Table 3.

Preclinical studies assessing therapeutic symptomatic efficacy of cannabinoids for movement disorders

Movement disorder	Model	Outcome	Reference
Parkinson’s disease	6-hydroxydopamine lesioned rats	AM404 (AEA transport inhibitor) reduced parkinsonian motor asymmetries possibly mediated through stimulation of 5-HT(1b) receptors.	44
	6-hydroxydopamine lesioned rats	Rimonabant (CB1 receptor antagonist) and AM251 (CB1 receptor antagonist) exert antiparkinsonian effects after very severe (>95%) but not severe (85–94%) nigral degeneration possibly due to antagonistic effects of nigra-mediated activity with partial lesions.	46
	6-hydroxydopamine lesioned rats	D9-THCV (CB1 receptor antagonist in vivo per authors) and rimonobant (CB1 receptor antagonist) improved mobility. CP55,940 (CB1 and CB2 receptor agonist) reduced ambulation. Effects appear to be mediated by increased glutamate and not dopamine.	118
	6-hydroxydopamine lesioned rats	HU-211 (CB1 receptor agonist) improved dopamine induced rotations. HU-211 (NMDA antagonist), cannabidiol and 7-hydroxy-cannabidiol did not improve affect rotations.	119
	6-hydroxydopamine lesioned rat	Rimonabant CB1 receptor antagonist) decreased LID with minimal increase in hypokinesia. Effect increased over time and was associated with relative preservation of dopamine neurons in treated animals.	128
	6-hydroxydopamine lesioned rats	Rimonabant (CB1 receptor antagonist) attenuated hypokinesia in rats without influencing dopamine, GABA or glutamatergic transmission.	49
	6-hydroxydopamine lesioned rats	Acute injections of rimonabant (CB1 receptor antagonist) improved parkinsonism when given without levodopa, improved effect of moderate dose levodopa but did not alter dyskinetic effects of high dose levodopa.	48
	6-hydroxydopamine lesioned rats	WIN55,212-2 (CB1 and CB2 receptor agonist) ameliorated levodopa induced abnormal involuntary movements. The beneficial effects of WIN55,212-2 were reversed by AM251 (selective CB1 receptor antagonist) and with reductions in protein kinase A (PKA) and cAMP-regulated phosphorylation of DARPP-32.	131
	6-hydroxydopamine lesioned rats	WIN 55,212-2 (CB1 and CB2 receptor agonist) ameliorated levodopa induced abnormal involuntary movements (AIMs). URB597 (FAAH inhibitor) amerliorated AIMs only when coadministered with capsazepine (TRPV1 antagonist).	54
	6-hydroxydopamine lesioned rats	Intrpallidal and intrstriatal ifusions of CP55,940 (CB1 and CB2 receptor agonist) induced contralateral rotational behavior which was greater in lesioned than unlesioned rats.	40
	6-hydroxydopamine lesioned rats made dyskinetic with 6 weeks of levodopa injections	Highest dose of HU210 (CB1 and CB2 receptor agonist) reduced some abnormal involuntary movements (AIMs) but also impaired normal motor functioning in dyskinetic animals. AM251 (CB1 antagonist) had no effect on AIMs and rimonabant (CB1 antagonist) induced certain AIMs.	55
	6-hydroxydopamine lesioned mice; reserpine administration to mice	Administration of URB597 (FAAH inhibitor) improved long-term depression in globus pallidus medium spiny neurons and enhanced quinpirole (D2/D3 agonist) effects on hypokinesia but had no effect given in isolation.	42
	MPTP-lesioned rhesus monkeys	CE (selective CB1 receptor antagonist) had did not effect motor behavior but increased responses to low levodopa doses. CE did not affect LID.	53
	MPTP lesioned marmosets	Coadministration of levodopa and nabilone (CB1 and CB2 receptor agonist) reduced on-period dyskinesia without reducing antiparkinsonian effects.	52
	MPTP lesioned marmosets	URB597 (FAAH inhibitor) reduced levodopa induced hyperactivity but not dyskinesias, antiparkinsonian actions or psychosis. There were no behavioral effects when given without levodopa.	129
	MPTP lesioned cynomolgus monkeys	SR141716A (CB1 receptor antagonist) did not induce behavioral changes in unlesioned animals and did not affect parkinsonism post-MPTP administration. In unlesioned animals, levonantrol (synthetic cannabinoid agonist) reduced general activity levels and produced bradykinesia and THC produced bradykinesia without effecting general activity.	38
	MPTP-lesioned marmosets and cynomolgus monkeys	Rimonabant (CB1 receptor antagonist) improved LID when coadministered with levodopa without affecting antiparkinsonian effects. Reductions in endogenous cannabinoid levels were associated with MPTP-lesion but no association was found with LID.	45
	MPTP treated marmosets	THC improved locomotor activity and hand-eye coordination but was associated with worsening AIMs score.	133
	Reserpine rat	THC had no hypokinetic effect by itself but produced a more than 20-fold increase in the reserpine-induced hypokinesia. This effect was slightly increased by physostigmine (cholinesterase inhibitor), completely blocked by ethopropzaine (anticholinergic) and unaffected by scopolamine or naloxone.	132
	Reserpine Rat	Rimonabant (CB1 receptor antagonist) levodopa induced hyperactivity. WIN55,212-2 (CB1 and CB2 receptor agonist) also reduced levodopa induced hyperactivity and reduced antiparkinsonian benefits when given at highest dose. AM404 (AEA transport inhibitor) had no effect on hyperkinesia.	43
	Anadamide (AEA) treated rats	AEA (CB1 and CB2 receptor agonist) induced hypokinesia. Capsazepine (vanilloid antagonist) reversed effects of AEA. In vitro experiments demonstrate AEA reduces K(+)-stimulated anigrostriatal dopamine release through vanilloid-like receptors.	134
Huntington’s Disease	3NP rats	Arvanil (CB1 and TRPV1 receptor agonist) significantly reduced hyperkinetic activity in lesioned animals and increased glutamate in the globus pallidus. It also reduced ambulation and other activity in both lesioned and control animals.	66
	3NP rats	UCM707 (AEA transport inhibitor) reduced hyperkinetic activity and increased both glutamate and GABA levels in the globus pallidus.	67
	3NP rats	AM404 (AEA transport inhibitor) attenuated motor hyperactivity, reduced ambulatory activity and improved toxin-induced GABA and dopamine deficits.	63
	3NP rats	AM404 (AEA transport inhibitor) reduced hyperkinesia and was reversed by capsazepine (VR1 antagonist) but not rimonabant (CB1 antagonist). VDM11 (CB reuptake inhibitor) and AM374 (CB hydrolysis inhibitor) did not reduce chorea. Capsaicin (VR1 agonist) and CP55,940 (CB1 and CB2 receptor agonist) reduced hyperkinesia but only capsaicin improved basal ganglia GABA and dopamine deficits.	146
	R6/1 transgenic mice	HU210 (CB1 and CB2 agonist) and THC did not affect motor deterioration and HU210 treatment was associated with seizures and increased ubiquinated aggregates in the striatum.	135
Tremor	EAE mice	WIN 55,212, THC, and JWH-133 (CB1 and CB2 receptor agonists) and methanandamide, (CB1 agonist) reduced tremor and spasticity. Pretreatment with rimonabant or SR144528 (CB antagonists) eliminated ability of agonists to reduce tremor and CBD had no effect.	92
	NMDA induced tremor in mice	HU-211 (nonpsychotropic synthetic cannabinoid with NMDA antagonist effects and without CB receptor effects) blocks NMDA-induced tremor.	137
Dystonia	SKF81297 (D1 agonist) or haloperidol (D2 antagonist) treated Cebus apella monkeys	SKF-induced oral dyskinesia was dose dependently reduced by CP55,940 (CB1 and CB2 receptor agonist), with no effect of rimonabant (CB1 antagonist). Haloperidol-induced dystonia was not affected by either CP55,940 or rimonabant.	130
	dt sz mutant hamsters	Rimonabant (selective CB1 antagonist) did not affect dystonia. WIN55, 212-2 (CB1 and CB2 receptor agonist) exerted antidystonic effects. Cannabidiol delayed the progression of dystonia only at a high dose. The effects of WIN 55,212-2 were antagonized by pretreatment with rimonabant.	75
	dt sz mutant hamsters	WIN 55,212-2 (CB1 and CB2 receptor agonist) improved dystonia at higher doses but also reduced spontaneous motor activity and induced catalepsy. At lower doses, WIN 55,212-2 had no effect but had therapeutic efficacy when coadministered with a subtherapeutic dose of diazepam.	74

Abbreviations: AEA: anandamide; AIM: Abnormal Involuntary Movements, CB1: cannabinoid receptor type 1, CB2: cannabinoid receptor type 2, EAE: experimental autoimmune encephalomyelitis, LID: levodopa-induced dyskinesia, MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxin, PD: Parkinson’s Disease, 3NP: 3-Nitropropionic acid