Lithium enema in cluster headache treatment acts by modulating central nervous system neurotransmitter activity, particularly affecting serotonergic and dopaminergic pathways. The therapeutic mechanism involves reducing neurogenic inflammation and potentially stabilizing neuronal excitability, which can help prevent or reduce the frequency and intensity of cluster headache episodes. By delivering lithium directly through rectal administration, the treatment achieves targeted neurochemical modulation with potentially enhanced bioavailability.