The government then scheduled MDMA as a Schedule I drug in 1985, and it has remained illegal ever since. However, that might soon be changing as more evidence attests to its therapeutic value in treating a variety of mental health conditions. Currently MDMA is in phase III clinical trials for FDA approval as a psychedelic therapy for PTSD. As a derivative of amphetamine, MDMA has stimulating and empathic effects that generally last about three to six hours. Currently, it is undergoing Phase III clinical trials to determine its effectiveness in treating post-traumatic stress disorder during psychedelic-assisted psychotherapy sessions.
These clinical trials are putting pressure on the United States government to reclassify the substance for therapeutic use. In 2014, it was the fifth most commonly used drug worldwide and the fourth most commonly used in the United Kingdom according to the Global Drug Survey. MDMA is a popular drug that acts as both a psychedelic and a stimulant. It is a derivative of amphetamine, and a member of the phenethylamine family which includes substances such as mescaline, 2C-B, speed, and methamphetamine. It induces the release of serotonin, norepinephrine, and dopamine from the presynaptic neuron into the synapse. This causes the user to experience energizing effects, euphoria, empathy, reduced inhibitions, feelings of connection to others, and enhanced sensation and perception. After ingestion, concentration of MDMA in the blood stream begins to rise after about 30 minutes and reaches its maximum concentration after 1.5-3 hours. MDMA’s half-life is 6-7 hours.
These time frames cause the effects to start about 30 minutes after ingestion, the peak of the effects to occur around 2 to 3 hours after ingestion, and the effects lasting a total of 3-5 hours. MDMA stands for 3,4-methylenedioxymethamphetamine, a derivative of amphetamine, which is why it produces some stimulant effects. It is a member of the larger group of ring-substituted phenethylamines. Phenethylamines without ring substitution usually behave solely as stimulants. However, the ring substitution in MDMA causes additional psychoactive effects, yet it is still less hallucinogenic than it’s homolog, methylenedioxyamphetamine (commonly known as MDA). As a synthetically made substance, MDMA is fabricated from scratch.
The four most common precursors used to manufacture it are safrole, isosafrole, piperonal, and 3,4-methylenedioxyphenyl-2-propanone (PMK). One of these precursors is typically synthesized into MDP2P, or 3,4-methylenedioxyphenyl-2-propanone, then through reductive amination synthesized into MDMA. MDP2P can be synthesized by the isomerization of safrole within a strong base to create isosafrole then isosafrole is oxidized to create MDP2P. It can also be produced using the Wacker process which oxidizes safrole directly to MDP2P in the presence of a palladium catalyst. MDMA comes in tablet, powder, or crystal form. Molly refers to the powder form (usually comes in capsules). Whereas ecstasy is the tablet form. Most users consume it orally; although some occasionally consume it intranasally. MDMA is measured in milligrams. A standard dose is between 1.15-2.35mg/kg, although lower doses have been used in therapy. 100 milligrams is commonly the starting dose. Most commonly, MDMA comes as an ecstasy tablet. Most high quality ecstasy tablets contain somewhere in the range of 80-150mg of the drug itself. However, pure MDMA powder must be mixed with other ingredients, such as lactose, to bind the powder together in order to make a tablet. MDMA could be cut with other potentially dangerous substances, so it is important to test its purity before use. (See Safety).
The onset of effects from tablets takes anywhere from 20 to 60 minutes.
These feelings typically last for 3 to 5 hours. Snorting MDMA powder can cause effects to come on faster, typically around 15 minutes depending on the dosage and the individual’s metabolism, and may cause a shorter, but more intense peak. It reaches the brain faster because the nasal membrane allows the bloodstream to absorb the drug quicker. This method also allows some the drug to bypass being broken down by the liver. Because snorting causes the effects to come on faster and more intense, the risks associated with the drug increase.
The user could experience extreme damage and/or irritation to their nasal cavity, as snorting any powder can cause lasting effects. In 1912, Anton Kollisch first synthesized MDMA with Merck Pharmaceuticals in Germany while investigating hemostatic substances, agents that stop abnormal bleeding. Two years later, Merck Pharmaceuticals patented MDMA. In 1927, a chemist from Merck named Max Oberlin performed the first animal testing with the drug while investigating substances similar to adrenaline or ephedrine. It wasn’t until the 70s however that scientists discovered its therapeutic potential in psychotherapy. It was particularly productive in helping with marriage counseling.
The drug quickly became popular for recreational use because of its euphoric/empathetic effects on the user. Much like other psychedelics, after a rushed introduction to the public, the government quickly made it illegal and placed it on the Schedule I list in 1985. In 1953, the Army Chemical Center tested MDMA toxicity on guinea pigs, dogs, mice, and rats as part of the MK-Ultra project. MK-Ultra was a set of experiments, most would consider unethical, performed by the CIA investigating hypnosis, neurosurgery, electroshock, torture, sexual blackmail, stage magic, and poison.
These experiments did not stop until 1964. Eventually the New York Times exposed the truth in 1974 leading the Senate to call for an immediate inquiry into the U.S. Intelligence’s abuse of power. These inquiries provoked President Ford to issue Executive Order 11905 putting an end to human testing without consent.
The tests conducted on MDMA were able to determine that the drug was “less toxic” than MDA. MDA’s similarity to MDMA causes many to confuse the two. It is one of the most common substitutes and many times sold as MDMA. However, it generally causes stronger hallucinations and neurotoxicity. Recreational use of MDMA did not begin until the late 1960s, and law enforcement agencies did not know about it until The Bureau of Narcotics and Dangerous Drugs published their first encounter of the drug in 1970. It appears that MDMA became popular for recreational use as a legal replacement for MDA, which was highly sought after, and made illegal in 1970 by the Controlled Substances Act.
The recreational use of MDMA quickly spread throughout the United States in the early 1980s, which led to its ban in 1985. Alexander Shulgin was an American chemist and pharmacologist who became well-known in the psychedelic community. Because of his wife, Ann Shulgin, MDMA became extremely popular in the psychedelic psychotherapy community. It began to show measurably positive effects in psychotherapy particularly in treatments for Post-Traumatic Stress Disorder. During this period, MDMA gained its nickname “Adam,” because many therapists felt that it brought their patients into an innocent-like state and helped them communicate more willingly. Alexander Shulgin famously created the Shulgin Rating Scale which provided a method for ranking the visual, auditory, and physical sensations of psychoactive substances and is still in use today.
The scale uses simple pluses and minuses to detail the strength of the effects of a substance. In September of 1976, Shulgin reported taking 16mg of MDMA and increasing doses until he reached 81mg on September 27th. He later reported the effects in his lab book as “amphetamine-like.”In 1991, Alexander and his wife Ann Shulgin published PIHKAL, which documented over 250 phenethylamines, including MDMA, mescaline, and 2C-B. Michael Clegg was a catholic priest who got into MDMA during his student years. Clegg was one of the main pioneers responsible popularizing MDMA in the late ’70s and early ’80s — right up it’s ban in the mid ’80’s. He was also selling the substance and making a profit. Clegg came up with the name “ecstasy” because his own experience with this substance, as he stated, was similar to the experience of “ecstasy” described in the bible.
There’s currently a television series in production about his life. In 1992, FDA reviewed a MAPS supported protocol from Dr. Charles Grob for a study of MDMA and it’s potential to treat pain, anxiety, and depression in cancer patients.
The FDA approved the study in 1992 as a phase I safety study, which ended in 1995.
The study showed no unusual risks, which indicated that it could be safely administered within a clinical research context. Afterwards, Dr. Charles Grob requested permission to further study the substance with cancer patients, but was denied by the FDA twice. Between the years of 1994 to 1999, 27 related ecstasy deaths occurred in the United States reported by SAMSA. Ecstasy tablets became notoriously impure and laced with other harmful substances such as amphetamines, bath salts (cathinones), methamphetamine, MDA, PMA, and PMMA. Rick Doblin is the founder of the Multidisciplinary Association for Psychedelic Studies, or MAPS. Previously, he had owned and operated a construction company that relocated houses from 1975 to 1982. He then received a degree in psychology from the New College of Florida in 1987 and a doctorate in public policy from Harvard University in 2001. He co-founded MAPS in 1986 with the objective of getting the FDA to approve MDMA. After many years of work, it looks like Rick Doblin might finally achieve his goal. MDMA is currently at the final stage for FDA approval as a legal treatment for PTSD. MDMA is a Schedule I substance under the Controlled Substances Act. This makes MDMA illegal to manufacture, buy, possess, and distribute without a license from the DEA. By categorizing it as a Schedule I substance, the DEA believes that it meets the following three criteria: having a high potential for abuse, no legitimate medical use in treatment, and a lack of accepted safety laws for its use under medical supervision.
The FDA has approved research for MDMA to explore whether it treats depression, PTSD, and psychological or emotional damage.
The Phase III trials are expected to be complete by 2022, meaning MDMA-assisted psychotherapy may be a legal medical option by 2023. It became a Schedule I substance under the Controlled Substances Act in 1985 after an emergency classification by the DEA. It is illegal to buy, sell, or produce MDMA in most countries. However, it is more of a “gray area” in certain countries. In Peru, it is legal to possess up to 250mg, as long as it’s the only drug on you. The gastrointestinal tract absorbs MDMA.
Then the liver metabolizes into an active metabolite called methoxyamphetamine. It is a serotonergic drug acting as a presynaptic releasing agent of serotonin, norepinephrine, and dopamine.
The neurotransmitter serotonin (or 5-HT) is synthesized in 5-HT neurons and stored in synaptic vesicles.
They then release 5-HT into the synaptic cleft in response to the activation of the 5-HT neurons. 5-HT is pumped back into the neuron through the reuptake pump where it is stored in the synaptic vesicles. When ingested, it blocks the reuptake of 5-HT. Overall, MDMA affects 5-HT similarly to the way amphetamines affect dopamine (by inhibiting reuptake and causing the release of 5-HT). However, it has micromolar potency for the serotonin 5-HT2 (the psychedelic site), muscarinic M1, alpha-2 adrenergic (the cardiovascular site), and histamine H1 receptors. Many classic psychedelics (LSD, psilocybin, mescaline) seem to have agonist properties at the 5-HT2 receptor, so it is possible that the “psychedelic” effects occur because of the activity at this receptor. Some of the cardiovascular effects (increased heart rate, etc.) may be due to MDMA’s activity at the alpha-2adrenergic receptor. Before we can discuss whether or not MDMA is toxic, we first need to define what makes a substance toxic. Toxicity is defined based on the levels of exposure required for a substance to cause harm to a human or animal.
The level of toxicity is measured based on the dose required to cause harm to a human. Even water can be toxic in too high of a dose and lethal snake venom can be non-toxic in a small enough dose. LD50 is a common measurement of toxicity, which measures the lethal dose for half of the tested organisms. When the government first started performing animal tests with MDMA in the 70s, they gave exorbitant amounts of the drug to animals and deemed it neurotoxic. Since then, extensive evidence proves that this is not the case. Considering the large amount of users internationally, serious acute adverse effects seem to be rare.
The main thing to look out for is the danger of becoming dehydrated (especially because it is so popular in the rave scene). Additionally beware increased heart rate (especially if you have pre-existing heart conditions). Between the years of 1977 and 1981, only eight individuals had to seek emergency room treatment after using the drug recreationally (according to the Drug Abuse Warning Network). Like most other drugs, “neurotoxicity” is dose-dependent. One important thing about MDMA neurotoxicity however is its relationship with SSRIs. SSRIs inhibit the reuptake of serotonin causing serotonin to remain in the synaptic gap longer than it normally would which causes the presynaptic neuron to release less serotonin. Because of this, many researchers believe that SSRIs can reduce the ability of MDMA to cause neurotoxicity, but they also reduce MDMA’s ability to affect an individual. In conclusion, someone who regularly takes SSRIs may experience less neurotoxicity from MDMA, but will also not experience the normal effects of MDMA. MDMA can and does produce adverse neurotoxic effects at some large and repeated doses.
These adverse effects include decreases in concentration of serotonin (5-HT) and its metabolite 5-hydroxyindoleacetic acid (5-HIAA).
These effects suggest that the drug causes either “down regulation,” meaning the neuron isn’t making nor retaining as many serotonergic markers, or the permanent loss of serotonergic axons. However, we don’t know which of these effects MDMA causes in the brain. Factors like diet and lifestyle also affect serotonin levels. This “down regulation” may happen because MDMA rapidly inactivates the enzyme TPH and, thus, decreases serotonin levels until TPH activity returns to normal. Risks associated with possible long-term brain damage are more difficult to research. Government studies in animals show that MDMA can cause long-lasting decreases in the neurotransmitter serotonin. For these reasons, the “three-month rule” became a guideline amongst members in the community, to wait at least three months between each dose in order for their serotonin levels to become normal again.
The true long-term effects however from exposure are still unknown. Mixing ecstasy with alcohol can be very dangerous, and cause severe dehydration. Furthermore, MDMA’s stimulant effects can hide alcohol’s sedating effects, causing an individual to drink more and become dangerously drunk. Basically, an individual could feel more sober than they actually are. A study done in 2002 found that the concentration of MDMA in each individual’s blood increased 13% after they drank alcohol. Research on rodents also suggests that mixing alcohol and MDMA may negatively affect the heart by placing unnecessary stress on it. MDMA and MAOIs do not mix! If you are not sure if you are taking prescription MAOIs, you should know that Nardil, Parnate, Marplan, Eldepryl, and Aurorix/Manerix fall under this category. Ayahuasca brew also contains MAOIs in the form of harmine and harmaline. Mixing MDMA and MAOIs can cause a potentially fatal condition called “serotonin syndrome”. A number of people have died from the result of taking MDMA and MAOIs. MDMA taken with other drugs that metabolize through the same liver enzyme known as CYP2D6, can interact dangerously. CYP2D6 also metabolizes Ritonavir (also mentioned below). Other drugs metabolized by CYP2D6 include codeine, opiate derivatives, and DXM. DXM is commonly found in impure ecstasy tablets. Also note that CYP2D6 also metabolizes Prozac. If you combine MDMA with any of these substances or any other drug metabolized by CYP2D6, both drugs will take longer to metabolize. In turn, the user will feel like they took a higher dose of each drug. Never take MDMA with a protease inhibitor, a class of antiviral drugs. If you are using the protease inhibitor Ritonavir, do not take MDMA. This combination could be life-threatening. Avoid other stimulants (prescription or recreational) when taking Ecstasy. Common stimulants include adderall, anabolic steroids, cocaine, Concerta, crack, Dexedrine, methamphetamine, and Ritalin. This can cause increased heart rate, blood pressure, and body temperature risks. A small number of MDMA users have reportedly experienced seizures after taking moderate doses of pure MDMA. While the cause remain unknown, it is thought to be from the acute systemic effects hyponatremia and hyperthermia. It is important to remain aware that MDMA can affect everyone differently. For a more thorough list of interactions, consult the image below by Tripsit: Besides the above mentioned interactions, there are two main things to be cautious of when taking MDMA.
The first is remaining hydrated, and the second is purity. Because of the drug could accelerate one’s heart rate, users could become extremely dehydrated and overheated. Making it very important to stay hydrated during use. It is very rare to find completely pure MDMA in the United States. Some use a series of harmful substances to cut MDMA in the black market making it extremely important to test any MDMA purchased for adulterants. Erowid runs an anonymous drug analysis program that catalogues common types of pills ecstasy comes in with their results. Even if you identify the pill you received on this database, it is still important to test as there are issues with counterfeit pills. Finding the right MDMA dosage is important. Consuming more than an appropriate dose of MDMA, can happen, but overdosing is extremely uncommon. One of the few cases of a pure MDMA overdose states that an individual took 2.3 grams of MDMA at once — almost twenty times a normal dose. According to the community, most overdoses occur because of consuming impure MDMA, or consuming a substance that isn’t even MDMA at all. A psychedelic’s effects will have large variances, depending on the individual. A variety of factors contribute to what one will experience. For example, set and setting. Timothy Leary conducted a study with 175 individuals to whom he administered psilocybin in a setting similar to a common living room. In the larger groups of eight people or more the individuals felt less support from the group overall and had less pleasant experiences than those placed in smaller groups of six people or less. This is just one example but demonstrates how that can impact the experience and effects of a psychedelic experience. Sometimes sensations will come on as the substance is taking effect as body is processing new information, and as the person goes through their experience. So it is important to remember that there is a range of effects possible. Every body is different. While everyone’s experience with MDMA will differ and the effects will shift throughout the experience, most users experience these common side effects: Like all psychedelics, do not take MDMA if predisposed to any mental health conditions (especially schizophrenia and psychosis). MDMA can possibly exacerbate the symptoms of depression when used recreationally. However, current clinical trials indicate that MDMA can help drastically with conditions such as PTSD. Do not use MDMA if you have pre-existing heart conditions, a history of heart ailments, high blood pressure, glaucoma, liver/kidney disorders, or hypoglycemia. Although MDMA remains a popular drug today for recreational use, the most astonishing developments occur within the research of MDMA-assisted psychotherapy. Within the current renaissance of psychedelic research, MDMA is showing among the most promising results in trails. Because of extraordinary results, the FDA has granted MAPS permission for phase three trials of MDMA-assisted psychotherapy for PTSD. This research involved a $26.9 million dollar plan to make MDMA an FDA-approved prescription medicine by 2021. MAPS, founded by Rick Doblin, is the only organization funding clinical trials of MDMA-assisted psychotherapy for PTSD, social anxiety in autistic adults, and anxiety associated with life-threatening illnesses. Unlike commonly prescribed medications, psychiatrists only have to administer MDMA a few times during psychotherapy sessions to achieve long-lasting and positive results. MDMA is effective in treatment because it helps the individual feel more comfortable, safe, and communicative while remaining emotionally engaged through the processing of their trauma. Current drugs prescribed for a condition like PTSD only manage the symptoms. Whereas MDMA appears to aide the patient in dealing with the root of the problem.
Therefore, MDMA is a possible permanent solution. MDMA’s half-life is between six to seven hours. It is detectable in urine for 2-4 days after consumption due to the metabolites it produces. When ingested orally, it takes about 30 minutes for the effects to begin. When taken intranasally, effects begin after about 15 minutes. The effects last for 3-5 hours. It is made synthetically from one of four common precursors, safrole, isosafrole, piperonal, and 3,4-methylenedioxyphenyl-2-propanone (PMK). One of these precursors is typically synthesized into MDP2P, or 3,4-methylenedioxyphenyl-2-propanone, then through reductive amination synthesized into MDMA As a presynaptic releasing agent, it induces the release of serotonin, norepinephrine, and dopamine from the presynaptic neuron into the synapse. As a recommendation, use a Marquis test, Simon test, and Froehde test to ensure the purity of your MDMA. MDMA is typically a white powder or crystal, or pressed into a tablet.
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