MDMA Metabolism and Toxicity

We’re most interested in what happens when a drug reaches our brains, but drugs go everywhere else in your body too.  So, let’s follow a pill through your system!

The digestive system

After swallowing a pill, it of course goes to your stomach, where it dissolves.   The stomach doesn’t absorb most things very easily; it’s more a holding tank where digestive enzymes and stomach acids go to work preparing food for the small intestine.  As a result, very little of the MDMA can get into your system while it’s still in your stomach.  Instead, it will have to wait until your stomach contents get passed along to the small intestine, which is very good at absorbing things.

Once in the small intestine, your body will begin to absorb the drug, passing it into your bloodstream.  As this happens, there’s a chance you may experience digestive upset (such as heartburn, loose bowl movements, or even throwing up!)  The reason this happens is because your digestive system is full of nerve cells that control digestion, and these nerve cells are very similar to the ones in your brain, responding to many of the same drugs.  Your stomach and intestines are in essence ‘getting high’ off the drug, and as a result, may behave oddly (such as by making you barf all over your mates.)

As the drug begins to move out throughout your body, levels in the brain begin to rise.    The first ‘alert’ signs may be feeling chilled or warm or excited.  However the high begins, it’s worth remembering that you will start to be affected by the drug before you conciously feel ‘high’, so don’t drive or do anything else potentially dangerous in between swallowing the pills and feeling the MDMA kick in.  (What happens when MDMA reaches the brain is complicated, so it has its own section:  How does MDMA work?)

The heart, lungs, and blood vessels

As MDMA gets into your bloodstream, it starts to cause blood vessels to constrict slightly.  This can raise your blood pressure a little, but it’s nothing to worry about for a reasonably healthy person.  It also reduces blood flow to your extremities, so your hands might feel cold if you’re in a cool room.  And of course, there’s the legendary ‘speed willy’.  Since the penis is pretty much just a big blood vessel, MDMA can cause dramatic (but only temporary) ‘shrinkage’ and difficulty getting or keeping an erection.  Some users turn to erectile dysfunction drugs to combat this effect (which appears to be reasonably safe, but does add more possible side effects.)

MDMA doesn’t seem to have any particular toxicity to the heart.  Instead, the danger is that high doses, drug mixing, or an underlying serious health problem might cause your heart to be over-worked.  If you aren’t confident you can survive several hours of moderate exercise (such as walking or riding a bike), you shouldn’t be using MDMA.

In the lungs, MDMA can have a temporary effect similar to a rescue inhaler, constricting blood vessels and reducing inflamation.   This can help you breath more easily in the short term, but there may be a rebound effect (where inflamation in the lungs gets worse than before) after you come down, so MDMA may be dangerous to people with asthma or other breathing problems.

A surprisingly large number of people have a mitral valve prolapse (MVP), more commonly known as a ‘heart murmur’.  This is caused by a heart valve that doesn’t quite fit, allowing a little blood to flow past it when it should be completely closed.  (This small flow of blood is what causes the ‘murmur’ sound.)   For most people with MVP, their condition is mild enough that MDMA shouldn’t pose any increased risk.  Talk to your doctor.  If they feel vigerous exercise could kill you, MDMA could pose a serious risk to you.  Heavy, long-term use of MDMA may worsen MVP.

Mucus and saliva

As part of it’s vasoconstrictive effect, MDMA can reduce the amount of mucus being produced in your sinuses.  Since mucus is an important part of your body’s defenses against infection, this may increase your chances of catching a cold or other illness while high.  MDMA also reduces saliva production, which can lead to a dry mouth.  (Chewing gum can help.)

The jaw and other muscles

Why do a lot of people clench or grind their teeth on MDMA?  Part of the answer is simply that the drug increases muscle tension throughout your body, including the jaw.  This increased muscle tension will increase your metabolism (which can make you warmer), and might cause some muscle stiffness the next day.  In the case of your jaw, it’s also responding to your mental state.  The more excited you are, the more ‘expressive’ your face and jaws become; it’s like your cheerfully high brain is trying to communicate it’s internal state through your jaw muscles.

The mind-muscle connection to your mental state also cause tiny muscles in the irises of your eyes to contract, causing those wide-eye dilated pupils that MDMA is famous for.   (Paramedics check people’s irises because it gives information about what’s happening inside a person’s brain.  Wide, dilated pupils suggest stimulants or agitation.  Tiny constricted pupils suggest that the brain is going to sleep, perhaps from a sedative drug like heroin or some other problem.  Uneven pupils (one more dilated than the other) can be a sign of damage in one side of the brain, such as from a stroke.)

MDMA’s effects on muscle tension can also affect small muscles, such as the one that holds urine in your bladder.  This can make it hard to go to the bathroom.   Most users find that they just need to relax to urinate, such as by thinking of something boring (like doing math in your head.)

In cases of severe overheating (such as a very large MDMA overdose can cause), muscle tissue can break down.  This rare (and extremely dangerous) condition is the result of the victim’s temperature; MDMA itself is not particularly toxic to muscle tissue.

Kidneys

As MDMA (and its metabolites) reaches your kidneys, they begin to filter it out of your bloodstream, dumping it into your bladder to eventually be peed out.   You may not have to go to the bathroom for hours, though; one side effect of MDMA is to release a hormone (anti-diuretic hormone) that tells your kidneys to conserve water.  As a result, your body usually produces less urine while high.   MDMA is not particularly toxic to the kidneys, but kidney damage can be caused by severe overheating from a large overdose.[5][6]

Liver

The liver is the body’s waste treatment plant.  It’s packed full of enzymes that break down anything ‘undesirable’ or unusual floating around in your bloodstream; pretty much anything and everything, from broken down red blood cells to hormones and medications.  This, of course, includes MDMA.  Eventually, about two-thirds of the MDMA you take will be broken down into other compounds (metabolites) by your liver.  These enzymes are specialized; different substances get broken down by different enzymes.  (Alcohol, for instance, is metabolized by a completely different set of enzymes than MDMA is.)  The enzyme type that does most of the work breaking down MDMA is called Cytochrome P450 2D6.  Fortunately, everybody just calls it “2D6”.   If another drug or medication that you’ve taken is also broken down by 2D6, it leaves less of the enzyme free to deal with the MDMA in your system.  As a result, you may be at a greater risk for overdosing or having other side effects (since your body can’t eliminate the MDMA very effectively.)

MDMA metabolites produced by your liver mostly end up getting filtered out by your kidneys, but the liver also sends some MDMA and metabolites to the gall bladder, which dumps them back into the lower digestive tract.   As a result, most of the dose of MDMA that you take will eventually be urinated out, but some ends up in your poop.   (An adventurous users asks “could I drink my pee to get high again/extend the high?”  Probably not; most of the MDMA has been broken down.)

There have been somewhat regular (though still very rare) cases of liver damage in ‘ecstasy’ users.  Sometimes this damage has been severe, even fatal, which of course makes you wonder if MDMA is particularly hard on the liver.  The answer turns out to be…mostly not.   Researchers have discovered that MDMA, by itself, doesn’t seem to be very toxic to liver cells.[1]  So what was causing these cases of liver damage?  The answer seems to be severe overheating caused by cases of heatstroke and the occassional serious overdose.[2]   Although extremely rare, if somebody on MDMA seems to be running a fever, seek medical attention!

Reproductive tissues

There is some evidence that MDMA can cause a slight increase in birth defects if taken by women while they are pregnant. This may be due to the drug introducing some strange signals that might confuse normal development of the fetus, or it might just be secondary to the stress that drugs like MDMA cause your body.  Either way, if you are pregnant or might be pregnant, you should avoid MDMA (and frankly, any other recreational drug, including alcohol.)

Skin and hair

Small amounts of MDMA will be excreted by your sweat glands onto your skin, and traces might be incorporated into growing hair fibers.  Drug tests that take a swab from your skin can detect very recent (within a few days) use, and hair drug tests may be able to detect heavy use from several months ago.

Although MDMA feels relatively unique, its actual metabolism and effects on the brain/body are unremarkable. The cardiovascular response, stress reaction, metabolic pathways, etc. are well studied and have shown no surprises. The methoxyphenethylamine group of drugs has been around for a long time, with some examples such as mescaline having seen widespread use for literally thousands of years with no detectable negative impact. Likewise, amphetamine type drugs have been in extremely widespread use and abuse for much of this century; Germany and Japan virtually drowned themselves under amphetamine and methamphetamine during and after WW2. I don’t foresee any novel pharmacology or mechanism that might yield a nasty surprise down the road. Of course, I may be horribly wrong and we’re all going to grow extra arms out of our assholes in a few more years…but I doubt it.

That being said, safer drug use always means less drug use.  Take good care of yourself!

[1] Beitia G, Cobreros A, Sainz L, Cenarruzabeitia E “MDMA (ecstasy)-induced hepatoxicity; effect on cytosolic calcium signals in isolated hepatocytes”, Liver 1999; 19(3):234-41. Abstract.

[2] Carvalho M, Carvalho F, and Bastos ML “Is hyperthermia the triggering factor for the hepatoxicity induced by 3,4-methylenedioxymethamphetamine (ecstasy)? An in vitro study using freshly isolated mouse hepatocytes”, Arch Toxicol 2001; 74:789-93. Abstract.[3] Carvalho M, Carvalho F, Remiao F, de Lourdes Pereira M, Pires-Das-Neves R, de Lourdes Bastos M “Effect of 3,4-methylenedioxymethamphetamine (‘ecstasy’) on body temperature and liver antioxidant status in mice: influence of ambient temperature”, Arch Toxicol 2002; 76(3):166-172. Abstract.[4] Woodrow G, Harnden P, Turney JH “Acute renal failure due to accelerated hypertension following ingestion of 3,4-methylenedioxymethamphetamine (‘ecstasy’)”, Nephrol Dial Transplant 1995; 10(3):399-400. Abstract.[5] Carvalho M, Hawksworth G, Milhazes N, Borges F, Monks TJ, Fernandes E, Carvalho F, Bastos ML “Role of metabolites in MDMA (ecstasy)-induced nephrotoxicity: an in vitro study using rat and human renal proximal tubular cells”, Arch Toxicology 2002; 76(10):581-8. Abstract.[6] Cunningham M. “Ecstasy-induced rhabdomyolysis and its role in the development of acute renal failure”, Intensive Crit Care Nursing 1997; 13(4):216-23. Abstract.[7] Gesi M, Lenzi P, Soldani P, Ferrucci M, Giusiani A, Fornai F, Paparelli A “Morphological effects in the mouse myocardium after methylenedioxymethamphetamine administration combined with loud noise exposure” Anat Rec 2002; 267(1):37-46. Abstract.[10] Badon LA, Hicks A, Lord K, Ogden BA, Meleg-Smith S, Varner KJ “Changes in Cardiovascular Responsiveness and Cardiotoxicity Elicited during Binge Administration of Ecstasy” J Pharmacol Exp Ther, 2002; 302(3):898-907. Abstract.[11] Setola V, Hufeisen SJ, Grande-Allen KJ, Vesely I, Glennon RA, Blough B, Rothman RB, Roth BL (2003) 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) Induces Fenfluramine-Like Proliferative Actions on Human Cardiac Valvular Interstitial Cells in Vitro” Mol Pharmacol. 2003;63, 6:1223-9. Abstract.