Surprisingly, when comparing the slope differences between the PCIS and the SIL-ISTD in Fig. , the PCIS correction outperformed the correction using the spiked SIL-ISTD, which is considered the golden standard. Considering the high variability in suppression in this chromatographic area, the suboptimal performance of the SIL-ISTD correction may be due to the minor retention time difference between the analyte and its slightly more polar deuterated analogue . Indeed, when overlaying peaks of LEA and d4-LEA (see SI Figure ) it becomes clear that LEA-d4 elutes slightly earlier and thereby suffers more from ion suppression, resulting in an overcorrection of the LEA peak (and a steeper slope of the calibration curve). These results indicate that in areas of serious and variable matrix effect, a perfectly coeluting structural analogue (like the PCIS) might correct even better than a spiked SIL-ISTD with a slight difference in retention time. Taking into account the difficulty to correct the slopes for matrix effect even with a spiked SIL-ISTD, we consider a difference in slope up to +/-15% preferable, but up to +/-20% acceptable; the latter being a cut-off applied before by Godoy et al. comparing slopes of calibration curves of metabolites in serum and urine versus a synthetic surrogate matrix . The difference in slope of SEA (-24%) was outside of the acceptable limit. In the earlier tests, SEA, being the last eluting endocannabinoid and almost completely suppressed by the matrix, was also at the limits of the acceptance criteria. The slope differences of LEA, AEA, DHEA, PEA, OEA and even 2-AG easily fall within the preferable range (with a maximum of +9%). Therefore, these compounds could all be quantified using 2F-AEA as a PCIS to correct for matrix effect and calibration standards in neat solution.