Purpose: Pharmacokinetic; To examine whether MDMA and metabolites can be detected in saliva after drug administration, to examine whether salivary MDMA, if present, correlates with plasma values for MDMA and to investigate the relationship between salivary pH on the salivary / plasma (s/p) MDMA ratio.

Design: Randomized, double blind within-subjects design, with drug treatment (placebo versus 100 mg MDMA) as a within-subjects factor. Pharmacokinetic study design also measured fluid (plasma versus saliva) as a within-subjects factor. All subjects underwent sampling of blood and saliva.

Subjects: 8 MDMA-experienced volunteers (8 men, 0 women), mean age 24.4 years (range, 21-33). No information is provided on recruitment; previous papers indicate recruitment via "word of mouth."

Criteria for Inclusion - Male, having used ecstasy at least 5 times over a lifetime, being in good physical health as assessed through medical examination, laboratory tests, urinalysis and ECG, and being an extensive metabolizer of MDMA as assessed through dextromethorphan probe.

Measures: Saliva and Plasma - Samples of mixed saliva (secreted by all salivary glands) and blood were collected at 0, 1.5, 4, 6, 10 and 24 h post-drug administration. Saliva was collected without any stimulation and collected over a 5-min period. Samples of blood and saliva collected in the placebo condition were used as drug-free blanks.

MDMA and Metabolites - MDMA, MDA and HMMA concentrations in saliva and plasma were measured via GC-MS.

Salivary pH - pH was measured with pH indicator stick with range of 6.4-8 (in 0.2 increments) at same intervals as when saliva sampled (0, 1.5, 4, 6, 10 and 24 h post-drug). Results were recorded by 2 observers blind to participant's condition.

Analyses: Pharmacokinetics - Cmax, Tmax, AUC, and elimination (plasma) or disappearance (saliva) time (T1/24), and elimination or disappearance constant (Kc or Kd) calculated for saliva and plasma. AUC was calculated via linear trapezoidal rule, and elimination and disappearance constants calculated via log-linear regressions of the 3 last points with concentration above the quantifiable limit.

Relationships between salivary and plasma concentrations - Correlations between plasma and salivary values were assessed via regression analysis, with p = 0.05. Differences between salivary pH after 100 mg MDMA and placebo were analyzed via Wilcoxon test (nonparametric).

Results: Concentration and Pharmacokinetic Profiles - MDMA concentration is highest in both plasma (range: 134.9-223 mg/L) and saliva (range: 1728.9-6510.6 mg/L) 1.5 h post-drug. 2/8 participants had salivary MDMA concentrations that were 2 times higher than those of the rest of the sample (6/8), and these individuals also had the highest plasma Cmax. 24 h post-drug, salivary concentration was 126.2 ± 101.8 mg/L and plasma MDMA concentration was 13.5 ± 18.6 mgL. Tmax was obtained in both saliva and plasma at 1.5 h post-drug, and Tc (Td) was obtained at 7.2 ±1.4 h for plasma and 5.6 ±0.9 h for saliva. AUC for saliva was 20,843.1 ± 12,656.6 and AUC in plasma was 1598.6 ± 733.3. Cmax (mg/L) for saliva was 3375.6 ± 1812.8 and for plasma, 181.4 ± 31.3. Kc (Kd) was 0.0988 ± 0.0189 in plasma and 0.1279 ± 0.0231 in saliva. Mean MDMA concentrations in saliva were 1 order higher than mean plasma MDMA concentrations. MDA was detectable in saliva, at approximately 4%-5% of the mean concentration for MDMA (AUC comparisons), as also observed in plasma. Peak salivary concentration of MDA was between 1.5 h and 4 h post-drug, but in plasma peak MDA concentration was between 4 and 6 h post-drug. Trace amounts of HMMA were detectable in saliva; quantification was not possible.

Relationships between Salivary and Plasma MDMA concentrations - Salivary and plasma concentrations of MDMA were significantly and positively correlated with each other. S/P ratio was significantly correlated with salivary MDMA concentration and plasma MDMA concentration, with the correlation higher for salivary concentrations. S/P ratio was also significantly and positively correlated with salivary pH values.

PH and salivary MDMA - There was a significant difference in salivary pH measured 1.5 h after 100 mg MDMA versus 1.5 h after placebo, with a decrease in pH appearing after MDMA. Salivary pH measured 4 h after treatment (MDMA or placebo) were no longer significantly different 4 h post-drug, though post-MDMA pH was still lower than pre-MDMA pH. Return to baseline pH was seen between 6 and 24 h post drug.

Overall Effects: MDMA and MDA were both detectable in saliva collected from 8 MDMA-experienced men after 100 mg MDMA. Trace amounts of the major metabolite HMMA were also detected in saliva, but only in trace amounts. Both plasma and salivary MDMA concentrations peaked at 1.5 h post-drug. However, MDMA concentration disappeared from saliva before it was eliminated from plasma. A greater concentration of MDMA was found in saliva than in plasma across all sampling times. Peak concentrations of MDA in saliva differed from peak plasma concentrations, with salivary peak in MDA concentration preceding peak in plasma MDA concentration. Salivary MDMA values were correlated with plasma concentrations of MDMA. Salivary pH 1.5 h after MDMA was lower (more acidic) after MDMA than after placebo. S/P ratio correlated with salivary and plasma MDMA concentration, and with salivary pH.

Adverse Effects: None reported in this paper.

Comments: This is the first publication that has tested the viability of salivary measures of MDMA by using samples taken from people after administration of a known quantity of pure drug. The higher concentration of MDMA in saliva versus plasma is explained by the authors as a result of passive diffusion into saliva and the lack of protein-binding capacity in saliva when compared with plasma. In passing, the authors note that much higher salivary and plasma levels of MDMA were detected in 2 of the 8 volunteers, but the significance of this inter-individual difference remains unknown. While it appears that saliva can be used as a non-invasive means to detect MDMA in humans, it is unknown whether salivary tests would remain accurate under different conditions, as when individuals mix drugs or ingest MDMA differently (insufflate rather than swallow). Sample size is small in this study and consists of men only. The authors note that saliva was nonstimulated to maintain true pH. The sample appearing in this study may be similar or identical to a sample used in other investigations of MDMA published by the same authors.