mg/kg i.p. + METH (2.5 or 5 mg/kg), D-amphetamine (5 mg/kg) or MDMA (20 mg/kg) 4x @ 2 hr intervals | ND | enhanced ↓ in striatal DAT and TH | ND | ↑ | (Angoa-Perez et al. 2013) | |
| M | mephedrone 30 mg/kg i.p. 2x daily for 4 d | ↓ spontaneous alt. in T-maze (3 wks post-Tx) n.c. MWM (5 wk post-Tx) | ND | ND | ↑ | (den Hollander et al. 2013) | |
| F | mephedrone 40 mg/kg i.p. 4x @ 2 hr intervals | ND | n.c. hipp SERT n.c. striatal GFAP |
ND | ↑ | (Angoa-Perez et al. 2014) | |
| F | mephedrone 40 mg/kg i.p. + METH 5 mg/kg or MDMA 20 mg/kg 4x @ 2 hr intervals | ND | n.c. hipp SERT, TPH2 or GFAP |
ND | ND | (Angoa-Perez et al. 2014) | |
| M | mephedrone 50 mg/kg s.c. 4x @ 2 hr intervals for 1 d | ND | ↓ DAT binding in striatum and FC; ↓ SERT binding in hipp and FC |
ND | ↑ | (Martinez-Clemente et al. 2014) | |
| M | mephedrone 25 mg/kg s.c. 4x @ 2 hr intervals | ND | ↓ DAT binding in FC but not striatum; n.c. SERT binding in FC or hipp | ND | ↑ | (Martinez-Clemente et al. 2014) | |
| M | mephedrone 25 mg/kg s.c. 3x @ 2 hr intervals for 2 d | ND | ↓ DAT binding in FC and striatum; ↓ SERT binding in FC and hipp; ↓ TPH2 levels in hipp; n.c. GFAP in hipp |
ND | ↑ | (Martinez-Clemente et al. 2014) | |
| F | mephedrone 40 mg/kg i.p. 4x @ 2 hr intervals | ND | ↓ striatal DAT | ND | ↓↑ | (Anneken et al. 2018) | |
| F | mephedrone 40 mg/kg i.p. + METH 2.5 mg/kg 4x @ 2 hr intervals | ND | ↓ striatal DAT, TH ↑ striatal GFAP |
↑ striatal Iba1 | ↑ | (Anneken et al. 2018) | |
| F | mephedrone 40 mg/kg s.c. 4x @ 2 hr intervals | ND | n.c. striatal DAT, TH, or GFAP; | ND | ↑ | (Anneken et al. 2015) | |
| F | mephedrone 40 mg/kg s.c + MDPV 30 mg/kg. 4x @ 2 hr intervals | ND | n.c. striatal DAT, TH, or GFAP; | ND | ND | (Anneken et al. 2015) | |
| F | mephedrone 40 mg/kg s.c + methylone 30 mg/kg 4x @ 2 hr intervals | ND | n.c. striatal DAT, TH, or GFAP; | ND | ND | (Anneken et al. 2015) | |
| M | mephedrone 25 mg/kg s.c. + ethanol (2, 1.5, 1.5, 1 g/kg i.p.) 4x @ 2 hr intervals | ↓ MWM acq.; potentiation of mephedrone- induced deficits in probe trial performance (1 wk post-Tx) | potentiated mephedrone- induced ↓ DAT binding & ↓ TH levels in FC, ↓ ↓ SERT binding & TPH2 levels in, Hipp, ↑ lipid peroxidation in FC and hipp, ↓ hipp neurogenesis |
ND | ND | (Ciudad-Roberts et al. 2016) | |
| M | mephedrone 2.5 mg/kg i.p. acute | n.c. passive avoidance (15 min post-Tx) | ND | ND | ND | (Budzynska et al. 2017) | |
| M | mephedrone 2.5 mg/kg i.p. + MDMA 1 mg/kg acute | ↓ passive avoidance (15 min post-Tx) | ND | ND | ND | (Budzynska et al. 2017) | |
| F (pd) | mephedrone 1 50 mg/kg s.c. 1x daily for 14 d GD 5–18 | ↓ acq. and reference memory in MWM in 60 d old offspring | ↓ cell proliferation and ↑ apoptosis in hipp of offspring | ND | ND | (Naseri et al. 2018) | |
| F (pd) | mephedrone 50 mg/kg s.c. 3x daily @ 2 h intervals on 6 of GD days 5–18 | ↓ acq. and reference memory in MWM in 60 d old offspring | ↓ cell proliferation and ↑ apoptosis in hipp of offspring | ND | ND | (Naseri et al. 2018) | |
| ? | MDPV 10 mg/kg i.p. acute (PND 7) | ND | ↑ apoptosis in cortex, hipp, nucleus accumbens | ND | n.c. | (Adam et al. 2014) | |
| F | MDPV 30 mg/kg s.c. 4x @ 2 hr intervals | ND | n.c. striatal DAT, TH, or GFAP; | ND | ↑ | (Anneken et al. 2015) | |
| F | MDPV 30 mg/kg s.c + methylone 30 mg/kg 4x @ 2 hr intervals | ND | n.c. striatal DAT, TH, or GFAP; | ND | ND | (Anneken et al. 2015) | |
| F | MDPV 10–30 mg/kg s.c + METH 2.5–10 mg/kg 4x @ 2 hr intervals | ND | protection against METH-induced ↓ in striatal DAT/TH and ↑ in GFAP | ND | ↑ | (Anneken et al. 2015) | |
| F | MDPV 10–30 mg/kg s.c + D-amphetamine 5 mg/kg 4x @ 2 hr intervals | ND | protection against METH- induced ↓ in striatal DAT/TH and ↑ in GFAP | ND | ND | (Anneken et al. 2015) | |
| F | MDPV 1 mg/kg i.p. 4x @ 2 h intervals | ND | n.c. striatal TH or GFAP | ND | n.c. | (Miner et al. 2017) | |
| F | MDPV 1 mg/kg i.p. + MDMA 15 mg/kg 4x @ 2 h intervals | ND | n.c. striatal TH or GFAP | ND | ↑↓ | (Miner et al. 2017) | |
| M | methylone 30 mg/kg i.p. | ↑ MWM probe trial performance (5 wks post-Tx) | ND | ND | ↑ | (den Hollander et al. 2013) | |
| F | methylone 20 mg/kg i.p. 4x @ 2 h intervals | ND | n.c. striatal TH or GFAP | ND | ↑↓ | (Miner et al. 2017) | |
| F | methylone 20 mg/kg i.p. + MDMA 15 mg/kg 4x @ 2 h intervals | ND | n.c. striatal TH or GFAP | ND | ↑↓ | (Miner et al. 2017) | |
| F | methylone 30 mg/kg s.c. 4x @ 2 hr intervals | ND | n.c. striatal DAT, TH, or GFAP; | ND | ↑ | (Anneken et al. 2015) | |
| F | methylone 30 mg/kg s.c + METH 2.5 mg/kg 4x @ 2 hr intervals | ND | enhancement of METH-induced ↓ in striatal DAT/TH and ↑ in GFAP | ND | ↑ | (Anneken et al. 2015) | |
| M | methylone 25 mg/kg s.c. 3x @ 3.5 hr intervals | ND | ↓ SERT binding in FC and hipp | ND | ↑ | (Lopez-Arnau et al. 2014a) | |
| M | methylone 25 mg/kg s.c. 4x @ 3 hr intervals | ND | ↓ SERT binding, ↓ TPH2 levels in FC and hipp; ↑ GFAP in hipp |
ND | ↑ | (Lopez-Arnau et al. 2014a) | |
| F | methcathinone 20–40 mg/kg i.p. 4x @ 2 hr intervals | ND | ↓ striatal DAT, TH ↑ striatal GFAP |
ND | ↑↓ | (Anneken et al. 2017) | |
| F | methcathinone 80 mg/kg i.p. 4x @ 2 hr intervals | ND | ↓ striatal DAT, TH ↑ striatal GFAP |
↑ Iba1 in striatum | ↓ | (Anneken et al. 2018) | |
| F | methcathinone 80 mg/kg i.p. + METH 2.5 mg/kg 4x @ 2 hr intervals |
ND | ↓ striatal DAT, TH ↑ striatal GFAP |
↑ Iba1 in striatum | ↓ | (Anneken et al. 2018) | |
| Rat | M | mephedrone 10 or 25 mg/kg. i.p. 4x @ 2 hr intervals | ND | ↓ hipp 5-HT uptake ↓ striatal DA uptake |
ND | ND | (Hadlock et al. 2011) |
| M | mephedrone 30 mg/kg i.p. 1x daily for 10 d | ↓ novel object exploration (5 wk post-Tx) | ↓ 5-HT metab. in hipp, striatum | n.c. TPSO binding in hipp, striatum | ND | (Motbey et al. 2012) | |
| M | mephedrone 0.3 mg/kg/inf IVSA for 10 d | ND | n.c. in DAT or SERT binding in various regions | non-sig. ↑ TPSO binding in various regions | ND | (Motbey et al. 2013) | |
| M | mephedrone 30 mg/kg i.p. 2x daily for 4 d | ND | ↓ SERT binding in hipp | ND | n.c. | (den Hollander et al. 2013) | |
| M | mephedrone 25 mg/kg s.c. 3x @ 2 hr intervals for 2 d | n.c. MWM acq. (1 wk post-Tx); ↓ ref. memory in probe trial | ↓ DAT binding and TH levels in FC ↓ SERT binding and TPH2 levels, and ↑ antioxidant enzyme levels in FC, striatum, and hipp; ↑ lipid in peroxidation in striatum |
ND | ↑ | (Lopez-Arnau et al. 2015) | |
| F | mephedrone 10 mg/kg i.p. 2 d/wk for 30 wk | ↑ errors in operant response sequence task; further ↑ by 17β-estriadiol (Tx during behavioral testing) | ND | ND | ND | (Weed et al. 2014) | |
| M | mephedrone 5 mg/kg i.p. acute | ND | ↑ DNA oxidation in cerebral cortex | ND | ND | (Kaminska et al. 2018) | |
| M | mephedrone 5 mg/kg i.p. 1x daily for 4 d (repeated 1x after 3 d drug free) | ND | ↑ DNA oxidative in cerebral cortex | ND | ND | (Kaminska et al. 2018) | |
| M | MDPV 0.03 mg/kg/inf i.v. self-administered 96-h sessions for 5 wk |
↓ novel object recognition; n.c. object placement memory (3 wks post self-admin) | ↑ neurodegeneration in entorhinal and | ND | ND | (Sewalia et al. 2018) | |
| M | methylone 30 mg/kg i.p. 2x daily for 4 d | ND | ↓ SERT binding in FC, hipp | ND | ↑ | (den Hollander et al. 2013) | |
| M | methylone 20 mg/kg s.c. 4x @ 3 hr intervals | n.c. MWM acq. (1 wk post-Tx); ↓ reference memory in probe trial |
↓ SERT binding and TPH2 levels in striatum, FC, hipp; ↑ GFAP in FC |
ND | ↑ | (Lopez-Arnau et al. 2014b) | |
| M/F | methylone 8 mg/kg i.p. 1x daily for 10 d | ↓ spatial memory in Y-maze test (40–50 d post-Tx) | ND | ND | ND | (Daniel and Hughes 2016) | |
| Monkey | M | mephedrone 0.32–0.56 mg/kg i.m. acute | ↑ visuospatial ND memory; n.c. spatial working memory (Tx immediately prior to testing) | ND | ND | ND | (Wright et al. 2012) |
Abbreviations: ↑, increased; ↓, decreased; ↑↓, biphasic effect; 5-HT, 5-hydroxytryptamine (serotonin); acq., acquisition; alt., alternation; DA, dopamine; DAT, dopamine transporter; F, female; FC, frontal cortex; GD, gestational dat; GFAP, glial fibrillary acidic protein; Iba1, ionized calcium binding adaptor molecule 1; LDH; lactose dehydrogenase; M, male; MDMA, methylenedioxymethamphetamine; MDPV, methylenedioxypyrovalerone; Morris water maze, MWM; n.c., no change; ND, not determined; pd, pregnant dam; SERT, serotonin transporter; TPH2, tryptophan hydroxylase 2; TSPO, 18 kDa translocator protein; Tx, treatment