The hyphenated technique HPLC-SPE-NMR is an important tool for rapid dereplication of complex mixtures of in particular small molecules and has been successfully employed in natural product research. However, positively charged alkaloids at low pH are often poorly trapped on the generally used SPE cartridge limiting the general application of the procedure. In this work, two new approaches for efficient SPE trapping of alkaloids and elution efficiencies were evaluated using 24 model alkaloids. Use of a 0.1M NaOH solution as the post-column dilution greatly enhanced trapping of alkaloids on the commonly used cartridge containing divinylbenzene polymer (GP resin). This procedure, however, was unsuitable for trapping phenolic alkaloids. Severe line broadening and immiscibility with water made chloroform-d unsuited as eluent. None of these problems occurred when methanol-d was used as eluent. Previously, mixed mode cation exchange sorbents have not been used in HPLC-SPE-NMR analysis of natural products. In contrast to GP resin this material showed good retention and elution characteristics for retention and elution of alkaloids. As well the use of methanol-d containing 1% aqueous NaOD (40%) as methanol-d containing 5% aqueous NHOH (30%) as eluents were successful, even though elution of alkaloids with pK of the corresponding acid above 10 proved difficult. Alkaloid extracts of Huperzia selago containing complex aliphatic alkaloids and Triclisia patens containing bisbenzylisoquinoline alkaloids were used for validation of the protocols for analysis of a diverse collection of alkaloids. Mixed mode cation exchange sorbent was efficient for trapping and elution of both types of alkaloids as evidenced by acquisition of 2D NMR data for all trapped compounds. In contrast, GP resin proved only viable for all the H. selago alkaloids whereas trapping and elution of bisbenzylisoquinoline alkaloids were dubious.