Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms

Panos Zanos; Ruin Moaddel; Patrick J. Morris; Lace M. Riggs; Jaclyn N. Highland; Polymnia Georgiou; Edna F. R. Pereira; Edson X. Albuquerque; Craig J. Thomas; Carlos A. Zarate; Todd D. Gould

doi:10.1124/pr.117.015198

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Fig. 1.
Major metabolic pathways. In the predominant metabolic pathway, racemic ketamine [(R,S)-KET] is initially metabolized to norketamine [(R,S)-norKET], by either CYP2B6 or CYP3A4. Subsequently, norketamine can be further metabolized to form DHNK or the HNKs. Hydroxylation of norketamine at the six position by CYP2A6 results in (2R,6S;2S,6S)-hydroxynorketamine [(2R,6R;2S,6S)-HNK]. Alternatively, CYP2B6 or CYP2A6 can hydroxylate norketamine at the four position, resulting in the 4-hydroxy isomers. In the third case, CYP2B6 can hydroxylate norketamine at the five position, resulting in (2R,5S;2S,5R)-HNK and (2R,5R;2S,5S)-HNK. (R,S)-DHNK can result either from direct dehydrogenation from norketamine via CYP2B6 or via dehydration from either diastereomer of the 5-hydroxynorketamines via a nonbiologically catalyzed process.
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Fig. 2.
Minor metabolic pathways. Although the majority of ketamine is metabolized via the major metabolic pathways (Fig. 1), there are several minor metabolic pathways, which provide unique, albeit low abundance, ketamine metabolites. The aryl ring of ketamine can be directly hydroxylated by flavin-containing mono-oxygenase enzymes or CYP2C9 to provide hydroxyphenyl-ketamine (hydroxyphenyl-KET). 4-Hydroxyketamine has also been observed; however, the metabolic enzymes responsible for this are currently unknown. CYP3A5 can directly hydroxylate ketamine at the six position to provide (2R,6S;2S,6R)-HK. Demethylation of (2R,6S;2S,6R)-HK with CYP3A5 provides (2R,6S;2S,6R)-HNK. CYP2A6 can also directly hydroxylate ketamine to provide (2R,6R;2S,6S)-HK, which is then transformed to (2R,6R;2S,6S)-HNK. Finally, norketamine can be hydroxylated via an unknown enzyme directly on the aryl rich to provide hydroxyphenyl-norketamine (hydroxyphenyl-norKET).

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TABLE 1

Relevant doses and plasma concentrations of ketamine for its clinical use and side effects in humans

Clinical Uses and Side Effects	Route of Administration	Ketamine Dose	Plasma C_max	References
Clinical effects
General anesthesia	Intravenous	1.0–2 mg/kg	1200–2400 ng/ml; 5–10 μM	Sussman (1974), Clements et al. (1982), Idvall et al. (1983), Malaquin (1984), Malinovsky et al. (1996), Dachs and Innes (1997), Yanagihara et al. (2003), Weber et al. (2004), Craven (2007), Gao et al. (2016)
	Intramuscular	4–11 mg/kg
	Rectal	8–10.6 mg/kg
	Oral	500 mg (max)—sedation
	Intranasal	For (S)-ketamine: 3–9 mg/kg	N/R	Weber et al. (2004), Huge et al. (2010), Reid et al. (2011)
Analgesia	Intravenous	0.15 mg/kg	70–160 ng/ml; 0.29–0.67 μM	Grant et al. (1981), Clements et al. (1982), Hirlinger and Dick (1984), Weksler et al. (1993), Eide et al. (1995), Malinovsky et al. (1996), Stubhaug et al. (1997), Lauretti et al. (1999), Azevedo et al. (2000), Flood and Krasowski (2000), Tanaka et al. (2000), Carr et al. (2004), Marchetti et al. (2015)
	Intramuscular	0.5–1 mg/kg
	Intranasal	2 × 10–50 mg
	Transdermal	25 mg released throughout a 24-hour period
	Subcutaneous	0.05–0.15 mg/kg per hour for 7 days
	Rectal	10 mg/kg
	Oral	2 mg/kg
	Oral	0.5 mg/kg	45 ± 10 ng/ml; 0.19 ± 0.04 μM	Grant et al. (1981)
Anti-inflammation	Intravenous	0.15–0.25 mg/kg	N/R	Roytblat et al. (1998), Beilin et al. (2007), Russabrov et al. (2008)
Antidepressant	Intravenous	0.5 mg/kg; 40-min infusion	185 ng/ml; 0.78 μM	Zarate et al. (2006)
Side effects
Dissociation	Intravenous	0.5 mg/kg; 40-min infusion	100–250 ng/ml; 0.42–1.1 μM	Krystal et al. (1994)
Psychotomimetic effects in subjects with schizophrenia	Intravenous	0.3 mg/kg bolus	120 ng/ml; 0.5 μM	Lahti et al. (2001)
Psychotomimetic effects in subjects with schizophrenia	Intravenous	0.12 mg/kg bolus followed by a 60-min infusion of 0.65 mg/kg (total dose 0.77 mg/kg)	N/R	Malhotra et al. (1997)
Cognitive and memory impairment	Intravenous	40- to 120-min infusion of 0.4–0.8 mg/kg	N/R	Malhotra et al. (1996), Newcomer et al. (1999), Morgan et al. (2004), Mathew et al. (2010)
		0.5 mg/kg bolus	350 ng/ml; 1.5 μM	Pfenninger et al. (2002)
		infusion over length of testing (total dose variable)	N/R	Harris et al. (1975), Driesen et al. (2013)
	Intramuscular	0.25–0.5 mg/kg bolus	N/R	Ghoneim et al. (1985)
Abuse (recreational use)	Intravenous	1–2 mg/kg	N/R	Siegel (1978), Dalgarno and Shewan (1996), Jansen (2000), Arditti et al. (2002), Wolff and Winstock (2006), Bokor and Anderson (2014)
	Intramuscular	50–150 mg
	Oral	100–500 mg
	Intranasal	30–400 mg

N/R, not reported.

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TABLE 2

Pharmacokinetic comparison for (2R,6R) and (2S,6S)-HNK in humans and rodents

Values represent mean ± S.D.

Species	Drug	Administration Paradigm	Tissue	C_max (R,S)-KET (plasma: µM; brain: µmol/kg)	C_max (R,S)-KET (plasma: ng/ml; brain: ng/g)	AUC_last (R,S)-KET (plasma: h.µM; brain h. µmol/kg)	AUC_last (R,S)-KET (plasma: h.ng/ml; brain: h.ng/g)	C_max (2R,6R;2S,6S)-HNK (plasma: µM; brain: µmol/kg)	C_max (2R,6R;2S,6S)-HNK (plasma: ng/ml; brain: ng/g)	AUC_last (2R,6R;2S,6S)-HNK (plasma: h.µM; brain h. µmol/kg)	AUC_last (2R,6R;2S,6S)-HNK (plasma: h.ng/ml; brain: h.ng/g)	References
Humans	(R,S)-KET	0.5 mg/kg, 40-min i.v. infusion	Plasma	0.75 ± 0.23 (BD)	177.23 ± 53.8 (BD)	4.10 (BD)	975.4 (BD)	0.16 ± 0.06 (BD)	37.59 ± 14.23 (BD)	5.70 (BD)	1366 (BD)	Zarate et al. (2012a), Unpublished data
Humans	(R,S)-KET	0.5 mg/kg, 40-min i.v. infusion	Plasma	0.86 ± 0.43 (MDD)	204.13 ± 101.46 (MDD)	3.67 (MDD)	873.5 (MDD)	0.097 ± 0.05 (MDD)	23.19 ± 11.88 (MDD)	4.33 (MDD)	1038 (MDD)	Zarate et al. (2012a), Unpublished data
Rats	(R,S)-KET	40 mg/kg, i.v. infusion	Plasma	34.52 ± 2.93	8206 ± 697	48.01 ± 21.30	11,410 ± 5064	18.59 ± 2.81	4455 ± 673	141.19 ± 18.5	33,843 ± 4432	Moaddel et al. (2015b), Unpublished data
	(R,S)-KET	40 mg/kg, i.p. infusion	Brain	137 ± 6	32,600 ± 1400	N/A	N/A	30 ± 5	7200 ± 1200	N/A	N/A	Paul et al. (2014)
	(R)-KET	20 mg/kg, i.v. infusion	Plasma	14.4 ± 1.68^{^a}	3430 ± 400^{^a}	N/A	N/A	1.44 ± 0.48^{^b}	345 ± 115^{^b}	N/A	N/A	Moaddel et al. (2015b)
	(R)-KET	20 mg/kg, i.v. infusion	Brain	68.84 ± 8.12^{^a}	16,365 ± 1931^{^a}	N/A	N/A	1.14 ± 0.20^{^b}	274 ± 47^{^b}	N/A	N/A
	(S)-KET	20 mg/kg, i.v. infusion	Plasma	11.49 ± 2.25^{^c}	2732 ± 535^{^c}	N/A	N/A	5.52 ± 0.28^{^d}	1323 ± 67^{^d}	N/A	N/A
	(S)-KET	20 mg/kg, i.v. infusion	Brain	65.25 ± 1.91^{^c}	15,512 ± 453^{^c}	N/A	N/A	3.21 ± 0.55^{^d}	769 ± 133^{^d}	N/A	N/A
	(R,S)-norKET	20 mg/kg, i.v. infusion	Brain	N/A	N/A	N/A	N/A	16 ± 3^{^b}	N/A	N/A	N/A	Paul et al. (2014)
	(2S,6S)-HNK	20 mg/kg, i.v. infusion	Brain	N/A	N/A	N/A	N/A	127 ± 4^{^d}	N/A	N/A	N/A	Paul et al. (2014)
		20 mg/kg, i.v. infusion	Plasma	N/A	N/A	N/A	N/A	49.89 ± 1.52^{^d}	11,958 ± 364^{^d}	120.91 ± 25.71^{^d}	28,981 ± 6162^{^d}	Moaddel et al. (2015b)
		20 mg/kg, i.v. infusion	Brain	N/A	N/A	N/A	N/A	127.09 ± 3.51^{^d}	30,463 ± 841^{^d}	N/A	N/A
		20 mg/kg, oral gavage	Plasma	N/A	N/A	N/A	N/A	19.66 ± 5.05	4713 ± 1211	42.22 ± 5.48	10,120 ± 1313
		20 mg/kg, oral gavage	Brain	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A
Mice	(R,S)-KET	10 mg/kg, i.p. injection	Plasma	2.36 ± 0.36	561.89 ± 86.09	0.75	177.9	2.81 ± 1.16	674.59 ± 278.23	2.01	480.9	Zanos et al. (2016)
	(R,S)-KET	10 mg/kg, i.p. injection	Brain	4.89 ± 0.85	1162.34 ± 202.05	2.07	492.2	2.08 ± 0.21	498.35 ± 50.99	2.49	597.0	Zanos et al. (2016)
	(R)-KET	10 mg/kg, i.p. injection	Plasma	1.40 ± 0.18^{^a}	332.8 ± 42.99^{^a}	0.44^{^a}	104.8^{^a}	2.83 ± 0.31^{^b}	678.3 ± 74.54^{^b}	1.85^{^b}	443.0^{^b}	Unpublished data
	(R)-KET	10 mg/kg, i.p. injection	Brain	7.93 ± 1.93^{^a}	1886 ± 459.6^{^a}	2.48^{^a}	591.9^{^a}	2.47 ± 0.31^{^b}	590.9 ± 74.10^{^b}	2.58^{^b}	618.7^{^b}	Zanos et al. (2016)
	(S)-KET	10 mg/kg, i.p. injection	Plasma	4.32 ± 1.12	1028 ± 266.7^{^c}	1.23^{^c}	293.1^{^c}	2.97 ± 0.87^{^d}	711.5 ± 209.4^{^d}	3.62^{^d}	868.1^{^d}	Unpublished data
	(S)-KET	10 mg/kg, i.p. injection	Brain	7.33 ± 2.36^{^c}	1743 ± 560.6^{^c}	2.03^{^c}	483.1^{^c}	2.21 ± 0.46^{^d}	530.7 ± 111.2^{^d}	4.15^{^d}	995.8^{^d}	Zanos et al. (2016)
	(2S,6S)-HNK	10 mg/kg, i.p. injection	Plasma	N/A	N/A	N/A	N/A	17.57 ± 8.72^{^d}	4211 ± 2089^{^d}	10.16^{^d}	2435^{^d}	Unpublished data
	(2S,6S)-HNK	10 mg/kg, i.p. injection	Brain	N/A	N/A	N/A	N/A	15.70 ± 8.98^{^d}	3764 ± 2152^{^d}	6.55^{^d}	1570^{^d}	Zanos et al. (2016)
	(2R,6R)-HNK	10 mg/kg, i.p. injection	Plasma	N/A	N/A	N/A	N/A	10.79 ± 4.76^{^b}	2587 ± 1141^{^b}	2.43^{^b}	583.5^{^b}	Unpublished data
	(2R,6R)-HNK	10 mg/kg, i.p. injection	Brain	N/A	N/A	N/A	N/A	10.66 ± 5.85^{^b}	2556 ± 1402^{^b}	2.19^{^b}	525.3^{^b}	Zanos et al. (2016)

BD, bipolar disorder; MDD, major depressive disorder.
↵^a Reported values represent (R)-KET levels.
↵^b Reported values represent (2R,6R)-HNK levels.
↵^c Reported values represent (S)-KET levels.
↵^d Reported values represent (2S,6S)-HNK levels.

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TABLE 3

Molecular targets of ketamine and its metabolites

Values represent mean ± S.E., unless otherwise indicated.

Receptor/Target	Drug	Action	Proposed Clinical Relevance	Affinity/ Potency (μM)	Method	Tissue/System	Species	Reference
NMDAR	(R,S)-KET	Antagonist	Anesthesia, antidepressant effects, amnesia, dissociative effects, abuse potential, cognitive impairment	K_i = 0.49 ± 0.05	RBA—[³H]MK-801 binding	Cerebral cortex	Rat	Wong et al. (1986)
				K_i = 1.09	RBA—[³H]MK-801 binding	Brain	Rat	Wong et al. (1988)
				K_i = 1.09	RBA—[³H]MK-801 binding	Brain	Rat	Wong et al. (1988)
				K_i = 1.93	RBA—[³H]TCP binding	Brain	Rat	Wong et al. (1988)
				K_i = 0.42 ± 0.03	RBA—[³H]MK-801 binding	Cortex	Human	Kornhuber et al. (1989)
				K_i = 0.18 ± 0.03	RBA—[³H]MK-801 binding (no added glutamate or glycine)	Brain	Rat	Reynolds and Miller (1989)
				K_i = 0.24 ± 0.10	RBA—[³H]MK-801 binding (added 100 µM glutamate and 30 µM glycine)	Brain	Rat	Reynolds and Miller (1989)
				K_i = 0.58 ± 0.07	RBA—[³H]MK-801 binding	Brain	Mouse	Sharif et al. (1991)
				K_i = 0.76 ± 0.047	RBA—[³H]MK-801 binding	Brain	Guinea pig	Sharif et al. (1991)
				K_i = 0.48 ± 0.1	RBA—[³H]MK-801 binding	Brain	Dog	Sharif et al. (1991)
				K_i = 0.71 ± 0.06	RBA—[³H]MK-801 binding	Cortex	Dog	Sharif et al. (1991)
				K_i = 0.6 ± 0.04	RBA—[³H]MK-801 binding	Spinal cord	Rat	Sharif et al. (1991)
				K_i > 10	RBA—[³H]TCP binding	Rat glioma hybrid cells NG108-15	Rat	Georg and Friedl (1991)
				K_i = 1.19 ± 0.24	RBA—[³H]MK-801 binding	Cortex	Rat	Bresink et al. (1995)
				K_i = 0.20 ± 0.02	RBA—[³H]MK-801 binding	Brain (synaptic membranes)	Rat	Parsons et al. (1995)
				K_i = 1.0 ± 0.5	RBA—[¹²⁵I]MK-801 binding	Membranes from HEK293 cells transfected with GluN1/2A receptors	Rat	Lynch et al. (1995)
				K_i = 2.5 ± 1.2	RBA—[¹²⁵I]MK-801 binding	Membranes from HEK293 cells transfected with GluN1/2B receptors	Rat	Lynch et al. (1995)
				K_i = 2.51 ± 1.90	Autoradiographic binding—[³H]MK-801	Cerebellum	Rat	Bresink et al. (1995)
				K_i = 0.5 ± 0.15	RBA—[³H]MK-801 binding	Striatum	Rat	Kapur and Seeman (2001, 2002)
				K_i = 0.92	RBA—[³H]MK-801 binding	Brain membranes	Rat	Sun and Wessinger (2004)
				K_i = 3.1 ± 0.3	RBA—[³H]MK-801 binding	Striatum	Rat	Seeman et al. (2005)
				K_i = 1.35 ± 0.43	RBA—[³H]MK-801 binding	Cortex	Rat	Gilling et al. (2009)
				K_i = 0.67 ± 0.15	RBA—[³H]MK-801 binding	Cortex	Human	Gilling et al. (2009)
				K_i = 1.47 ± 0.68	Whole-cell patch-clamp recordings—holding potential at −70 mV	HEK293 cells transfected with GluN1/2A receptors	Human	Gilling et al. (2009)
				K_i = 0.32 ± 0.02	RBA—[³H]MK-801 binding	Forebrain	Rat	Wallach et al. (2016), Kang et al. (2017)
				K_i = 0.25	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ = 3.91	RBA—[³H]TCP binding	Rat brain (minus cerebellum) synaptoneurosomal fractions	Rat	Allaoua and Chicheportiche (1989)
				IC₅₀ = 5.4 ± 0.6	Autoradiographic binding—[³H]MK-801	Frontal cortex	Rat	Porter and Greenamyre (1995)
				IC₅₀ = 5.0 ± 0.6	Autoradiographic binding—[³H]MK-801	Striatum	Rat	Porter and Greenamyre (1995)
				IC₅₀ = 3.9 ± 0.5	Autoradiographic binding—[³H]MK-801	Entorhinal cortex	Rat	Porter and Greenamyre (1995)
				IC₅₀ = 6.7 ± 0.8	Autoradiographic binding—[³H]MK-801	Hippocampus (CA1)	Rat	Porter and Greenamyre (1995)
				IC₅₀ = 5.4 ± 0.6	Autoradiographic binding—[³H]MK-801	Dentate gyrus	Rat	Porter and Greenamyre (1995)
				IC₅₀ = 8.2 ± 0.6	Autoradiographic binding—[³H]MK-801	Cerebellar granule cell layer	Rat	Porter and Greenamyre (1995)
				IC₅₀ = 1.6 ± 0.01	Whole-cell patch-clamp recordings	Cultured superior collicular neurones	Rat	Parsons et al. (1995)
				IC₅₀ > 10; 100 μM induced a 63% inhibition	NMDA (10 μM)-evoked extracellular postsynaptic currents	Ventral tegmental area	Rat	Wu and Johnson (1996)

				IC₅₀ = 1.03 ± 0.06	Glutamate (0.3 μM)-evoked GluN1/2A currents	tsA201 cells	Rat	Glasgow et al. (2017)
				IC₅₀ = 0.89 ± 0.07	Glutamate (1 mM)-evoked GluN1/2A currents	tsA201 cells	Rat	Glasgow et al. (2017)
				IC₅₀ = 0.59 ± 0.03	Glutamate (0.3 μM)-evoked GluN1/2B currents	tsA201 cells	Rat	Glasgow et al. (2017)
				IC₅₀ = 0.43 ± 0.04	Glutamate (1 mM)-evoked GluN1/2B currents	tsA201 cells	Rat	Glasgow et al. (2017)
				IC₅₀ = 0.43 ± 0.10	Whole-cell patch-clamp recordings	Hippocampus	Rat	Parsons et al. (1996)
				IC₅₀ = 0.92 ± 0.21	Whole-cell patch-clamp recordings	Striatum	Rat	Parsons et al. (1996)
				2 mM Mg²⁺	Two-microelectrode recording	Rat receptors expressed in Xenopus oocytes	Rat	Dravid et al. (2007)
				GluN1/2A: IC₅₀ = 3.31		Rat receptors expressed in Xenopus oocytes
				GluN1/2B: IC₅₀ = 0.93
				GluN1/2C: IC₅₀ = 1.65
				GluN1/2D: IC₅₀ = 2.42
				IC₅₀ = 7.97	FLIPR calcium influx assay	HEK293 cells	Human	Gilling et al. (2009)
				IC₅₀ = 0.71 ± 0.03	Whole-cell patch-clamp recordings—holding potential at −70 mV		Human	Gilling et al. (2009)
				IC₅₀ = 6.05 ± 0.66	Whole-cell patch-clamp recordings—holding potential at 0 mV	HEK293 cells transfected with GluN1/2A receptors	Human	Gilling et al. (2009)
				Mg²⁺ free	Whole-cell recordings	Rat receptor expressed in HEK293 cells	Rat	Kotermanski and Johnson (2009)
				GluN1/2A: IC₅₀ = 0.33 ± 0.01; GluN1/2B: IC₅₀ = 0.31 ± 0.02; GluN1/2C: IC₅₀ = 0.51 ± 0.01; GluN1/2D: IC₅₀ = 0.83 ± 0.02	Whole-cell recordings	Rat receptor expressed in HEK293 cells	Rat	Kotermanski and Johnson (2009)
				1 mM Mg²⁺	Whole-cell recordings	Rat receptor expressed in HEK293 cells	Rat	Kotermanski and Johnson (2009)
				GluN1/2A: IC₅₀ = 5.35 ± 0.34; GluN1/2B: IC₅₀ = 5.08 ± 0.02; GluN1/2C: IC₅₀ = 1.18 ± 0.04; GluN1/2D: IC₅₀ = 2.95 ± 0.02	Whole-cell recordings	Rat receptor expressed in HEK293 cells	Rat	Kotermanski and Johnson (2009)
				IC₅₀ = 10	Extracellular recordings (EPSPs)	Hippocampus (CA1)	Rat	Izumi and Zorumski (2014)
				IC₅₀ = 0.40	Whole-cell patch-clamp recordings	Hippocampal neuron culture	Rat	Emnett et al. (2016)
				IC₅₀ = 0.51 ± 0.04	RBA—[³H]MK-801 binding	Forebrain	Rat	Wallach et al. (2016), Kang et al. (2017)
				IC₅₀ = 0.35	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(S)-KET	Antagonist	Anesthesia, antidepressant effects, dissociative effects, cognitive impairment	K_i = 0.30 ± 0.013	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 0.69 ± 0.09	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 0.42 ± 0.04	RBA—[³H]MK-801 binding	Cortex	Pig	Bonifazi et al. (2015)
				K_i = 0.44 ± 0.10	RBA—[³H]MK-801 binding	Cortex	Pig	Temme et al. (2018)
				IC₅₀ = 1.6–1.9	RBA—[³H]MK-801 binding	Hippocampus (two brain samples only)	Human	Oye et al. (1992)
				IC₅₀ = 1.5–2.8	RBA—[³H]MK-801 binding	Frontal cortex (two brain samples only)	Human	Oye et al. (1992)
				IC₅₀ = 1.6–2.1	RBA—[³H]MK-801 binding	Occibital cortex (two brain samples only)	Human	Oye et al. (1992)
				IC₅₀ = 0.80	Whole-cell patch-clamp recordings	Hippocampus	Rat	Zeilhofer et al. (1992)
				IC₅₀ = 0.9 ± 1.4	NMDA (μM)-evoked currents	Cortex	Rat	Ebert et al. (1997)
				2 mM Mg²⁺	Two-microelectrode recording	Rat receptors expressed in Xenopus ooctyes	Rat	Dravid et al. (2007)
				GluN1/2A: IC₅₀ = 16.10
				GluN1/2B: IC₅₀ = 1.55
				GluN1/2C: IC₅₀ = 1.11
				GluN1/2D: IC₅₀ = 1.50
	(R)-KET	Antagonist	Anesthesia, antidepressant effects	K_i = 1.40 ± 0.1	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 2.57 ± 0.28	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 1.79 ± 0.31	RBA—[³H]MK-801 binding	Cortex	Pig	Temme et al. (2018)
				IC₅₀ = 7.2–10	RBA—[³H]MK-801 binding	Hippocampus (two brain samples only)	Human	Oye et al. (1992)
				IC₅₀ = 8.2–13.7	RBA—[³H]MK-801 binding	Frontal cortex (two brain samples only)	Human	Oye et al. (1992)
				IC₅₀ = 10.9–11.4	RBA—[³H]MK-801 binding	Occibital cortex (two brain samples only)	Human	Oye et al. (1992)
				IC₅₀ = 1.53	Whole-cell patch-clamp recordings	Hippocampus	Rat	Zeilhofer et al. (1992)
				IC₅₀ = 3.0 ± 1.4	NMDA (μM)-evoked currents	Cortex	Rat	Ebert et al. (1997)
	(R,S)-norKET	Antagonist	Anesthesia	K_i = 3.60 ± 0.49	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				2 mM Mg²⁺	Two-microelectrode recording	Rat receptors expressed in Xenopus ooctyes	Rat	Dravid et al. (2007)
				GluN1/2A: IC₅₀ = 50.90
				GluN1/2B: IC₅₀ = 8.74
				GluN1/2C: IC₅₀ = 5.6
				GluN1/2D: IC₅₀ = 7.5
				IC₅₀ = 2.00	Whole-cell recordings	Hippocampal neuron culture	Rat	Emnett et al. (2016)
	(S)-norKET	Antagonist		K_i = 1.7 ± 0.050	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 2.25 ± 0.22	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				Ki = 0.87	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ = 3.0 ± 0.8	NMDA (μM)-evoked currents	Cortex	Rat	Ebert et al. (1997)
				IC₅₀ = 1.23	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(R)-norKET	Antagonist		K_i = 13 ± 1.8	RBA—[³H]MK-801 binding	Cortex	Rat	Ebert et al. (1997)
				K_i = 26.46	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 0.60	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ = 39.0 ± 1.4	NMDA (μM)-evoked currents	Cortex	Rat	Ebert et al. (1997)
				IC₅₀ = 0.85	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(S)-DHNK	Antagonist	N/A	K_i = 38.95	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 29.7	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ = 42.0	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(R)-DHNK	Antagonist	N/A	K_i = 74.55	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i = 42.1	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ = 59.7	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,6S)-HNK	Antagonist	N/A	K_i = 21.19	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				Ki > 10	RBA—[³H]MK-801 binding	Whole brain	Rat	Zanos et al. (2016)
				Ki = 7.34	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ = 10.4	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,6R)-HNK	No effect	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain	Rat	Moaddel et al. (2013)
				K_i > 10	RBA—[³H]MK-801 binding	Whole brain	Rat	Zanos et al. (2016)
				K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
		Antagonist	Antidepressant	IC₅₀ > 50	Whole-cell recordings	Hippocampal neuron culture	Mouse	Suzuki et al. (2017)
	(2R,6S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
				IC₅₀ > 100
	(2S,6R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,6R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,5S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,5R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4R)-HNK	N/A	N/A	K_i > 100	RBA —[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4R)-HNK	N/A	N/A	IC₅₀ > 100	RBA —[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4S)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2R,4S)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4R)-HNK	N/A	N/A	K_i > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
	(2S,4R)-HNK	N/A	N/A	IC₅₀ > 100	RBA—[³H]MK-801 binding	Whole brain (excluding cerebellum)	Rat	Morris et al. (2017)
D-serine	(S)-KET	Transport inhibitor	Antidepressant effects and dissociative side effects	EC₅₀ = 0.82 ± 0.29^{^a} (intracellular); 0.76 ± 0.13^{^a} (extracellular)	CE-LIF (intracellular); LC-MS (extracellular)	PC-12 cells	Rat-derived cell line	Singh et al. (2015)
	(S)-KET	Transport inhibitor		EC₅₀ = 0.46 ± 0.25^{^a} (intracellular); 0.57 ± 0.32^{^a} (extracellular)	CE-LIF (intracellular); LC-MS (extracellular)	1321N1 cells	Human-derived cell line	Singh et al. (2015)
	(R)-KET	α7 nAChR inhibition		IC₅₀ = 0.94 ± 0.16^{^a} (intracellular); 0.70 ± 0.10^{^a} (extracellular)	CE-LIF (intracellular); LC-MS (extracellular)	PC-12 cells	Rat-derived cell line	Singh et al. (2015)
	(R)-KET			IC₅₀ = 0.75 ± 0.27^{^a} (intracellular); 0.88 ± 0.25^{^a} (extracellular)	CE-LIF (intracellular); LC-MS (extracellular)	1321N1 cells	Human-derived cell line	Singh et al. (2015)
	DHNK			IC₅₀ = 0.115 (intracellular)	CE-LIF	PC-12 cells	Rat-derived cell line	Singh et al. (2013)
				IC₅₀ = 0.035	CE-LIF	1321N1 cells	Human-derived cell line	Singh et al. (2013)
				(intracellular)	CE-LIF	1321N1 cells	Human-derived cell line	Singh et al. (2013)
	(2S,6S)-HNK			IC₅₀ = 0.00018 ± 0.00004^{^a} (intracellular)	CE-LIF	PC-12 cells	Rat-derived cell line	Singh et al. (2016c)
	(2R,6R)-HNK			IC₅₀ = 0.00068 ± 0.00009^{^a} (intracellular)	CE-LIF	PC-12 cells	Rat-derived cell line	Singh et al. (2016c)
HCN1	(R,S)-KET	Inhibitor	Anesthesia, antidepressant effects	EC₅₀ = 8.2–15.6	Whole-cell recording	Mouse channels expressed in HEK293 cells	Mouse	Chen et al. (2009)
HCN1	(S)-KET	Inhibitor	Anesthesia, antidepressant effects	EC₅₀ = 4.1–7.4	Whole-cell recording	Mouse channels expressed in HEK293 cells	Mouse	Chen et al. (2009)
GABA uptake	(R,S)-KET	Reversible noncompetitive inhibitor	N/A	K_i = 6.2 ± 1.1^{^a};	RBA—[³H]GABA binding	Striatal synaptosomes	Rat	Mantz et al. (1995)
		Inhibitor	Anesthesia (due to observed increased GABA content)	IC₅₀ = ∼400	RBA—[³H]GABA binding	Cultured neurons from cerebral hemispheres	Mouse	Wood and Hertz (1980)
				IC₅₀ > 1000	RBA—[³H]GABA binding	Cultured astrocytes from cerebral hemispheres	Mouse	Wood and Hertz (1980)
				IC₅₀ > 1000	RBA—[³H]GABA binding	Brain synaptosomes	Mouse	Wood and Hertz 1980)
		Reversible noncompetitive inhibitor	N/A	IC₅₀ = 50	RBA—[³H]GABA binding	Striatal synaptosomes	Rat	Mantz et al. (1995)
GABA_AR	(R,S)-KET	Positive modulator	N/A	EC₅₀ = 1200 ± 600	Whole-cell recording	Human receptor expressed in HEK293 cells	Human	Flood and Krasowski (2000)
GABA_AR	(R,S)-KET	No effect	N/A	EC₅₀ > 1000	Human receptor expressed in Xenopus oocytes	Human	Human receptor expressed in Xenopus oocytes	Yamakura et al. (2000)
M1 mAChR	(R,S)-KET	N/R	N/A	K_i = 45	RBA	Human receptor expressed in CHO cells	Human	Hirota et al. (2002)
M1 mAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 5.7	Two-microelectrode recording	Rat receptor expressed in Xenopus oocytes	Rat	Durieux (1995)
M2 mAChR	(R,S)-KET	N/R	N/A	K_i = 294	RBA	Human receptor expressed in CHO cells	Human	Hirota et al. (2002)
M3 mAChR	(R,S)-KET	N/R	N/A	K_i = 246	RBA	Human receptor expressed in CHO cells	Human	Hirota et al. (2002)
nAChR (muscle type)	(R,S)-KET	Antagonist	N/A	K_i = 16.5 ± 0.7^{^a} (resting); K_i = 13.1 ± 1.8^{^a} (desensitized)	RBA—[³H]TCP binding	AChR native membranes	T. californica	Arias et al. (2002)
		Antagonist		K_i = 20.9 ± 3.0^{^a}	RBA—[³H]tetracaine binding	AChR native membranes	T. californica	Arias et al. (2002)
		No effect		No effect	RBA—[¹⁴C]amobarbital binding	AChR native membranes	T. californica	Arias et al. (2002)
	(S)-KET	Antagonist	N/A	K_i = 18.2 ± 1.2^{^a} (resting); K_i = 15.4 ± 2.3^{^a} (desensitized)	RBA—[³H]TCP binding	AChR native membranes	T. californica	Arias et al. (2002)
				K_i = 19.9 ± 2.8^{^a}	RBA—[³H]tetracaine binding	AChR native membranes	T. californica	Arias et al. (2002)
				K_i = 430 ± 330^{^a}	RBA—[¹⁴C]amobarbital binding	AChR native membranes	T. californica	Arias et al. (2002)
α nAChR	(R,S)-KET	Antagonist	N/A	EC₅₀ = 18.7 ± 7.4^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
α nAChR	(S)-KET	Antagonist		EC₅₀ = 9.7 ± 2.2^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
β nAChR	(R,S)-KET	Antagonist		EC₅₀ = 15.2 ± 3.6^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
β nAChR	(S)-KET	Antagonist		EC₅₀ = 7.4 ± 4.5^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
γ nAChR	(R,S)-KET	Antagonist		EC₅₀ = 20.4 ± 10.1^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
γ nAChR	(S)-KET	Antagonist		EC₅₀ = 6.6 ± 2.9^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
δ nAChR	(R,S)-KET	Antagonist		EC₅₀ = 19.4 ± 6.5^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
δ nAChR	(S)-KET	Antagonist		EC₅₀ = 8.5 ± 2.4^{^a}	RBA—[¹²⁵I]TID photoincorporation	AChR native membranes	T. californica	Arias et al. (2002)
α2β2 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 92	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
α4β4 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 0.24 ± 0.03	Whole-cell recording	Chicken receptor expressed in Xenopus oocytes	Chicken	Flood and Krasowski (2000)
α4β4 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 18	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
α2β4 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 29	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
α4β2 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 72	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
α4β2 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 50 ± 4	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Coates and Flood (2001)
α7 nAChR	(R,S)-KET	Antagonist	Antidepressant effects	IC₅₀ = 20 ± 2	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Coates and Flood (2001)
	(R,S)-KET	Antagonist		IC₅₀ = 17.3 ± 2	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Ho and Flood (2004)
	(R,S)-DHNK	Antagonist		IC₅₀ = 0.055 ± 0.006	Whole-cell recording	KXα7R1 cells (express rat receptors)	Rat	Moaddel et al. (2013)
α3β2 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 50	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
α3β4 nAChR	(R,S)-KET	Antagonist	N/A	IC₅₀ = 9.5	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
	(R,S)-KET	Antagonist		IC₅₀ = 3.1	Whole-cell recording	KXα3β4R2 cells (express rat receptors)	Rat	Moaddel et al. (2013)
	(R,S)-norKET	Antagonist		IC₅₀ = 9.1	Whole-cell recording	KXα3β4R2 cells (express rat receptors)	Rat	Moaddel et al. (2013)
	(R,S)-DHNK	No significant effect		IC₅₀ > 200	Whole-cell recording	KXα3β4R2 cells (express rat receptors)	Rat	Moaddel et al. (2013)
	(2S,6S)-HNK			IC₅₀ > 200	Whole-cell recording	KXα3β4R2 cells (express rat receptors)	Rat	Moaddel et al. (2013)
	(2R,6R)-HNK			IC₅₀ > 200	Whole-cell recording	KXα3β4R2 cells (express rat receptors)	Rat	Moaddel et al. (2013)
D_1–5R	(S)-KET	N/A	N/A	No functional effect up to 10 μM	RBA	Human receptor expressed in HEKT (for D_1/3/5R), or stable fibroblast (for D₂R) cells	Human	Can et al. (2016)
	(R)-KET
	(S)-norKET
	(R)-norKET
	(S)-DHNK
	(R)-DHNK
	(2S,6S)-HNK
	(2R,6R)-HNK
D₂R	(R,S)-KET	Partial agonist	Psychotomimetic effects	K_i = 1.0 ± 0.15	RBA	Striatum	Rat	Kapur and Seeman (2001, 2002)
				K_i = 0.5 ± 0.2 EC₅₀ = 0.9 ± 0.4	RBA	Human D₂R expressed in CHO cells	Human	Kapur and Seeman (2002)
				EC₅₀ = 0.4	RBA/[³⁵S]-GTPγS	Human D2R expressed in CHO cells	Human	Seeman and Kapur (2003)
				K_i = 0.055 ± 0.012	RBA	Human receptor expressed in CHO cells	Human	Seeman et al. (2005)
		Antagonist	N/A	IC₅₀ = 2	RBA—[³⁵S]-GTPγS	Human D₂R expressed in CHO cells	Human	Seeman and Kapur (2003)
DAT	(R,S)-KET	Reversible, noncompetitive inhibition	N/A	IC₅₀ = 4.6	RBA—[³H]dopamine uptake	Striatum	Rat	Keita et al. (1996)
	(R,S)-KET	Uptake inhibitor	N/A	K_i = 62.9 ± 2.3^{^a}	RUA—[³H]dopamine uptake	Rat transporter expressed in HEK293 cells	Rat	Nishimura et al. (1998)
	(S)-KET	No binding or functional activity up to 10 μM	N/A	N/A	RBA	Human transporter expressed in HEK cells	Human	Can et al. (2016)
	(R)-KET
	(S)-norKET
	(R)-norKET
	(S)-DHNK
	(R)-DHNK
	(2S,6S)-HNK
	(2R,6R)-HNK
5-HT₂R	(R,S)-KET	N/R	Analgesic effects	K_i = 15 ± 5	RBA	Frontal cortex	Rat	Kapur and Seeman (2002)
5-HT₃R	(R,S)-KET	Antagonist	N/A	K_i = 96.9 ± 3.5	RBA—[³H]BRL43,694	Neuroblastoma cell cultures (N1E-115)	Mouse	Appadu and Lambert (1996)
5-HT₃R	(R,S)-KET	Competitive antagonist	N/A	K_i = 420 ± 60	5-HT–induced currents: whole-cell recordings	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
5-HT₃R	(R,S)-KET	Noncompetitive antagonist	N/A	IC_50i = 910 ± 30	5-HT–induced currents: whole-cell recordings	Human receptor expressed in Xenopus oocytes	Human	Yamakura et al. (2000)
5-HT_3AR	(R,S)-KET	Antagonist	N/A	IC₅₀ > 100	Whole-cell recording	Human receptor expressed in Xenopus oocytes	Human	Ho and Flood (2004)
SERT	(R,S)-KET	Uptake inhibitor	N/A	IC₅₀ = 20.2 ± 2.75	RUA—[³H]5-HT uptake	Brain (except cerebellum)	Rat	Martin et al. (1988)
			N/A	IC₅₀ = 18.8	RUA—[³H]paroxetine	Brain (except cerebellum)	Rat	Martin et al. (1990)
			N/A	K_i = 161.7 ± 28.3^{^a}	RUA—[³H]serotonin	Rat transporter expressed in HEK293 cells	Rat	Nishimura et al. (1998)
				IC₅₀ = 75 ± 8	RUA—[³H]5-HT uptake	Cortical synaptosomes	Rat	Azzaro and Smith (1977)
				IC₅₀ = 125.2	RUA—[³H]5-HT uptake	NE transporter expressed in HEK293 cells	Human	Zhao and Sun (2008)
	(S)-KET	N/A		No binding or functional activity up to 10 μM	RBA	Human transporter expressed in HEK cells	Human	Can et al. (2016)
	(R)-KET
	(S)-norKET
	(R)-norKET
	(S)-DHNK
	(R)-DHNK
	(2S,6S)-HNK
	(2R,6R)-HNK
NET	(R,S)-KET	Uptake inhibitor	N/A	K_i = 66.8 ± 25.9^{^a}	RUA—[³H]NE	Human transporter expressed in HEK293 cells	Human	Nishimura et al. (1998)
				100 μM—estimated ∼50% noncompetitive inhibition	RUA—[³H]NE	Bovine adrenal medullary cells	Bovine	Hara et al. (1998a)
				10–100 μM—estimated ∼50% noncompetitive inhibition	RUA—[³H]NE	Xenopus oocytes expressing bovine NE transporters	Bovine	Hara et al. (1998a)
				300 μM—competitive inhibition	RUA—[³H]desipramine	Plasma membranes of bovine adrenal medulla	Bovine	Hara et al. (1998a)
				IC₅₀ = 290.7	RUA—[³H]NE	NE transporter expressed in HEK293 cells	Human	Zhao and Sun (2008)
	(S)-KET	N/A		No binding or functional activity up to 10 μM	RBA	Human transporter expressed in HEK cells	Human	Can et al. (2016)
	(R)-KET
	(S)-norKET
	(R)-norKET
	(S)-DHNK
	(R)-DHNK
	(2S,6S)-HNK
	(2R,6R)-HNK
µ opioid receptor	(R,S)-KET	Agonist	Analgesia	K_i = 42.1	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 28.6	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 11	RBA—[³H]DAMGO	Whole brain	Rat	Hustveit et al. (1995)
	(R)-KET	Agonist		K_i = 83.8	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R)-KET	Agonist		K_i = 28	RBA—[³H]DAMGO	Whole brain	Rat	Hustveit et al. (1995)
κ opioid receptor	(R,S)-KET	Agonist		K_i = 28.1	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R,S)-KET	Agonist		K_i = 25.0; EC₅₀ = 29.0	RBA—[³⁵S]-GTPγS	Human receptor expressed in CHO cells	Human	Nemeth et al. (2010)
	(S)-KET	Agonist		K_i = 23.7	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 24	RBA—[³H]U69,593	Whole brain	Rat	Hustveit et al. (1995)
	(R)-KET	Agonist		K_i = 60.0	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R)-KET	Agonist		K_i = 100	RBA—[³H]U69,593	Whole brain	Rat	Hustveit et al. (1995)
δ opioid receptor	(R,S)-KET	Agonist		K_i = 272	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 205	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(S)-KET	Agonist		K_i = 130	RBA—[³H]DPDPE	Whole brain	Rat	Hustveit et al. (1995)
	(R)-KET	Agonist		K_i = 286	RBA—[³H]DPN	Human receptor expressed in CHO cells	Human	Hirota et al. (1999)
	(R)-KET	Agonist		K_i = 130	RBA—[³H]DPDPE	Whole brain	Rat	Hustveit et al. (1995)
σ_1/2R	(R,S)-KET	N/R	Antidepressant effects	IC₅₀ = 66.0 ± 10.0	RBA – [³H] + SKF10,047	Spinal cord	Rat	Smith et al. (1987)
				K_i = 0.15	RBA—[³H] + SKF10,047	Whole brain	Rat	Hustveit et al. (1995)
				K_i > 10	RBA—[³H]DTG	Rat glioma hybrid cells NG108-15	Rat	Georg and Friedl (1991)
	(R)-KET			K_i = 19	RBA—[³H] + SKF10,047	Whole brain	Rat	Hustveit et al. (1995)
	(S)-KET			K_i = 131	RBA—[³H] + SKF10,047	Whole brain	Rat	Hustveit et al. (1995)
σ₁R	(R,S)-KET			K_i = 139.60 ± 6.13	RBA—[³H] (+) pentazocine	Liver membrane	Rat	Robson et al. (2012)
σ₂R	(R,S)-KET			K_i = 26.30 ± 2.98	RBA—[³H]di-o-tolylguanidine	Liver membrane	Rat	Robson et al. (2012)
TTX-sensitive VGSC	(R,S)-KET	Antagonist	Local anesthesia	IC₅₀ = 146.7 ± 8.4 (tonic)	Whole-cell recording	Dorsal root ganglion	Rat	Zhou and Zhao (2000)
TTX-resistant VGSC	(R,S)-KET	Antagonist		IC₅₀ = 866.2 ± 34.7 (tonic), 314.8 ± 12.4 (phasic)	Whole-cell recording	Dorsal root ganglion	Rat	Zhou and Zhao (2000)
VGSC	(R,S)-KET	Antagonist		IC₅₀ = 800 (tonic), 2300 (phasic)	Two-microelectrode recording	Rat channels expressed in Xenopus oocytes	Rat	Wagner et al. (2001)
				IC₅₀ = 222.0	²²Na⁺-stimulated influx (measure sodium uptake)	Brain (minus cerebellum) synaptoneurosomal fractions	Rat	Allaoua and Chicheportiche (1989)
				K_i = 11.5	²²Na⁺-stimulated influx (measure sodium uptake)	Brain (minus cerebellum) synaptoneurosomal fractions	Rat	Allaoua and Chicheportiche (1989)
				ED₅₀ = 1100	Single channel recordings	Cortical synaptosome bilayer	Human	Frenkel and Urban (1992)
	(S)-KET	Antagonist		IC₅₀ = 240 ± 60^{^a} (neuronal), 59 ± 10^{^a} (skeletal)	Whole-cell recording	Rat channels expressed in HEK293 cells	Rat	Haeseler et al. (2003)
	(R)-KET	Antagonist		IC₅₀ = 333 ± 93^{^a} (neuronal), 181 ± 49^{^a} (skeletal)	Whole-cell recording	Rat channels expressed in HEK293 cells	Rat	Haeseler et al. (2003)
L-type VDCC	(R,S)-KET	Antagonist	Antidepressant effects	IC₅₀ = 1000	Whole-cell recording	Tracheal smooth muscle	Pig	Yamakage et al. (1995)
L-type VDCC	(R,S)-KET	Antagonist	Antidepressant effects	IC₅₀ = 9.2	Whole-cell recording	Atrial myocytes	Bullfrog	Hatakeyama et al. (2001)

CE-LIF, capillary electrophoresis-laser-induced fluorescence; D_1–5R, dopamine receptor subtypes 1–5; DAMGO, [D-Ala2, N-MePhe4, Gly-ol]-enkephalin; DAT, dopamine transporter; DPDPE, [D-Pen2,D-Pen5]enkephalin; DPN, diprenorphine; DTG, 1,3-Di-o-tolylguanidine; EPSP, excitatory postsynaptic potential; FLIPR, fluorescence imaging plate reader; GABA_AR, GABA receptor A; GTPγS, guanosine 5′-3-O-(thio)triphosphate; HEK, human embryonic kidney cells; 5-HT₂R, serotonin receptor subtype 2; KET, ketamine; LC-MS, liquid chromatography–mass spectrometry; NMDA, N-methyl-D-aspartate; norKET, norketamine; NE, norepinephrine; RBA, radioligand-binding assay; RUA, radioligand uptake assay; TCP, [1-(2-thienyl)cyclohexyl] piperidine; TID, 3-(Trifluoromethyl)-3-(3-iodophenyl)diazirine; TTX, tetrodotoxin; VGSC, voltage-gated sodium channel.
↵^a Values reported as mean ± S.D.