The alkaloid rich extracts from an acid/base extraction of bulb material of Haemanthus coccineus L., H. montanus Baker and H. sanguineus Jacq. revealed that two montanine type Amaryllidaceae alkaloids, montanine (1) and coccinine (2) were the major alkaloid constituents. Together these two alkaloids constituted 88, 91 and 98% of the total alkaloid extract from each species respectively. GC-MS analysis revealed that H. coccineus and H. sanguineus had a relative abundance of coccinine (74 and 91% respectively) to montanine (14 and 7% respectively); where as H. montanus had 20% coccinine and 71% montanine. The three extracts and two isolated alkaloids were evaluated for binding to the serotonin transporter protein (SERT) in vitro. Affinity to SERT was highest in H. coccineus (IC50 = 2.0 ± 1.1 μg/ml) followed by H. montanus (IC50 = 6.8 ± 1.0 μg/ml) and H. sanguineus (IC50 = 28.7 ± 1.1 μg/ml). Montanine (IC50 = 121.3 ± 3.6 μM or 36.56 ± 1.14 μg/ml; Ki = 66.01 μM) was more active than coccinine (IC50 = 196.3 ± 3.8 μM or 59.15 ± 1.08 μg/ml; Ki = 106.8 μM), both of which were less active than the total alkaloid extracts of each species investigated. The possible synergistic effects of two coccinine/montanine mixtures (80:20 and 20:80) were investigated, however the mixtures gave similar activities as the pure compounds and did not show any increase in activity or activity similar to the total alkaloid extracts. Thus the considerably higher activity observed in the total alkaloid extracts is not correlated to the relative proportions of coccinine and montanine in the extracts and thus are likely to be due to more potent unidentified minor constituents. Both alkaloids exhibited low binding affinity to P-glycoprotein (P-gp) as demonstrated by low inhibition of calcein-AM efflux in the MDCK-MDR1 cell line. This indicates that P-gp efflux will not be limiting for blood-brain-barrier passage of the alkaloids.