Summary of active immunopharmacotherapies developed for METH abuse.

Mod	Vaccine	Hapten structure	Carrier protein	Adjuvant	Admin	Vaccinations/overall time	Functional tests	Results	Ref.
Phenyl	1		KLH	Alum	SC	3 injections/6 weeks	Locomotor activity	No differences between METH-challenged and non-challenged groups in generating antibody titer and affinity. Failed to attenuate hyperlocomotion	65
	2		None	EP54 (peptide)	SC and IP	5 injections/5 weeks	Self-administration	Antibody titers were highest in vaccine 3, then vaccine 5, followed by similar levels generated for vaccine 2 and 4. The antibodies generated for vaccine 3 showed high specificity. Self-administration studies showed compensatory effects in vaccinated animals, leading to increased drug intake	72
	3		TT
	4		None
	5		TT
	6		OVA and BSA	Freund's complete adjuvant	SC	3 injections/6 weeks	None	Vaccine 6 produced a significantly higher immune response by providing high epitope densities on maleimide-activated proteins.	73
	7	Same structure as vaccine 6	KLH	Alhydrogel	SC	4 injections/12 weeks	Food maintained behaviour	The vaccine reduced effects induced by high doses of METH through high affinity antibodies	66
	8	Same structure as vaccine 6	KLH	Alhydrogel vs. Sigma Adjuvant System vs. GLA-SE	IM	3 injections/9 weeks	None	GLA-SE produced double the antibody concentration with enhanced affinities against METH. Significantly, these results were sustained without boosts	74
	9	Same structure as vaccine 6	KLH	Sigma Adjuvant System	SC	4 injections/15 weeks	Blood–brain biodistribution	Vaccine 10 showed significant increases in METH sera concentrations in vaccinated animals and decreases in brain concentrations, compared to passive immunization	64
	10
Methyl	11		TT	Alum and CpG ODN 1826	IP	3 injections/4 weeks	Locomotor activity, blood–brain biodistribution, and lethality challenge	All stereoisomers generated antibodies that could affect blood–brain drug partitioning. However, vaccine 12 produced antibodies with 10-fold higher affinities, compared to single isomers and racemate. Only vaccine 12 effectively attenuated METH-induced hyperlocomotion. Lethality studies for vaccine 11, 13, and 12 exhibited survival rates of 16.7%, 33.3% and 83.3%, respectively	56
	12
	13
N-methyl	14		KLH or BSA	Sigma Adjuvant System	IP	3 injections/5 weeks	None	Vaccines 15, 18, and 19 were able to successfully induce increased levels of high affinity antibodies in murine models, with vaccine 15 and 19 producing antibodies with specificities toward METH and amphetamine. Vaccine 18 and 19 produced the highest titers	75
	15
	16
	17
	18
	19
	20	Same structure as vaccine 19	KLH	Sigma Adjuvant System	SC and IP	4 injections/9 weeks	Thermoregulation, wheel activity, locomotor activity, and blood–brain biodistribution	The vaccine attenuated METH-induced thermoregulatory and locomotor responses. Pharmacokinetics showed the vaccine produced higher drug concentrations in sera and lower METH presence in the brain after exposure to drugs	62
	21	Same structure as vaccine 19	KLH	Sigma adjuvant system	SC and IP	3 injections/5 weeks or 5 injections/13 weeks	Self-administration and acute challenge	The vaccine attenuated self-administration at 0.1 mg per kg. Plasma METH concentrations were increased in vaccinated groups after drug challenges	76
	22		DT and BSA	Lipid Tucaresol	SC	3 injections/5 weeks	None	Vaccines with lipid tucaresol induced antibodies with higher specificity	77
	23	Same structure as vaccine 22	DT	Sigma adjuvant system	SC	3 injections/5 weeks	Locomotor activity	Vaccines 24 and 25 produced antibodies with comparable affinities, but vaccine 25, containing peptidic linkers, enhanced antibody concentration. Vaccine 29 elicited higher affinity antibodies, but produced drastically lower titers. Thus, the vaccine was optimized by changing the carrier protein and adjuvant cocktail, which generated antibodies with exceptionally high titers and abilities to attenuate METH-induced locomotor effects	78
	24
	25
	26
	27
	28
	29
	30	Same structure as vaccine 29	TT	Alum and CpG ODN 1826		3 injections/4 weeks
	31		KLH or TT	Alum and CpG ODN 1826	IP	3 injections/4 weeks	Blood–brain biodistribution	Vaccines 32, 33, 34, and 35 induced antibodies with increased drug affinity, but lower concentrations than control vaccine 31. Since vaccine 35 generated the highest titers, vaccine 36 and 37 were probed for antibody effects. Both elicited antibodies with similar affinities to vaccine 35, but generated increased titers. Vaccine 36 was the most efficient in attenuating drug CNS interaction	79
	32
	33
	34
	35
	36
	37
	38		KLH	MPLA	SC	3 injections/20 weeks	Locomotor activity and conditioned place preference	The vaccine generated antibodies at high titers, reduced drug-conditioned approach behaviours, and attenuated METH-induced locomotion at varying doses	80
	39	same structure as vaccine 38	TT	Alum	IM	2 injections/3 weeks	conditioned place preference	The vaccine produced higher and sustained antibody concentrations that decreased drug entry into the brain and inhibited METH acquisition and reinstatement	63
	40	Same structure as vaccine 38	TT	E6020 and Alum	SC	3 injections/6 weeks	Locomotor activity and blood–brain biodistribution	Vaccines with E6020 produced x3 increase in titers, nanomolar affinities, attenuated METH-induced hyperlocomotion, and decreased brain METH levels while increasing drug sera concentration	81