MDMA
Targets in the model
10
each with a measured Kᵢ
A one-compartment model of what MDMA might do over time, at a dose and by a route you choose. The affinities driving the occupancy calculation are measured and this archive holds them; the pharmacokinetics are mostly estimated, and the table at the foot of the page says which is which. The measured dossier · method
The input
First-order gastrointestinal absorption with a rate constant giving a peak near one hour, and a bioavailability reduced by first-pass metabolism. Both are class placeholders; where a compound has a published oral F it overrides this. Bioavailability for this route is 0.3 and the absorption rate constant 1.2 h⁻¹, both properties of the route rather than of MDMA.
Modelled concentration
3 h 36 min
One compartment with first-order absorption. It cannot show a distribution phase, so the first minutes after an intravenous dose are the least trustworthy part of the curve. Peak effect-site concentration is 266 nM.
Reported milestones
1 Autonomic thresholds crossed at 0
Times at which a named human study recorded an effect. These are observations, not model output: they stay where the study put them however you change the settings, so where a marker and the curve disagree, the curve is what is wrong. Each one names its study and what was read to confirm it, including how the study was designed. Except where a marker states its own dose, all of them were measured at 75 or 125 mg MDMA, oral.
- 1
Autonomic thresholds crossed0(0–4.20 h)physiological
Across the acute phase, systolic blood pressure exceeded 160 mmHg in 33% of subjects, heart rate exceeded 100 beats/min in 29%, and body temperature exceeded 38 °C in 19%. All three proportions were significantly higher after 125 mg than after 75 mg.
Vizeli P et al., Journal of Psychopharmacology 2017 — The paper gives these as proportions of subjects, not as times: it does not say when in the session each threshold was crossed. The span drawn here is the same paper's mean duration of subjective effects, used only to place the observation in the acute phase, and it should not be read as the time the thresholds were crossed.
- 2
Effects over4.20 h(1.40 h–8.20 h)mental
Duration of subjective effects 4.2 ± 1.3 h across 166 subjects, range 1.4-8.2 h. The 125 mg dose produced higher 'good drug effect' ratings than 75 mg; 'bad drug effect' ratings were moderate, transient, and higher in women than in men.
Vizeli P et al., Journal of Psychopharmacology 2017 — Stated in the abstract of the pooled analysis. The range is wide because it spans nine studies and two doses.
Model landmarks
These are not observations. Each one is a feature of the curve above, read off the figure and moving with it whenever you change a parameter.
Dose given0
The model starts here.
Peak plasma2 h 22 min
Modelled maximum of 452 nM total plasma concentration.
Peak effect site3 h 4 min
Modelled maximum of 266 nM at the effect site — the concentration the occupancy below is computed from.
Modelled receptor occupancy at 3 h 36 min
O = C/(C+Kᵢ) at the effect-site concentration above. The Kᵢ is measured and this archive holds it; the C is modelled. Equilibrium is assumed at every instant, with no receptor reserve, no active metabolite and no tolerance.
The archive holds measurements of this pair that disagree by more than a hundredfold, so the single number beside it is not settled. The strongest is shown — in this archive the strongest measurement is usually the best one rather than an outlier, because weak values are disproportionately old tissue preparations — but the range is what the sources actually support: SERT 0.73–425 nM across 6.
Modelled regional engagement
Occupancy at each target multiplied by that target’s transcript level in the region, summed. This product is the model speaking. A dossier’s Systems plate deliberately refuses to compute it, because there it would read as a finding; here it is an output with its assumptions on the page. Transcript is not receptor density, and a region shaded here is a region where the model says binding could occur, not one shown to be affected.
And nothing checks it. The concentration plot above carries reported milestones because human studies state times; this figure has no counterpart. The human imaging work this archive cites reports connectivity change across a cortical parcellation, which is a different quantity in a different set of regions — the atlas holds the cortex as one — so it can neither confirm nor contradict the shading here, and translating it onto these thirteen regions would assert a correspondence nobody has published.
Brain
Body
Shading is on a fixed scale — the strongest engagement reached anywhere during the whole run — so the figures dim as the compound clears instead of renormalising to whatever the current instant happens to hold. Outlines from the EMBL-EBI Anatomogram, the same plates the dossiers use.
Brain regions
- midbrain
- basal ganglia
- cerebral cortex
- retina
- amygdala
- hypothalamus
- hippocampal formation
- cerebellum
- pituitary gland
- spinal cord
Peripheral & autonomic
- small intestine
- lung
- adrenal gland
- duodenum
- kidney
- spleen
- smooth muscle
- heart muscle
- liver
- colon
- pancreas
- urinary bladder
Parameters
The whole model is these five numbers plus the route. Each says whether anyone measured it for MDMA. Edit any of them; nothing here is written back to the archive.
How long the plasma concentration takes to halve once absorption is over.
Longer than the class prior. MDMA inhibits its own metabolism, so half-life rises with dose and a single constant cannot capture that.
Apparent volume the dose would occupy at the plasma concentration. Large means the compound leaves the blood for tissue.
Class prior, slightly raised.
The share of plasma drug not bound to protein. Only unbound drug crosses into the brain.
Modest protein binding assumed for a small amine.
Unbound brain concentration divided by unbound plasma. Below 1 implies active efflux; 1 is passive equilibration.
Passive equilibration assumed.
How fast the receptor compartment follows plasma. Small values put the peak effect long after the peak concentration.
Class prior, slightly lowered.