MDMA - Ecstasy: A Current Overview

Transcription

1 MDMA - Ecstasy: A Current Overview Introduction MDMA (3,4-methylenedioxy-methamphetamine) is a synthetic stimulant that alters a person s perception and mood. A person using MDMA will have an altered awareness of surrounding objects and conditions. The drug is similar chemically to hallucinogens and stimulants. It can produce feelings of increased pleasure, energy, emotional warmth, and a distorted perception of time. Although MDMA has psychedelic effects that cause a sense of euphoria and increased energy, over the long-term the drug may lead to fatigue and depression. MDMA is often combined with other drugs, which increases its potentially harmful effects on the user. Because of these harmful effects, MDMA was made illegal and listed as a Schedule I drug. Nevertheless, experimental use of MDMA has increased for psychiatric disorders, for example, posttraumatic stress disorder (PTSD), in an attempt to treat symptoms. 5 The History And Evolving Use Of MDMA Anton Kollisch discovered MDMA in Germany in Kollisch was a chemist working for the German pharmaceutical company Merck. The research interest in the drug was to synthesize methylhydrastinine as a possible treatment for uterine bleeding. 6 Ecstasy was patented in 1914 by Merck and was used in therapy. Major tests for MDMA took place in the 1950s at the University of Michigan for the U.S. Army to study its toxicity in animals. In the mid 1970s the substance came to the attention of Alexander Shulgin. Shulgin was a former chemist with Dow Chemical Company and he is known 1

2 as the godfather of Ecstasy. MDMA came to his attention when he was researching another psychoactive compound called MDA. Shulgin worked with David Nichols from Perdue University and in 1978 they published a report about the effects of MDMA in humans. They compared the drug to mushrooms and marijuana.the report by Shulgin and Nichols caught the attention of psychotherapists interested in the disinhibiting effects of MDMA. They saw the drug as a possible tool to overcome fear in patients. The drug was thought to increase patients insight into their emotions. Eventually, MDMA became the drug of choice within the rave culture, house parties, clubs, and festivals, and goes by the popular name Ecstasy or Molly. 1-6 After MDMA was introduced into psychotherapy, people began using MDMA recreationally. MDMA became attractive recreationally because it has the effects of both a hallucinogenic drug and a stimulant. The name Ecstasy was coined because it described the drug s effect on people. Production of the drug in the 1980s could not keep up with its use. Safrole and sassafras oil was used to manufacture MDMA. Initially popular at nightclubs and all-night dance parties known as raves, MDMA spread through networks including young, urban professionals (yuppies), users of psychedelics, psychiatrists, and psychotherapists. A psychedelic drug closely related to MDMA, methylenedioxyemphetamine (MDA), nicknamed Sally, spread to U.S. college campuses. Recreational users and psychotherapists were hopeful that MDMA and MDA would remain legal in the United States. 1-6 MDMA: Schedule I Substance Because of the perceived, serious dangers of MDMA, in 1985 the United States Drug Enforcement Agency (DEA) issued an emergency notice declaring MDMA a Schedule I substance and the DEA also issued an alert to 2

3 individuals and businesses that it was illegal in the U.S. to use safrole and sassafras oil to manufacture MDMA. 7 Some psychiatrists and psychotherapists objected to the DEA classifying MDMA as it did. They cited anecdotal use of its benefits in their practices. These objections failed and in 1988 MDMA and similar psychedelic drugs were classified as Schedule I substances. The Schedule I classification is according to the federal Controlled Substances Act, which is part of the Comprehensive Drug Abuse Prevention and Control Act of Other examples of Schedule I drugs include heroin, LSD, peyote, and marijuana (cannabis). 8 Under federal law, substances are categorized under schedules listed from Schedule I to Schedule V. Schedule I drugs are considered to be the most dangerous drugs. The schedule is assigned based on a drug s 1) potential for abuse, 2) safety, 3) addictive potential, and 4) whether there is a legitimate medical application for the drug. The potential for severe psychological or physical addiction exists with Schedule I drugs and there is no legitimate medical application No clinical studies have established the safety and efficacy of Ecstasy in a psychotherapy setting, which could make MDMA become a Schedule II drug, so the classification as a Schedule I drug remains. Statistics On MDMA Use Use of MDMA is reported at age 12 and older. There are indications that the peak age for use is between ages 18 to 25. There is less use above the age of 26 and under the age of 17. Statistics show that the use among adults 3

4 may be decreasing overall but this may not be true of adolescents. 2,3 This could be because younger users may think that MDMA provides a high that is safe; however, it is not safe. Table 1 Use of MDMA (%): Grade 8, 10, and 12 (2016) Drug Time period Grade 8 Grade 10 Grade 12 MDMA Lifetime Past year Past month Table 2 MDMA % Use: Ages 12 and older, 12-17, 18-25, and 26 or older (2015) Time Period 12 and older 12 to to and older Lifetime Past year Past month MDMA shares toxicities with amphetamines. It is also associated with specific adverse effects that can be serious or even lead to death. Deaths associated with the use of MDMA have increased since In other countries around the same time, such as Germany, the highest percent of MDMA reached increased for people aged 25 to 29. In Europe, in 2012 the estimate was that 37 percent of club goers ages 14 to 35 used MDMA. 1-4 The cost of Ecstasy varies across the globe. Prices tend to be higher in North American than in Europe. A tablet of MDMA/Ecstasy in the United States can be as high as $50 for mg of the drug. The lower prices can be $10 to 4

5 $25 per tablet. Production of Ecstasy is mainly in Canada but it is also imported from China. High Risk Drugs And Substance Use Disorder Before beginning an in depth discussion of MDMA, Ecstasy/Molly, a review of the drugs known to have high risk to develop into a substance use disorder and addiction are raised here. It is important for clinicians to be aware of other substances known to commonly have a high risk of addiction as they are often combined with MDMA use and are co-occurring disorders that need to be diagnosed as multiple or poly-substance use disorders, which complicate the medical management and treatment plan for recovery. When determining drug of use, the medical guidelines for testing can vary between regions, however, the clinician diagnosing a problem of MDMA or co-occurring will need to review a laboratory drug screen. Five drugs considered most important in a routine drug screen have evolved over time, such as new variants of amphetamines, synthetic marijuana/cannabinoids, opioids, and PCP not detectable with a routine drug test. PCP has been reported to be relatively obscure and used with lower frequency than numerous other street drugs, and amphetamine use is relatively infrequent compared now with methamphetamine and amphetamine derivatives, such as MDMA (Ecstasy), MDPV (bath salts), and numerous other drugs in this class. It is important that clinicians stay abreast of the drugs reported as frequently used, as the popular notion of drug use evolves based on media report, supply, demand and cost. 47 In the United States, currently only amphetamine, cocaine, marijuana, opioids, and PCP should be expected on drug screen test, unless otherwise 5

6 specified or requested. Certain drugs and substances have strong potential for a substance use disorder while others do not. Drugs such as cocaine and heroin and substances such as alcohol are intensely psychoactive, and the user will prefer them for a more powerful feeling of being high. This is certainly one of the known reasons for why they are the agents of choice for people who develop a substance use disorder. However, the pleasures of being intoxicated or high cannot fully explain a substance use disorder, and research has shown that continued and excessive use of these harmful agents causes changes in the central nervous system. These changes both cause and reinforce substance use. Of course, there are many people who take illicit or prescription drugs and/or drink alcohol that do not develop a substance use disorder, and these individual responses to commonly used drugs and substances further complicate the efforts at understanding the development of a substance use disorder. The mechanism of action and medical consequences of long-term use of alcohol, amphetamines/stimulants, cocaine, opioids, and sedative-hypnotics are important considerations when starting and continuing a patient treatment plan. The mechanisms of action by which alcohol and specific high risk drugs cause a substance use disorder, and the withdrawal syndromes associated with each one, is highlighted below. 46 Alcohol Aside from tobacco, alcohol is the most commonly used psychoactive drug in our society. There are many types of alcohol, for example, ethylene glycol, isopropyl, but the one that is most often consumed for its intoxicating effects is ethanol. 6

7 The exact mechanisms by which ethanol alters consciousness and causes tolerance and withdrawal are not completely understood. But it is thought that these effects are due to ethanol changing the activity of two neurotransmitters and their receptors: a major inhibitory neurotransmitter called gamma aminobutyric acid (GABA) and a sub-type of the major excitatory neurotransmitter glutamate called N-methyl-d-aspartate (NDMA). Gamma aminobuytric acid acts as an inhibitory neurotransmitter by increasing intracellular chloride concentration and decreasing intracellular potassium concentration. This hyperpolarizes the cells and makes them less able to respond. N-methyl-d-aspartate increases the movement of calcium and sodium across cell membranes, and this increases the cells ability to respond to a stimulus and depolarize. Ethanol binds to receptors that are associated with GABA and NDMA receptors on cell membranes in the CNS. This binding increases the affinity of GABA for GABA receptors and it decreases the affinity of NDMA for DMA receptors. The result is increased inhibition and decreased excitation. However, when large amounts of alcohol are used chronically the body responds by decreasing the number, sensitivity, and function of GABA receptors and increases the number, sensitivity, and function of NDMA receptors. This effect explains alcohol intoxication as well as tolerance to alcohol, for example, the need for larger amounts of alcohol to produce the same effect; and, it explains withdrawal, the clinical state that is produced when alcohol intake is stopped. Intoxication is caused by increased inhibition and decreased excitation in the central nervous system. Tolerance occurs because of the effect of chronic alcohol intake on the neurotransmitter receptors. Furthermore, when the intake of alcohol is stopped, withdrawal is 7

8 caused because there are large numbers of highly active NDMA receptors that can respond to NDMA and a greatly decreased number of GABA receptors that can respond to GABA. Alcohol intoxication is characterized primarily by CNS depression and impairment. Someone who has ingested an excess amount of ethanol will be drowsy, may be ataxic (incoordination of movement), have impaired judgment, decreased impulse control, and slurred speech. Extreme intoxication can cause coma, hypoglycemia, hypotension, respiratory depression, and death. Long-term use is associated with liver disease, heart failure, brain atrophy, gastritis and ulcers, anemia, and various cancers; it is particularly dangerous to the unborn child. Amphetamines and Stimulants Amphetamines and stimulants act by directly stimulating the adrenergic nerve endings. This causes a release into the synapses of norepinephrine and dopamine, neurotransmitters that stimulate the peripheral α receptors and β receptors. Acute intoxication causes anxiety, diaphoresis, hypertension, mydriasis, and tachycardia. More serious effects such as dysrhythmias, hallucinations, hyperthermia, myocardial ischemia, myocardial infarction, psychosis, seizures, stroke, and rhabdomyolysis are possible, as well. Long-term effects of amphetamine and stimulant use include aortic and mitral valve regurgitation, cardiomyopathy vasculitis, cardiomyopathy, pulmonary hypertension, and permanent damage to the dopaminergic and serotonergic neurons. Amphetamines and stimulants can be taken as tablets, injected, smoked, or insufflated (snorted). Probably the most commonly abused amphetamine is methamphetamine. 8

9 Methamphetamine is commercially produced, and it has labeled uses for the treatment of patients who have exogenous obesity or attention deficit disorder with hyperactivity disorder. Methamphetamine is lipid-soluble and crosses the blood-brain barrier more easily than the parent compound amphetamine, making it a more powerful drug. The great majority of the methamphetamine involved in substance use is illicitly produced, and this form of the drug is commonly called Crank or Speed. Cocaine Cocaine causes the release and blocks the re-uptake of the neurotransmitters dopamine, epinephrine, norepinephrine, and serotonin. These actions produce a hyper-adrenergic state, and the common signs and symptoms of cocaine intoxication are agitation, anxiety, chest pain, diaphoresis, hypertension, hyperthermia, mydriasis, tachycardia, and tachypnea. Cocaine also acts to stabilize the cardiac membrane by an effect on the sodium channels in the myocardium, and it bocks the movement of potassium through cardiac membrane ion channels. Blockade of the sodium channels produces cardiac membrane stabilization, typically called the quinidine-like effect. This can cause a prolonged QRS in the heart conduction pattern, and cardiac dysrhythmias. Blockade of the potassium ion channels can cause QTc prolongation and cardiac dysrhythmias, as well. Cocaine use has also been associated with serious medical problems affecting essentially every organ system; such as, acute angle-closure glaucoma, aortic dissection, coronary artery vasospasm, dystonic reactions, intestinal infarction, myocardial infarction, pneumothorax, pulmonary 9

10 infarction, rhabdomyolysis, seizures, stroke, and transient ischemic attack. Long-term effects of cocaine abuse include atherosclerosis, cardiomyopathy, endocarditis, malnutrition, and behavior that can be characterized as virtually identical to personality disturbances, paranoia, and schizophrenic syndromes. Cocaine can be ingested, applied to mucous membranes, insufflated, smoked, or injected. As mentioned previously, there are many welldocumented cases of dangerous contaminants and adulterants being added to cocaine, and these can cause significant harm. Opioids The opioids are a class of drugs that are derived from chemical modification of an opiate, an opiate being one of several alkaloids that are derived directly from the opium poppy. In common practice the term opioid is the one used for all drugs that have similar structure and clinical effects including, but not limited to, buprenorphine, codeine, dextromethorphan, fentanyl, heroin, hydrocodone, methadone, morphine, oxycodone, and propoxyphene. In the United States all of these drugs except for heroin are commercially produced and are commonly prescribed. In the United States, heroin is classified as a Schedule 1 drug with a high potential for substance use and addiction. Heroin has no currently accepted medical use, and there is a lack of accepted safety for use of the drug while under medical supervision. Heroin is commercially available in other countries and is used for treating people who have severe, intractable pain. The opioids act by binding to and stimulating opioid receptors in the brain, spinal cord, and peripheral sites. Opioid receptor stimulation causes the cells 10

11 to become hyperpolarized and thus less active and less able to respond to stimuli. As with alcohol and other drugs discussed in this module, chronic use of opioids affects the function and activity of neurotransmitters and their receptors, and this causes tolerance and the potential for a withdrawal syndrome. The therapeutic effects of the opioids are analgesia and an antitussive effect. Constipation, drowsiness, nausea, and vomiting are common side effects of the opioids. Opioid intoxication is characterized by ataxia, central nervous system depression, euphoria, hypotension, miosis, respiratory depression, and slurred speech. With profound intoxication coma, hypoxic seizures, hypoxic brain injury, pulmonary edema, and respiratory arrest are possible. Propoxyphene intoxication can cause myocardium sodium channel blockade and arrhythmias. Long-term effects of opioid use include heart valve infections, infectious diseases such as hepatitis B and C and human immunodeficiency virus (HIV) that occur with intravenous use, arthritis, collapsed and sclerotic veins, malnutrition, and a depressed immune system. Opioids can be taken as tablets, injected, smoked, or insufflated. As mentioned previously, there are many well-documented cases of dangerous contaminants and adulterants being added to illicit opioids (typically injectable heroin) and these can cause significant harm. Sedative-hypnotics The sedative-hypnotics are a group of drugs that are used to treat anxiety and/or agitation (sedatives) or to induce sleep (hypnotics). There are many drugs that are classified as sedatives or hypnotics, but the sedativehypnotics that are most often involved in substance abuse disorders are the benzodiazepines and the barbiturates. 11

12 The commonly available sedative-hypnotics are shown in the Table 1 below. Flunitrazepam is not commercially available in the United States but it is included here because of its highly publicized status as the date rape drug, also known as roofies. Midazolam is an injectable benzodiazepine that is used for pre-operative sedation. It is seldom a drug of choice for use but it is included here because it is well known and often used. The nonbenzodiazepine hypnotics shown in Table 2 have a similar mechanism of action as the benzodiazepines. The barbiturates, listed in Table 3, were at one time the drugs of choice for treating anxiety/agitation or for inducing sleep, but the benzodiazepines have been shown to have similar effectiveness for those purposes and a superior safety profile. The barbiturates are now used to help induce preoperative sedation or for the treatment of seizure disorders. The short-acting barbiturate butalbital is available in prescription analgesics, compounded in various combinations with acetaminophen, aspirin, caffeine, and codeine. These drugs are almost always used and used in tablet or capsule from, but injectable preparations are available. Table 1: Benzodiazepines Alprazolam (Xanax ) Chlordiazepoxide (Librium ) Clonazepam (Klonopin ) Diazepam (Valium ) Flunitrazepam (Rohypnol ) Flurazepam (Dalmane ) Lorazepam (Ativan ) Midazolam (Versed ) Oxazepam (Serax ) Temazepam (Restoril ) Triazolam (Halcion ) 12

13 Table 2: Non-Benzodiazepine Hypnotics Eszopiclone (Lunesta ) Zaleplon (Sonata ) Zolpidem (Ambien ) Table 3: Barbiturates 1. Amobarbital (Amytal ) 2. Butalbital 3. Pentobarbital (Nembutal ) 4. Phenobarbital (Luminal ) 5. Primidone (Mysoline ) 6. Secobarbital (Seconal ) 7. Thiopental (Pentothal ) The mechanism of action differs slightly for the three different categories, but essentially all these drugs act by binding to specific receptors that are part of the GABA receptor complex. This binding increases the affinity of GABA for GABA receptors and, as explained previously, this increases the inhibitory effect of GABA in the central nervous system. Intoxication with a sedative-hypnotic causes ataxia, central nervous system depression of varying degrees, from mild drowsiness to coma, hypotension, slurred speech, and respiratory depression. Death is caused by respiratory 13

14 depression. The barbiturates, compared to the benzodiazepines and the nonbenzodiazepine hypnotics, will produce more severe effects: if very large amounts are ingested coma and respiratory depression may last for days. Compared to alcohol, cocaine, amphetamine/stimulants, and opioids, the long-term medical consequences of sedative-hypnotic abuse are relatively mild. Perhaps the biggest risks are the potential for dependency and development of a substance use disorder. And although acute intoxication and the long-term medical consequences of alcohol, cocaine, amphetamines/stimulants, and opioids are much more severe, the sedativehypnotic withdrawal from the benzodiazepines and the barbiturates is comparatively more severe and can be life threatening. MDMA Effect On Neurotransmitters MDMA is known as a serotonin-norepinephrine-dopamine releasing agent (SNDRA), which is also known as a triple-releasing agent (TRA). Examples of SNDRAs include specific amphetamines such as MDMA and MDA. Other examples are mephedrone and methylone. These drugs produce a euphoria and psychostimulant effect. Some SNDRAs were once used as pharmaceutical drugs, specifically as antidepressants. With time these were withdrawn in the 1960s due to issues with toxicity and problems perceived with recreational use. 9,10 The effect of MDMA on neurotransmitters and potential for substance use and addiction will be introduced in this section, and discussed more in depth later on in subsequent sections of the course. MDMA is a drug that induces the release of serotonin, norepinephrine or epinephrine, and dopamine in the body and brain. Specifically, MDMA is reported to have ten times more affinity for uptake at serotonin transporters compared to dopamine and norepinephrine transporters. Within the brain, 14

15 MDMA increases the activity of at least three neurotransmitters - serotonin, dopamine, and norepinephrine. These neurotransmitters are the chemical messengers of brain cells. Factors to consider include that MDMA causes neurotransmitters to be released from storage sites in neurons. This is like other amphetamines, and results in increased neurotransmitter activity. Additionally, MDMA causes greater serotonin release and less dopamine release than a potent stimulant such as methamphetamine. MDMA is a monoamine transporter substrate. It enters monoamine neurons via neuronal membrane transport proteins; and acts as a monoamine transporter substrate and produces competitive reuptake inhibition at the neuronal membrane transporters. MDMA inhibits vesicular monoamine transporters with one of these two being highly expressed within monoamine neurons at vesicular membranes. MDMA also increases quantities of cortisol, prolactin, and oxytocin in serum. A study that was placebo controlled with 15 human volunteers found 100 mg of MDMA increased blood levels of oxytocin. The amount of oxytocin increase correlates with a subjective, prosocial effect of MDMA, which likely motivates the drug s recreational use. 9,10 Physical And Cognitive Effects Of MDMA Use The physical effects of MDMA are hard to predict because of adulterants added in the manufacture of the drug. There are no safety protocols. MDMA may be synthesized in a subpar lab. It can also be cut with volatile adulterants that increase health risks. Serotonin is an important neurotransmitter. It plays a role in regulating sleep, mood, pain, appetite, and other factors. The release of serotonin when using MDMA likely causes the elevated mood reported by MDMA users. 15

16 When a large amount of serotonin is released, MDMA causes the brain to get depleted of this neurotransmitter. This contributes to the low or negative after effects users can experience for days after taking MDMA. Measuring serotonin damage in humans can be difficult but studies of heavy MDMA users show that these users can experience confusion, depression, and problems with working memory and attention process that is longlasting. A memory impairment of this type is associated with decreased serotonin metabolites as well as other markers of serotonin function. Studies in animals showed that MDMA can damage serotonin-containing neurons. Some studies even showed that these effects can be long-lasting. Such damage could also occur in humans, and many clinicians carry the belief that there is long-lasting damage from MDMA as well as other hallucinogen drug use When imaging studies were conducted on MDMA users, changes in brain activity were seen. This involved the regions relating to cognition, emotion, and motor function. Multiple drug use, which is common with Ecstasy, could contribute additionally to behavioral effects from use. The drugabuse.gov site cautions that more research is needed in this area to confirm these findings and to determine exactly what effect MDMA has on the human brain. One hindrance to these studies involving human subjects is that they do not consider behavioral measures before users began taking drugs. This makes it difficult to rule out pre-existing conditions. Other factors that should be considered when studying humans with cognitive deficits resulting from MDMA use include gender, dosage, genetic factors, environmental factors, frequency and intensity of use, use of other drugs, and age at which use began

17 MDMA users may be young. A young female user could be pregnant when taking MDMA, and may believe that MDMA is a safe drug or not be aware that she is pregnant when taking MDMA. There is also great concern of the effects of MDMA on a developing fetus. Studies done with animals found adverse effects on tests of memory and learning from exposure to MDMA during a developmental period similar to the third trimester in humans. The effects on a fetus from MDMA on animals earlier in development are not clear. More research is needed to see the effect of MDMA on the development of the human nervous system. MDMA s Addictive Properties A significant consideration for clinicians during treatment and education of patients is that MDMA impacts many of the same neurotransmitter systems in the brain as do other addictive drugs. In fact, an experiment showed that animals will self-administer MDMA. This is an indicator that the drug has a dependency potential. The degree of self-administration is less than other drugs such as cocaine. Few studies have tried to determine MDMA use and addiction among the general population. The few studies done show widely varying results. This could be because of different population samples. It could be because of different types of measures also. Some MDMA users report continued use of MDMA while knowing of the physical and psychological harm. They also report tolerance with diminished response and withdrawal effects such as depressed feelings, trouble concentrating, loss of appetite, and fatigue. When considering what is known about preventing MDMA use, it should be realized that the social context and networks are an important factor. What could help might be peer led advocacy and drug prevention programs aimed 17

18 at lowering MDMA use among teenagers and young adults. A high school or college could be a venue for delivering messages about the possible harm done by using MDMA. Providing accurate information is important through education aims at prevention of MDMA use and addiction MDMA Use: Short-Term Effects This section discusses the short-term effects of MDMA use including euphoria, increased energy, distorted perception, nausea, muscle cramps, involuntary teeth clenching, blurred vision, chills, and sweating. Among the most serious, short-term risks to physical health when using MDMA are dehydration and hyperthermia. What can happen is a life-threatening or fatal hyponatremia. This can develop when a MDMA user tries to prevent dehydration by consuming a large quantity of water without replenishing electrolytes. Some of the immediate adverse effects of MDMA use can include not only dehydration and hyperthermia but also bruxism (the grinding and clenching of teeth). Other effects are increased wakefulness, insomnia, increased perspiration or sweating, increased heart rate and blood pressure, loss of appetite, nausea and vomiting, diarrhea, erectile dysfunction, visual and auditory hallucinations, and increased psychomotor activity. Dilation of the pupil has also been reported. The negative effects can last up to a week after cessation of moderate MDMA use. These effects can be physiological and include loss of appetite, insomnia, tiredness, lethargy, and lockjaw. The effects can also be psychological and include impulsiveness, irritability, depression, memory impairment, anxiety, paranoia, and restlessness While use of MDMA has been linked to reduced feelings of fatigue, increased psychomotor activity, suppressed appetite, blood pressure increase, impact on heart rate and body temperature, dilation of the pupils of the eye and 18

19 grinding of the teeth, rarely are visual or auditory hallucinations encountered. Complications that are severe include psychotic crises, hypertensive bleeding, dehydration, and hyperthermia. With high dosages and when taken with antidepressants such as MAO inhibitors and serotonin reuptake inhibitors, MDMA users can develop severe serotonin syndrome. Subjective experiences of those who use MDMA depend on the dose, the situation, and the mental and physical state of the user ,33 MDMA Use: Long-Term Effects The long-term effects of MDMA use involves both physical and mental health concerns. It can cause irritability, impulsiveness, aggression, depression, sleep problems, anxiety, memory problems, attention problems, decreased appetite, decreased sexual interest and pleasure, and increased body temperature. Reports have shown that the long-term effects of MDMA on human brain structure and function have not yet been fully determined. Chronic MDMA use results in serotonergic toxicity. This alters the regional cerebral blood flow that can be studied using functional magnetic resonance imaging (fmri) The effects of chronic MDMA use have been analyzed in various neurocognitive domains. This includes working memory, episodic memory, semantic memory, visual stimulation, motor function and impulsivity. Neuroimaging in MDMA users shows a reduction in brain 5-HT transporter and 5-HT2A receptor levels. This is shown when using positron emission tomography (PET) or single photon emission computed tomography (SPECT) and reduced grey matter density in various brain regions using the voxel based morphometry method. Using proton magnetic resonance spectroscopy, chemical neuroimaging and assaying the levels of important 19

20 biochemical markers and metabolites in the brains of MDMA users revealed no consistent results. 18 Functional magnetic resonance imaging studies have shown task evoked differences in regional brain activation. This is measured as blood oxygen level dependent signal intensity and/or spatial extent of activation. This is in MDMA users and controls. 18 Also, neurocognitive studies in MDMA users revealed memory and learning problems. Serotonergic innervation regulates cerebral microvasculature, and, as mentioned, chronic MDMA users have serotonin toxicity. MDMA users are expected to have altered regional blood flow, detectable in a functional MRI study. Data from animal studies suggests that MDMA is more toxic to the axons more distal to the brainstem cell bodies; that is, those present mainly in the occipital cortex. In addition, PET and SPECT studies in humans show reductions in serotonin transporter binding, most evident in the occipital cortex. The hyperthermia induced by MDMA is a pro-oxidant neurotoxic condition. Hyperthermia is known to accentuate the neurotoxic potential of MDMA same as with methamphetamine. It should also be noted that interventions to lower the core body temperature was shown to have a neuroprotective effect With a high, lifetime exposure to MDMA there is consistent evidence that MDMA users have structural and functional deficits. With moderate lifetime usage (less than 50 doses used and less than 100 tablets consumed), there is no such structural or functional changes. At high doses MDMA use can produce brain lesions, a form of brain damage in the serotonergic neural pathways of humans and animals. It is not clear if a typical user of MDMA develops neurotoxic brain lesions. With long-term exposure to MDMA in 20

21 humans, marked neurodegeneration in hippocampal, striatal, prefrontal, and occipital serotonergic axon terminals is found. Neurotoxic damage can persist for more than two years in serotonergic axon terminals MDMA-induced Neurotoxicity MDMA elevation in brain temperature correlates with MDMA induced neurotoxicity. Low doses of MDMA cause adverse neuroplastic changes to brain microvasculature and white matter in humans. MDMA users have also been found to have reduced gray matter density in certain brain structures. 22,23 For long term users, global reductions in gray matter volume, decreased hippocampal activity, and thinning of the parietal and orbitofrontal cortices has been found. With recreational use of Ecstasy, there is a range of moderate to large effects for SERT reduction. 24 For regular users of MDMA, impairments in several aspects of cognition include memory, learning, attention, visual processing, and sleep. The magnitude of the impairment related to lifetime MDMA use can be reversed in part with abstinence. With MDMA use there is an association with increased impulsivity and depression. Serotonin depletion can cause depression following several days of using MDMA. In certain cases, symptoms of depression persist longer. There are studies where even after quitting repeat recreational use of the drug there are increased rates of anxiety and depression. A major reason to stop using the drug is depression With a high dose of MDMA a neuro-immune response that increases the permeability of the blood brain barrier through several mechanisms is seen. This makes the brain more susceptible to environmental pathogens and toxins. MDMA in the peripheral nervous system has immunosuppressive effects and in the central nervous system a pro-inflammatory effect

22 With the serotonin depletion that is part of the post-ecstatic regeneration phase can come depressive symptoms during the days following consumption. This can also happen long after abstinence. This is a major reason to stop use of MDMA Axonal degeneration of serotonergic neurons has been found after exposure to MDMA in primates, detectable up to seven years later. The degree of neurotoxicity appears related to the maximum dose and duration of use. There is still controversy about the neurotoxic effect of MDMA in humans despite scientific evidence for such long-term effects. MDMA users had lower levels of serotonin and its metabolite in the cerebral spinal fluid. There was also lower prolactin and cortisol response to the serotonin indicating a lower sensitivity to serotonergic stimulation. This could be due to damage of the serotonergic system and decreased cortical concentration of the serotonin transporter. In long-term users, a reduced volume of gray matter plus a thinning of the parietal and orbitofrontal cortex is found. There is also decreased hippocampal activity. Concerning the human dopamine system, studies looked at a toxic influence but none was detected so the question is still controversial Neuropsychological effects due to long-term consumption of MDMA in humans has been studied. Several dimensions were found to be impaired. The impairments correlated in most cases to the amount and duration of consumption of MDMA. The impairments have been found to be reversible but only to an extent. As mentioned, they can persist for years after abstinence. 22

23 Functional Decision-making and Substance Use Functional decision-making refers to how a person functions in everyday life. It requires a multidimensional approach and analysis. Executive functions such as impulse control and action planning are part of the analysis. In addition to decision-making, investigated domains in the studies included intelligence, depressive mood, and impulsivity plus executive function and memory skills ,33 The striatum and orbitofrontal cortex are important neural structures known to be involved in decision-making. These areas also are associated with the reward system, and play a role in addictive disorders. A lesion, for example, of the orbitofrontal cortex leads to greater impulsivity. Damage to serotonergic and dopaminergic neurons that project into the orbitofrontal cortex due to lesions or chronic drug use impair functional decision-making behavior. Dysfunctional decision-making and increased impulsivity are considered predictors and consequences of a substance use disorder. 33 The assumption is that different conceptual aspects of motivation play a role in decision-making. They are also related to different neural systems. This can apply generally and specifically to substance related disorders. 34 Decision-making Paradigms and Testing Regarding decision-making, research studies have used multiple paradigms or approaches to evaluate outcomes the Risky Choice Task. In each trial, the participant may choose between a control and experimental gamble. In the outcome phase a green up or red down arrow is displayed with the amount of credit point to tell the participant if they won or lost the 23

24 gamble. This is followed by feedback on how many credit points the participant gathered overall, indicating level of risk-taking involved. This test has been useful when evaluating adolescents and risky behavior. Other studies used the Iowa Gambling Task. This is a computerized measure of decision-making. The conditions are high versus low risk with rewards and losses. Another tool is the Bets 16 task that measures risk-taking. Two studies also applied imaging data and cognitive tests. Magnetic resonance imaging used a diffusion tensor image (DTI) and provided structural information about the brain. Functional MRI measured metabolic activity of various brain areas during decision-making tasks. Allele length was identified for the promoter of the serotonin transporter gene to identify potential effects of this genotype on behavior. Results from imaging or genetic studies provide further information about the relationship of the results and brain structure and functional alterations or genetic predisposition. In addition to decision-making, the studies investigated intelligence, depressive mood, and impulsivity plus executive function and memory skills. With MDMA users, the tasks concerning decision-making showed a variety of results. One group found lower overall results for points or monetary gain and a tendency for high-risk gambling in the MDMA group. Four studies showed the MDMA group with a tendency toward riskier gambling option. Statistically significant differences with the control group were not concluded. One group had no group specific differences in the decisionmaking test. Another group found specific deficits and higher risk tolerance in the control groups. Overall, the results were inconsistent. This also applied to factors such as impulsivity. 24

25 MDMA and Decision-making Using Imaging Methods A major question is how the use of MDMA could influence decision-making in humans. Clinical trials addressing the influence of MDMA on human decisionmaking has reported whether subjects, investigated in a drug free-interval and compared to one or more control groups, an impact on human cognition. Such trials have occurred as early as Cognitive parameters and additional use of imaging methods have been included in studies looking at the acute effects of MDMA Using imaging, a study found a reduced, longitudinal diffusivity in the anterior corpus callosum of MDMA users. This correlated with decisionmaking related measures such as scores on an impulsiveness scale, risky gambling, and lower overall gains. The researchers considered this to mean possible MDMA associated axonal damage. When performing a decision-making task and undergoing a functional MRI, the result is increased signaling of the MDMA heavy users in the parietal cortex. This relates to anticipating rewards. There is a reduced orbitofrontal signal during reward feedback and outcome. This means an increased reward expectation and diminished reward sensitivity in MDMA users. MDMA and Functional Decision-Making Evaluation of a person s executive functioning and basic ability to perform tasks has been a promising approach for studying certain drug and alcohol addiction and other psychiatric disorders but similar patient evaluations have not been studied sufficiently with MDMA. What is known is more general. The serotonergic system is particularly affected by MDMA and plays a role in 25

26 negative consequences of decision-making; it also plays a role in behavioral reinforcements such as social rewards According to research, alterations in areas of the brain that process motivation, reward cues, and behavior are possible due to the long-term use of stimulants such as MDMA. This includes amphetamines and amphetamine-type stimulants. What also changes are regions of the brain that affect impulsivity and decision-making in response to these drugs. In humans and rats, choices involving a greater loss of rewards is associated with lower serotonergic activity. Subjects with serotonin depletion can prefer short-term and small rewards compared to long-term high rewards. With acute consumption of MDMA, researchers observed different effects on decision-making. Some measured impairments in attention, memory, and increased impulsivity but no impairment in decision-making. Other researchers showed increased error rates plus less flexibility in a predictive decision test. The potential long-term effects of MDMA on decision-making are important. This is because dysfunctional choices are a risk factor for initiation and maintenance of drug use. While the addictive potential of MDMA is small, it is generally believed that it is a substance that alters human decisionmaking and could facilitate development of other addictions. Decision-Making in Chronic Ecstasy Use With long-term use of MDMA come different cognitive impairments, as previously mentioned It should be emphasized how important it is to be aware of how decision-making can potentially become impaired due to MDMA use, as MDMA use increases impulsivity and altered decision-making associated with addictive disorders. When assessing the long-term effects of MDMA, a closer look at the literature on the possible effects of chronic MDMA 26

27 use on decision-making is helpful, which includes controlled trials that use specific tasks related to decision-making. The clinical trials involve subjects that meet specific criteria and this research focuses on findings related to decision-making disturbances with use of MDMA. More studies have reported increased risky decisions than those that did not. Concerning MDMA specific influences on decision-making, studies in general did show trends of increased impulsivity. In a group of studies, there was the suggestion of increased impulsivity and dysfunctional decision-making that was more strongly associated with the general extent of drug use rather than with the specific use of MDMA. The studies mainly concentrated on the behavioral and neurocognitive effects of MDMA and polydrug use. It remains difficult to determine whether observed neurocognitive effects are specifically attributable to single substances and to what extent distinctive personality traits and behavioral problems among drug users are predictors or consequences of drug use. A minority of studies reported a statistically significant MDMA-specific alteration of higher order decision-making than those that did not find MDMA-specific influences. A significant proportion of studies in the literature reported associations between risky decision-making and impulsivity and the extent of drug use in general. The current state of research does not conclude that long-term use of MDMA generally affects decision-making behavior. While more investigation is needed, risky decision-making has been observed but needs to be confirmed. Effects of MDMA on Memory 27

28 The current state of research regarding MDMA use and neurocognitive functions as presented in the introduction suggests specific alterations of the serotonergic system caused by MDMA or Ecstasy use, while the other transmitter systems seem to be less affected Additionally, mild to moderate impairments of memory functions, attention, and learning as well as higher levels of impulsivity and depression were found to be associated with the use of MDMA. As mentioned above, allele length was identified for the promoter of the serotonin transporter gene to identify potential effects of this genotype on behavior. Studies have found that subjects who were homozygous for the low count of allele-copies had a substantially better performance in a test on working memory. MDMA users of the genotype underperformed on the test. This suggests that carriers of specific alleles associated with serotonergic neurotransmission relative to other alleles are vulnerable to the effects of Ecstasy on cognitive function. Study Limitations on MDMA s Impact on Cognition Studies on MDMA s cognitive impact show strengths and weaknesses. A weakness in all studies is the way participants were recruited. This was usually through a newspaper ad or direct contact. This could lead to potential selection bias. Representation from groups was limited in some studies. One study had gender balance. Another study included only men. Another used a population with inpatients from a substance use residential treatment facility. In two studies only students participated. In all the studies, adults in the age range of 20 to 30 were over represented. This bias could also reflect the typical age of MDMA users. The highest prevalence of MDMA consumption is with young adults

29 It should also be noted that a psychiatric diagnosis either was not included or did not exclude other addictive disorders than MDMA in the substance use groups. The disclosure on abstinence and drug use that were submitted by subjects were verified by a drug test in some but not all studies. Only a small number of research used hair analysis. The MDMA groups in most cases showed a higher overall consumption of other drugs than the control group. Various difficulties involved in the method and interpretation of studies on MDMA associated cognitive functioning in humans has been seen. Studies show that most MDMA users also use other psychotropic substances. This could be a biasing factor. To control for it some studies use one or more substance groups with no use of MDMA. It is a challenge to get a clear distinction between groups. Potential interaction of MDMA with other drugs is disregarded. Another issue is that the purity of street Ecstasy and other forms of MDMA and the use of MDMA among young adults at clubs complicate a clear understanding of the findings presented. The representative sample can be called into question. Compliance from participants is another general challenge. Concerning identifying substance use and abstinence through user self-disclosure means information could be distorted by the subject. This could be intentional or unintentional. This could possibly be minimized by drug screenings. A combination of urine and blood tests plus hair analysis would be desirable for validity. This would exclude post-acute influence of substances and when abstinence is not given. 29

30 Causality is another significant consideration in this field of research. The question pertains to whether a measured cognitive change follows substance use or precedes it. This can hardly be clarified by a cross sectional study. Prospective studies are needed to answer this concern, and have been done only to a small degree. One study that was large and longitudinal was conducted on the long-term effects of MDMA in the Netherlands. This study found a negative effect on verbal memory due to chronic MDMA use. Other cognitive dimensions stayed the same. Another study showed persistently slower visual associative learning. This was with chronic MDMA users in two follow up studies. Another group observed a higher probability of starting MDMA use among people who previously underperformed in a decisionmaking task. One group presented the first randomized and double blinded placebo-controlled study using pure MDMA in a psychotherapeutic setting with an interest in the use of MDMA for psychiatric treatment. It has been reported that the benefits of MDMA facilitated treatment in patients with post-traumatic stress disorder with no relevant cognitive side effects Combining MDMA With Other Substances Current usage of MDMA includes combining it with caffeine, alcohol and prescription or illicit drugs. Young adults who use Ecstasy and other drugs have reported using alcohol and cigarettes/nicotine combined with the drug. Others have reported marijuana, meth, hallucinogen/lsd, powder cocaine use along with MDMA. Deaths have involved drug cocktails such as MDMA and cocaine. Another lethal combination is MDMA with cocaine and Viagra. Clinicians should be alerted to this trend when diagnosing and treating a drug user MDMA Drug Interactions 30