<<

MDMA - Ecstasy: A Current Overview

Introduction

MDMA (3,4-methylenedioxy-) is a synthetic that alters a person’s and mood. A person using MDMA will have an altered awareness of surrounding objects and conditions. The is similar chemically to and . It can produce feelings of increased pleasure, energy, emotional warmth, and a distorted perception of time. Although MDMA has psychedelic effects that cause a of and increased energy, over the long-term the drug may lead to and . MDMA is often combined with other , 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 1912. 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 of . Shulgin was a former chemist with Dow Chemical Company and he is known

1 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 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 to increase patients’ insight into their . Eventually, MDMA became the drug of choice within the culture, house parties, clubs, and festivals, and goes by the popular name Ecstasy or Molly.1-6

After MDMA was introduced into , 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 and all-night dance parties known as , MDMA spread through networks including young, urban professionals (yuppies), users of psychedelics, psychiatrists, and psychotherapists. A 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 1970. Other examples of Schedule I drugs include , LSD, , and marijuana ().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 exists with Schedule I drugs and there is no legitimate medical application.8-10 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 1.70 2.80 4.90 Past year 1.00 1.80 2.70 Past month 0.30 0.50 0.90

Table 2 MDMA % Use: Ages 12 and older, 12 - 17, 18 - 25, and 26 or older (2015) Time Period 12 and older 12 to 17 18 to 25 26 and older Lifetime 6.80 1.40 13.10 6.5 Past year 1.00 0.80 4.10 0.50 Past month 0.20 0.10 0.90 0.10

MDMA shares toxicities with . 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 2013.4 In other countries around the same time, such as Germany, the highest percent of MDMA reached increased for people aged 25 to 29. In , 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 50-150 mg of the drug. The lower prices can be $10 to

4 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

$25 per tablet. Production of Ecstasy is mainly in Canada but it is also imported from China.

High Risk Drugs And

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/, , and PCP not detectable with a routine . PCP has been reported to be relatively obscure and used with lower frequency than numerous other street drugs, and use is relatively infrequent compared now with methamphetamine and amphetamine derivatives, such as MDMA (Ecstasy), MDPV (), 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, , marijuana, opioids, and PCP should be expected on drug screen test, unless otherwise 5 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 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 . 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 and medical consequences of long-term use of alcohol, amphetamines/stimulants, cocaine, opioids, and - 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 , alcohol is the most commonly used 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

The exact mechanisms by which ethanol alters 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 and their receptors: a major inhibitory 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 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 . 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 , hypoglycemia, , respiratory depression, and death. Long-term use is associated with 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 and , neurotransmitters that stimulate the peripheral α receptors and β receptors. Acute intoxication causes , diaphoresis, , , and . More serious effects such as dysrhythmias, , , myocardial ischemia, , , , , and are possible, as well.

Long-term effects of amphetamine and stimulant use include aortic and mitral valve regurgitation, cardiomyopathy vasculitis, cardiomyopathy, , and permanent damage to the and neurons. Amphetamines and stimulants can be taken as tablets, injected, smoked, or insufflated (snorted). Probably the most commonly abused amphetamine is methamphetamine.

8 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Methamphetamine is commercially produced, and it has labeled uses for the treatment of patients who have exogenous or attention deficit disorder with hyperactivity disorder. Methamphetamine is -soluble and crosses the -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 . These actions produce a hyper-adrenergic state, and the common signs and symptoms of 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 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 , aortic dissection, coronary artery vasospasm, dystonic reactions, intestinal infarction, myocardial infarction, pneumothorax, pulmonary 9 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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, , and schizophrenic syndromes.

Cocaine can be ingested, applied to mucous membranes, insufflated, smoked, or injected. As mentioned previously, there are many well- documented 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 that are derived directly from the poppy. In common practice the term is the one used for all drugs that have similar structure and clinical effects including, but not limited to, , , , , heroin, , , , , 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. stimulation causes the cells

10 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 anti- tussive effect. , drowsiness, , and vomiting are common 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, , and respiratory arrest are possible. Propoxyphene intoxication can cause myocardium sodium channel blockade and . Long-term effects of opioid use include heart valve , 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 . 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 () or to induce sleep (hypnotics). There are many drugs that are classified as sedatives or hypnotics, but the sedative- hypnotics that are most often involved in disorders are the and the .

11 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 , also known as roofies. Midazolam is an injectable 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 non- benzodiazepine 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 pre- operative sedation or for the treatment of disorders. The short-acting butalbital is available in prescription , compounded in various combinations with acetaminophen, aspirin, , and codeine. These drugs are almost always used and used in tablet or from, but injectable preparations are available.

Table 1: Benzodiazepines

• Alprazolam (Xanax®) • Chlordiazepoxide (Librium®) • Clonazepam (Klonopin®) • (Valium®) • Flunitrazepam (Rohypnol®) • Flurazepam (Dalmane®) • Lorazepam (Ativan®) • Midazolam (Versed®) • Oxazepam (Serax®) • Temazepam (Restoril®) • Triazolam (Halcion®)

12 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Table 2: Non-Benzodiazepine Hypnotics

(Lunesta®) • (Sonata®) • (Ambien®)

Table 3: Barbiturates

1. (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- 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com depression. The barbiturates, compared to the benzodiazepines and the non- benzodiazepine 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 sedative- hypnotic 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 and . These drugs produce a euphoria and psychostimulant effect. Some SNDRAs were once used as pharmaceutical drugs, specifically as . 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 substrate. It enters monoamine neurons via neuronal membrane transport ; and acts as a monoamine transporter substrate and produces competitive 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 and attention process that is long- lasting. 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 drug use.18-21

When imaging studies were conducted on MDMA users, changes in brain activity were seen. This involved the regions relating to cognition, , 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 . 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.22-27

16 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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.10-12 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 (the grinding and clenching of teeth). Other effects are increased , , increased perspiration or sweating, increased heart rate and blood pressure, loss of appetite, nausea and vomiting, , , 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, , depression, memory impairment, anxiety, paranoia, and restlessness.18-21

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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 . Subjective experiences of those who use MDMA depend on the dose, the situation, and the mental and physical state of the user.18-21,33

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).17-19

The effects of chronic MDMA use have been analyzed in various neurocognitive domains. This includes working memory, , semantic memory, visual stimulation, motor function and . 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 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.18-21

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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com humans, marked in hippocampal, striatal, prefrontal, and occipital serotonergic axon terminals is found. Neurotoxic damage can persist for more than two years in serotonergic axon terminals.18-21 MDMA-induced

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.23-25

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.26-28

21 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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.30-33

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.30-33

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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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. 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.24-26,33

The and orbitofrontal cortex are important neural structures known to be involved in decision-making. These areas also are associated with the , 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.30-35 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 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 decision- making 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 decision- making 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 2016. Cognitive parameters and additional use of imaging methods have been included in studies looking at the acute effects of MDMA.30-35

Using imaging, a study found a reduced, longitudinal diffusivity in the anterior corpus callosum of MDMA users. This correlated with decision- making 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com negative consequences of decision-making; it also plays a role in behavioral such as social rewards.30-35 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 decision- making and could facilitate development of other .

Decision-Making in Chronic Ecstasy Use

With long-term use of MDMA come different cognitive impairments, as previously mentioned.30-35 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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.40-44 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 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.40-43

28 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 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 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

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 . 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 decision- making 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.40-44

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/ 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.36-39

MDMA Drug Interactions

30 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

MDMA can also interact with prescription drugs that inhibit certain enzymes like Norvir. Norvir is an antiviral that prevents human immunodeficiency virus (HIV) from multiplying within the body. Use of MDMA in high dosages with another serotonergic drug can lead to a life- threatening condition called serotonin syndrome. Severe overdose can result in death. This was reported by people who took MDMA with a inhibitor such as Nardil, Parnate, or Manerix. Some people mix MDMA with (sold under the brand name Ketalar), which is a medication used in anesthesia or for chronic pain and sedation.36-39

MDMA and Alcohol

Mixing MDMA with alcohol and other drugs is clearly dangerous. It is commonly known that mixing MDMA with alcohol will lead to greater strain on the kidneys. Heavy drinking can lead to dehydration and a worse come down from the drug. Overheating is more likely in such cases.

Most importantly, clinicians should be aware that alcohol is involved in most MDMA-related deaths. Mixing MDMA with an amphetamine can prolong the MDMA state. Too much amphetamine places a great strain on the heart and kidneys. Mixing can also lead to anxiety and paranoia. Some people also mix antidepressants with MDMA.

MDMA and Cocaine

Cocaine has already been described as a profound nervous system stimulant that increases energy, , and produces euphoria. Ecstasy, or MDMA, mimics the effects of both hallucinogens and stimulants and enhances a sense of emotional closeness, empathy, increased energy, sensory perception, and euphoria. Mixing the two can severely worsen these effects. 31 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Simultaneous use of cocaine and Ecstasy is common in the party or club culture, especially among teenagers and young adults. Both drugs are life- threatening when used alone and the risk is compounded when the two are used together. Among the most dangerous side effects of cocaine use are heart attack, sudden death even with use for the first time, cardiac arrhythmias, erratic behavior, paranoia, , , seizures, and coma. MDMA in the form of Ecstasy when combined with certain activity such as dancing can be life-threatening. The adverse effect of MDMA include sweating, nausea, teeth clenching, high blood pressure, panic attacks, seizures, loss of consciousness, heart failure, dehydration, and hyperthermia.36-39

While cocaine is not the drug most commonly used in combination with MDMA in the form of Ecstasy, one study reports 34 percent of participants used them together. Another study found that Ecstasy users were more likely to use cocaine as compared to a marijuana user.

Mortality with Ecstasy and Cocaine Use

A seven-year long study showed that the risk of death is four times greater in a 19 to 49-year-old who uses cocaine regularly, especially for a male. Research compared 437 sudden cardiovascular deaths to 126 deaths from other causes. This study excluded acute intoxication and disease. The suggestion was that the effect of cocaine on the cardiovascular system can explain the increase in risk of sudden death. The effects include high blood pressure and contractility of the left ventricle, increased heart rate, potential for , diminished coronary artery flow, increased clot formation, and increased risk of sudden death. MDMA is especially dangerous because the drug is highly variable and often contaminated. Other substances can 32 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com include cocaine, amphetamines, caffeine, and or PCP/angel dust. This increases the risk for adverse effects.36-39

MDMA, Cocaine and Alcohol: A Lethal Combination

A majority of MDMA users (in the form of Ecstasy) combine Ecstasy with alcohol and or cocaine, a trend that has been studied. Research indicates that concurrent use of cocaine and MDMA could amplify the long-term side effects. Further, alcohol in combination with cocaine creates a lethal combination called cocaethylene in the liver. This is a metabolite that increases the high risk of heart attack, arrhythmias, strokes, and cardiomyopathy (enlargement and weakening of the heart). Clinicians need to educate patients that the use of cocaine and alcohol together makes patients more prone to violent and behavior among other aforementioned impairments in cognitive function that can be significant.36-39

MDMA and Caffeine

Millions of people consume caffeine daily with an intake of 50 to 150 mg. Fatalities related to caffeine overdose are rare. They are associated with oral doses between 3 and 20 grams. Consumption of caffeine that is habitual is typically considered safe. Reviews of toxicity of caffeine and presentations of excess caffeine and overdose includes agitation, nervousness, anxiety, and insomnia. Caffeine has been found in as many as twenty percent of Ecstasy tablets analyzed. Caffeinated energy drinks have gained popularity in night club and rave environments where Ecstasy is consumed. The use of caffeine with a recreational psychostimulant drug such as MDMA can result in an acute adverse reaction. Caffeine also has an impact on the discriminative, stimulatory, and reinforcing effects of a psychostimulant drug. Caffeine increases the toxicity of psychostimulants because caffeine is an antagonist 33 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com of adenosine receptors. Caffeine also inhibits the enzyme phosphodiesterase (PDE), which is an important regulator of in the brain and other tissues.36-39 Drug-induced toxicity results due to MDMA-related enhancement of dopamine release. This results in changes in body temperature, lowering , and cardiotoxicity. Symptoms include high core body temperature, tachycardia, and increased mortality. Caffeine together with MDMA also enhances longer term serotonergic neurotoxicity. The effect of caffeine-related drug interactions and the adverse reaction of caffeine and

MDMA has been studied in animals. Caffeine taken together with MDMA enhances tremendously the acute toxicity of MDMA in rats. One of the first reports signaling this potential involved experiments with rats. Rats were administered caffeine with either amphetamine or cocaine. This resulted in seizures and mortality compared to administration of cocaine or dextroamphetamine alone. Further data continued to reveal that caffeine increases acute toxicity of the MDMA and MDA in a rat, as shown with seizures, hyperthermia, tachycardia, and lethality. These symptoms are not observed with equivalent doses of MDA or MDMA alone.36-39

An understanding of the basic mechanisms of how MDMA selectively affects brain chemistry has become an important area of research in order to better design intervention strategies to manage severe reactions and drug-related toxicity resulting from caffeine use with MDMA. It appears that higher doses of caffeine over 100 mg are needed to promote the toxicity of amphetamine and cocaine. Lower doses of caffeine at 5-20 mg are enough to promote toxicity and lethality when combined with MDMA or MDA. Notably, the interaction between caffeine and amphetamine or cocaine has not been reported as much as the profound interaction with caffeine and MDMA.36-39

34 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Such combination may influence the toxicity of MDMA and, consequently, warrant investigation of the potential for adverse interactive effects.

MDMA and Cannabis/Sedatives

Using cannabis with MDMA, according to some clinicians, can mellow the rush and help with the comedown. MDMA becomes more psychedelic with cannabis use. Some people mix MDMA and heroin, and others use sedatives.

MDMA Toxicity Symptoms

Symptoms of MDMA toxicity and overdose vary widely. This is because of the involvement of multiple organ systems. Some of the more overt symptoms are shown in the Table below. The number of instances of fatal MDMA intoxication is reportedly low compared to its usage rate. In most fatalities, MDMA was not the only drug involved. The toxicity of MDMA in overdose can be exacerbated by other substances. It is frequently cut or mixed to increase volume. Acute toxicity is primarily caused by serotonin syndrome and sympathomimetic effects.23,36-39

Emergency Room Encounters

It has been noted that emergency room visits related to use of the MDMA doubled in 2004. Other reports stated that Ecstasy-related emergency room visits more than doubled from 2005 to 2011. MDMA became increasingly popular among young people during that period. Over the last decade, Ecstasy use among young people had increased according to hospital records. This was between 2005 and 2011 for MDMA derivatives like Molly, rising 128 percent among patients under the age of 21. Even with well-

35 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com publicized hospitalizations and deaths, these findings show an alarming trend that has persisted.10-12

Symptoms of MDMA Overdose Minor/Moderate Severe Overdose Overdose

Cardiovascular Disseminated intravascular (DIC) Intracranial hemorrhage Severe hypertension or hypotension Hypotensive bleeding

Central nervous system Abnormally fast reflexes Cognitive and memory Agitation impairment (potentially to Mental confusion the point of retrograde or Paranoia anterograde amnesia) Coma Convulsions Hallucinations Loss of consciousness Serotonin syndrome

Musculoskeletal Muscle rigidity Rapid muscle breakdown

Urinary Acute injury

Respiratory Acute respiratory distress syndrome

Other Cerebral edema Hepatitis Elevation of body temp Hyponatremia

The drug’s popularity persists because of its stimulant and hallucinogenic effect. The downside is that the drug can cause confusion, anxiety, and other psychiatric discomfort. MDMA use can also lead to high blood pressure, heart failure, , and hyperthermia.

36 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

MDMA Substance Use Disorder Classifications

Research has indicated a significant percentage of those who use an amphetamine like stimulant may fall into the category of having a substance use and addiction disorder.10-13 Individuals that develop a substance use disorder are more likely to combine drugs with others known for a similar effect. For example, combining MDMA with cocaine becomes more likely for someone who uses MDMA, or the reverse. A study compared thirty people with used stimulants, looking at siblings and healthy controls. The report showed that siblings who had substance use and addiction problems had less impulse control. They also had a higher tendency to seek sensory extremes. This contrasts with a sibling who had no stimulant use disorder.

International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, (ICD-10) is used to code substance use disorders. Clinicians should be familiar with the ICD-10-CM Code F16 related to hallucinogen-related disorders. It is a non-billable code. To code a diagnosis of this type, one of the three child codes of F16 should be used that describes the diagnosis 'hallucinogen related disorders' in more detail. The ICD-10 codes for hallucinogenic related disorders are 1) F16.1 Hallucinogen abuse, 2) F16.2 Hallucinogen dependence, and 3) F16.9 Hallucinogen use, unspecified.14

The ICD code F16 is used to code with substance dependence also known as drug dependence. This is an adaptive state that develops from repeated drug administration. It also results in withdrawal

37 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com upon cessation of drug use. It should also be noted that the ICD coding system specifies a substance use disorder with descriptors no longer accepted by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) where the former terms “dependence” and “abuse” have been removed and replaced with the term “addiction.” While some clinicians continue to diagnose substance use based on the ICD coding system, for the purposes of discussion here the DSM-5 terminology of substance use and addiction will be used when attempting to describe impulse control, mental health conditions and co-occurring substance use included within DSM-5 diagnostic categories.15,45

In the ICD-10 coding system, a drug addiction is a distinct concept from substance dependence. Drug addiction is defined as compulsive drug use that is out of control despite negative consequences. An addictive drug is both reinforcing and rewarding. The ICD-10-CM Diagnosis Codes for Mental, Behavioral and Neurodevelopmental disorders F01-F99 and Mental and behavioral disorders due to psychoactive substance use F10-F19 - Hallucinogen related disorders F16 is shown below that includes Ecstasy, PCP, and phencyclidine.14,15

• F16 Hallucinogen related disorders • F16.1 Hallucinogen abuse • F16.10 is a specific ICD-10-CM diagnosis code F16.10 …… uncomplicated • F16.12 Hallucinogen abuse with intoxication • F16.120 is a specific ICD-10-CM diagnosis code F16.120 …… uncomplicated • F16.121 is a specific ICD-10-CM diagnosis code F16.121 …… with • F16.122 is a specific ICD-10-CM diagnosis code F16.122 …… with perceptual disturbance

38 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• F16.129 is a specific ICD-10-CM diagnosis code F16.129 …… unspecified • F16.14 is a specific ICD-10-CM diagnosis code F16.14 …… with hallucinogen-induced • F16.15 Hallucinogen abuse with hallucinogen-induced psychotic disorder • F16.150 is a specific ICD-10-CM diagnosis code F16.150 …… with • F16.151 is a specific ICD-10-CM diagnosis code F16.151 …… with hallucinations • F16.159 is a specific ICD-10-CM diagnosis code F16.159 …… unspecified • F16.18 Hallucinogen abuse with other hallucinogen-induced disorder • F16.180 is a specific ICD-10-CM diagnosis code F16.180 Hallucinogen abuse with hallucinogen-induced • F16.183 is a specific ICD-10-CM diagnosis code F16.183 Hallucinogen abuse with hallucinogen persisting perception disorder (flashbacks) • F16.188 is a specific ICD-10-CM diagnosis code F16.188 Hallucinogen abuse with other hallucinogen-induced disorder • F16.19 is a specific ICD-10-CM diagnosis code F16.19 …… with unspecified hallucinogen-induced disorder • F16.2 Hallucinogen dependence • F16.20 is a specific ICD-10-CM diagnosis code F16.20 …… uncomplicated • F16.21 is a specific ICD-10-CM diagnosis code F16.21 …… in remission • F16.22 Hallucinogen dependence with intoxication • F16.220 is a specific ICD-10-CM diagnosis code F16.220 …… uncomplicated • F16.221 is a specific ICD-10-CM diagnosis code F16.221 …… with delirium • F16.229 is a specific ICD-10-CM diagnosis code F16.229 …… unspecified • F16.24 is a specific ICD-10-CM diagnosis code F16.24 …… with hallucinogen-induced mood disorder

39 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• F16.25 Hallucinogen dependence with hallucinogen-induced psychotic disorder • F16.250 is a specific ICD-10-CM diagnosis code F16.250 …… with delusions • F16.251 is a specific ICD-10-CM diagnosis code F16.251 …… with hallucinations • F16.259 is a specific ICD-10-CM diagnosis code F16.259 …… unspecified • F16.28 Hallucinogen dependence with other hallucinogen-induced disorder • F16.280 is a specific ICD-10-CM diagnosis code F16.280 Hallucinogen dependence with hallucinogen-induced anxiety disorder • F16.283 is a specific ICD-10-CM diagnosis code F16.283 Hallucinogen dependence with hallucinogen persisting perception disorder (flashbacks) • F16.288 is a specific ICD-10-CM diagnosis code F16.288 Hallucinogen dependence with other hallucinogen-induced disorder • F16.29 is a specific ICD-10-CM diagnosis code F16.29 …… with unspecified hallucinogen-induced disorder • F16.9 Hallucinogen use, unspecified • F16.90 is a specific ICD-10-CM diagnosis code F16.90 …… uncomplicated • F16.92 Hallucinogen use, unspecified with intoxication • F16.920 is a specific ICD-10-CM diagnosis code F16.920 …… uncomplicated • F16.921 is a specific ICD-10-CM diagnosis code F16.921 …… with delirium • F16.929 is a specific ICD-10-CM diagnosis code F16.929 …… unspecified • F16.94 is a specific ICD-10-CM diagnosis code F16.94 …… with hallucinogen-induced mood disorder • F16.95 Hallucinogen use, unspecified with hallucinogen-induced psychotic disorder

40 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• F16.950 is a specific ICD-10-CM diagnosis code F16.950 …… with delusions • F16.951 is a specific ICD-10-CM diagnosis code F16.951 …… with hallucinations • F16.959 is a specific ICD-10-CM diagnosis code F16.959 …… unspecified • F16.98 Hallucinogen use, unspecified with other specified hallucinogen- induced disorder • F16.980 is a specific ICD-10-CM diagnosis code F16.980 Hallucinogen use, unspecified with hallucinogen-induced anxiety disorder • F16.983 is a specific ICD-10-CM diagnosis code F16.983 Hallucinogen use, unspecified with hallucinogen persisting perception disorder (flashbacks) • F16.988 is a specific ICD-10-CM diagnosis code F16.988 Hallucinogen use, unspecified with other hallucinogen-induced disorder • F16.99 is a specific ICD-10-CM diagnosis code F16.99 …… with unspecified hallucinogen-induced disorder

Steps to help clinicians select the appropriate ICD-10-CM diagnostic code related to substance use disorders and MDMA are covered here. It should be pointed out that ICD-10-CM overall does not contain more codes related to behavioral and mental disorders than found previously. The ICD-10-CM does have a section that is more detailed than previous versions.14,15

The ICD-10-CM codes became mandatory in 2015. Psychologists who treat people with a substance use disorder should indicate through their choice of codes the substance involved and the extent of the problem. With substance use codes in ICD-10-CM the format F1x.xxx must be followed. In this format, F shows that the code is from Chapter 5: Mental, Behavioral and Neurodevelopmental Disorders, of ICD-10-CM. The numeral 1 shows a

41 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com mental or behavioral disorder due to psychoactive substance use. The next digit in the F1x.xxx format shows the problematic substance. The .xxx digits further specify the nature and severity of the problem.

A downloadable version of the ICD-10-CM is provided through the Centers for Disease Control and Prevention (CDC) website. Clinicians may go to "FY 2016 release of ICD-10-CM" section, and select the ICD-10-CM PDF format. This accesses a PDF version of the document. It directs clinicians to an index of compressed files where the selection ICD10CM_FY2016_Full_PDF.ZIP can be made. This folder contains five files and the clinician should open the final file labeled 'Tabular’.16

National Center for Health Statistics

The National Center for Health Statistics (NCHS) is the Federal agency responsible for use of the International Statistical Classification of Diseases (ICD). The ICD-10 is used to code and classify mortality data from death certificates. The World Health Organization (WHO) copyrights and publishes the ICD-10. To select the appropriate ICD-10-CM diagnostic code related to substance use disorders and MDMA, the clinician should follow the steps covered below.14,15

• Identify the substance involved. • F16 is the use of hallucinogens. • F10 is for the use of alcohol. • F11 is for the use of opioids. • F12 is for the use of cannabis. • F13 is for the use of sedatives, hypnotics, . • F14 is the use of cocaine. • F15 is the use of other stimulants including caffeine.

42 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

• F17 is the use of nicotine. • F18 is the use of . • F19 is the use of other psychoactive substances and multiple drug use. • Identify the specifiers and code extension. This is an example of the specifier and code extension in ICD-10.

• Abuse .1

• Uncomplicated .10

• With intoxication .12

… uncomplicated .120 … delirium .121 … with perceptual disturbance .122 … unspecified .129 • Dependence .2

DSM-5: Definition Of A Substance Use Disorder

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lists more than 20 separate substance use disorders.48 Each of the substance use disorders are defined with specific features. This section provides a brief review of the key aspects of the DSM-5 definitions and criterion on substance use disorders, and relates that to aspects of treatment and recovery.

In general, a person with a substance use disorder exhibits: 1) a constant craving for, and preoccupation with the drug, 2 more drug use than is necessary to become intoxicated or high, 3) a decreased interest in, and motivation for, normal life activities, 4) tolerance to the drug so that there is

43 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com a need for increasingly larger doses and more frequent use, 5) neurological changes that result in craving and a need to use more, and 6) withdrawal signs and symptoms if the drug cannot be obtained.

All of these are further explained by the DSM-5 in the diagnostic criteria of a substance use disorder. These criteria are divided into five categories.46,48

Impaired Control

Impaired control is one of the hallmarks of a substance use disorder. Someone with a substance use disorder finds that over time larger amounts of the drug(s) are needed despite a desire to cut down or stop use. The life of a person with a substance use disorder slowly begins to revolve around substance use, and daily activities become focused on obtaining, using, and recovering from use. The individual’s desire for the drug or substance becomes intense and unmanageable.

Social Impairment

The second diagnostic criterion of substance use disorder is social impairment. Because of impaired control and the priority on obtaining and using the drug or substance, the substance user cannot function at home, at work, or in other areas of attachment and responsibility. The consequences of the substance use are often quite serious, such as divorce, loss of job and income, estrangement and isolation from friends and family, homelessness, and possibly encounters with law enforcement and legal issues. However, despite these consequences, some substance users cannot or will not change.

Risky Use

44 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Risky use relates to risky behavior and impulsivity, and the research correlates risk use with factors of age and history of mental illness. A person who has a substance use disorder will continue to use the drug or substance even if doing so involves significant and obvious risks to health and lifestyle. The person may do some very risky and impulsive things to obtain their preferred drug and get high.

Tolerance

Chemical dependency specialists will typically evaluate a person’s tolerance to a substance used during the phase of obtaining a patient history and assessment of symptoms. Tolerance is defined as the need for increasingly higher amounts of the drug or substance to achieve the desired effect or a decreased effect from the usual dose or amount. Tolerance is a complicated phenomenon that involves changes in the central nervous system and the degree of tolerance developed varies widely from individual to individual.

Withdrawal

Withdrawal is the final diagnostic criterion of substance use disorders. Withdrawal is defined as specific signs and symptoms that occur when someone with a substance use disorder abruptly discontinues or greatly decreases use. The seriousness of withdrawal depends on the drug or substance that has been used and the pattern and duration of use. Considering these diagnostic criteria, the picture of a substance user begins to emerge.

Drug or substance use is compulsive and causes intense craving. Acquisition and use can become the sole focus of that person’s life, and recovery from “highs” can be lengthy and debilitating. Other areas of life suffer and may be completely neglected, and the substance user may lose home ownership, 45 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com friends and family, and a job. The health risks and social and personal consequences of the use are clear, but the substance user feels compelled to continue and will frequently take ever-increasing risks to get the drug and get high. The substance user may express a desire to stop use, but the desire to continue remains intense and discontinuation becomes discouraging because of withdrawal signs and symptoms, which further reinforces the need for continued substance use.

Substance Use Disorder: Predisposition To Use

There is no single cause of a substance use disorder, and despite many years of research there are still no answers to the most pressing questions about substance use, such as why some people use and become addicted while others do not. There has been a vast amount of effort and research directed towards uncovering the root cause(s) of substance use disorders. Biological, psychological, and sociological reasons for these afflictions have all been advanced, and strong arguments can be made for each of these as major contributors to the genesis of, and continued presence of, substance use disorders.46-48

Current thinking is that there is no single cause of substance use disorders, and that substance use involves complex neuro-psychological phenomena that are behaviorally expressed within a social context. However, although there has been much research, more work needs to be done. Much of the published literature involves animal experiments or a single drug, and it is clear that the true basis for substance use disorders is not known.

Substance Use Disorders: a Multi-factorial Process

46 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

A substance use disorder is a multi-factorial process, and the nuances of how biology, psychology and sociology contribute to it have not been sorted out. However, although it is not entirely clear what causes a substance use disorder, there is very strong evidence about how a substance use disorder develops in, and affects, the neurologic system. A substance use disorder involves changes in several areas of the brain and in neurotransmitters, but perhaps the most important part of the brain that is affected by substance use is the reward system. Drugs stimulate areas of the brain that are involved with very pleasurable survival behaviors such as eating, sex, and bonding. When these areas of the brain (there are several, but the is considered to be the most important) are stimulated, they receive a surge in the neurotransmitter dopamine. Dopamine is a neurotransmitter that is found in the areas of the brain that control emotion, motivation, and pleasure, and increases in dopamine levels of the central nervous system have many effects and one of them is the experience of pleasure.

Cocaine, heroin, etc., stimulate a direct release of dopamine or prevent its breakdown, and the more dopamine the higher the level of pleasure. Alcohol, and the drugs that are involved in substance use disorders, cause a higher brain dopamine level than do natural rewards such as food or sex.

This surge in dopamine and the intensity of the experience - the high - is especially strong when it is caused by drugs used and the information about that experience gets stored and remembered: the drug is associated with pleasure. However, with succeeding exposures to these drugs, the dopamine surge become less and less, and the dopamine levels go lower and lower below normal baseline as less is produced. There is a reduction in dopamine receptors as well. The result is that the person who is chemically dependent

47 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com gets less of a “high” each time he/she use the drug and he/she feels less happy when they are not intoxicated, which leads to more drug seeking, and a vicious cycle because the chemically dependent person has now developed a tolerance.

Individuals with an addiction disorder have a term that is called “chasing the dragon.” It means that there is no high like the first high, and is proving that to be correct. There is also evidence that the faster the increases in dopamine concentration in the brain (which occurs with early, heavy drug use and with certain drugs such as cocaine) the stronger the reinforcing effect of the drug. Even worse, long-term use of addictive drugs produces long-lasting changes in brain structure that make the person who has a substance use disorder susceptible to months and years after successful rehabilitation and abstinence; a phenomenon that partially explains the high relapse rate in people who have had a substance use disorder and they are chemically dependent. Also, these changes in brain structure make the brain less able to react to the “weaker” pleasure stimuli such as food, sex, bonding, etc.

However, it has been shown that increases in brain dopamine concentrations caused by drugs happen to people who become addicted and to people who do not, so the short-term increase in dopamine cannot explain the development of chemical dependency. It may be that there is a difference in the dopamine circuits between those who are chemically dependent and those who are not. The chemically dependent person may have a particularly “weak” circuit that doesn’t respond to normal pleasurable activities so he/she needs strong levels of stimulation to feel good, and there is supporting evidence for this idea in the literature.

48 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

It is also possible that people who develop a substance use disorder have a biological susceptibility to drugs of use. Their brains react to drugs by decreasing the numbers of dopamine receptors and decreasing the amount of dopamine released, thus inhibiting their ability to feel pleasure. This may not happen to people who do not develop a substance use disorder. Treatment Approaches And Withdrawal

Treatment for substance use disorders is a process as complex as the disorders themselves. There are many treatment approaches, some which have strong supporting evidence in the medical literature and some that do not. It does seem clear though that early interventions are more likely to be successful. If someone has had a substance use disorder for a relatively brief period of time the chances for him/her successfully discontinuing use are much greater. However, regardless of the specifics of any approach to treating substance use disorders the process must involve the following: 1) stopping the use of alcohol and or the drug, 2) if possible, administer the patient an equivalent drug that has a more limited potential for dependency and tolerance, 3) manage the physical signs and symptoms of withdrawal, and 4) provide psychiatric and social support. Treatment for substance use must be a fluid process and be able to change over time. The patient at times will have a need for medical support, rehabilitation, and continuing care, and there is a myriad of personal, social, legal, and medical issues to address. Varied approaches to substance use withdrawal are reviewed here, which can pose a challenging dilemma for clinicians in the setting of multiple or poly-substance use and addiction.12,45-49

Withdrawal Defined

Discontinuation of alcohol or one of the drugs discussed in this course will cause withdrawal. Withdrawal is a group of characteristic signs and

49 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com symptoms of varying severity, which occur after cessation or reduction of use of a psychoactive substance. Withdrawal happens when someone has taken the psychoactive substance in high doses for a prolonged period of time.

The intensity and duration of withdrawal depends on many factors. For some people and for certain drugs the withdrawal process is quite uncomfortable, but it is self-limiting and poses no serious risk. But for certain individuals and with some drugs, the withdrawal process can be dangerous.

Alcohol Withdrawal

The pathophysiology of alcohol withdrawal is not completely understood, but the primary mechanism is thought to be adaptation and insensitivity of the CNS to GABA and NDMA. In response to chronic alcohol ingestion and its effects on GABA and NDMA, the body decreases the number, sensitivity, and function of the GABA receptors and increases the number, sensitivity, and function of NDMA receptors. When someone who chronically uses alcohol stops drinking, the stimulation and inhibition respectively of the GABA and NDMA receptors is removed and the patient experiences an intense excitatory state which explains, in part, the signs and symptoms of alcohol withdrawal syndrome.

Alcohol withdrawal syndrome usually starts within six hours or so after cessation of drinking, but the onset may be delayed for several days. It is possible for withdrawal to occur even if the patient still has a relatively high alcohol level. The signs and symptoms of alcohol withdrawal syndrome are primarily cardiac, neurologic, and gastrointestinal and can be mild to severe. Commonly noted signs and symptoms include agitation, anxiety, depression, elevated blood pressure and heart rate, , insomnia, nausea, and 50 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com tremors. Patients may present with a relatively mild to moderate clinical picture. However, there are three serious complications of alcohol withdrawal syndrome that are possible: 1) withdrawal seizures; 2) alcoholic hallucinations; and, 3) .

Withdrawal seizures affect approximately 10% of all patients with an alcohol withdrawal syndrome. They typically occur within 12-24 hour after the last drink is consumed; they are usually single seizures or several seizures occurring within a short period of time, and they are self-limiting.

Alcoholic hallucinations (sometimes called ) are usually visual, but auditory and tactile hallucinations are possible. Alcoholic hallucinations are self-limiting and usually resolve within 24-48 hours. It is important to note that alcoholic hallucinations are a separate phenomenon from delirium tremens.

Delirium tremens, typically called the DTs, is a specific alcohol withdrawal syndrome complication. It affects approximately 5% of all patients who are going through alcohol withdrawal syndrome. The DTs are more likely to occur if the patient 1) has had DTs before, 2) has been a long-time alcohol abuser, 3) is greater than age 30, 4) is experiencing alcohol withdrawal and has a high blood alcohol level, 5) has a concurrent illness, and 6) the onset of alcohol withdrawal is delayed. Delirium tremens produces a clinical picture essentially identical to mild to moderate alcohol withdrawal syndrome, but the intensity of the signs and symptoms is much more intense.

Patients who have DTs have severe agitation, confusion and disorientation, diaphoresis, fluid and electrolyte losses, hallucinations, fever, hypertension, and tachycardia. Delirium tremens has a mortality rate of approximately

51 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

5%. Patients who succumb are those who are elderly and/or have significant comorbidities.

Factors that have been correlated with an increased risk of developing complicated alcohol withdrawal include: • The use of alcohol within the past 30 days or a measurable blood alcohol level. • Previous episodes of alcohol withdrawal. • A history of alcohol withdrawal seizures. • A history of DTs. • A history of blackouts caused by alcohol ingestion. • Prior admission to an alcohol rehabilitation program. • The use of alcohol and a CNS drug such as a benzodiazepine within the past 90 days. • The use of alcohol and a substance of abuse within the past 90 days. • A blood alcohol level > 200 mg/dL. • Evidence of autonomic hyperactivity, i.e., diaphoresis, tachycardia.

Opioid Withdrawal

The pathophysiology of opioid withdrawal is incompletely understood, but it is thought to be similar to other withdrawal syndromes, i.e., continued excessive use of an opioid causes changes to neurotransmitters and their receptors; in the case of opioids, GABA and noradrenaline. When the opioid is discontinued the changes in circulating levels of neurotransmitters and the altered function of the receptors are no longer inhibited by the opioid, resulting in the clinical picture of withdrawal.

52 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Opioid withdrawal begins 6-12 hours after last use and the severity of the signs and symptoms will peak within 24 to 48 hours. The clinical course of opioid withdrawal syndrome often follows the progression outlined below, starting from the last time the opioid was used. 1. 6-12 hours: Diaphoresis, lacrimation, mydriasis, rhinorrhea, yawning 2. 12-18 hours: Anxiety, insomnia, irritability, nausea 3. 18-24 hours: Abdominal cramps, , piloerection, restlessness, 4. > 24 hours: Chills, diarrhea, hyperthermia, muscle spasms, severe insomnia, tachycardia

The severity of opioid withdrawal can be evaluated by using the Clinical Opiate Withdrawal Scale (COWS). The use of COWS can help clinicians make an objective assessment of the severity of withdrawal and it also involves patient input.

Clinical Opiate Withdrawal Scale (COWS)

• Resting heart rate: a. 0 - 80 beats/min or below b. 1 - 81-100 beats/min c. 2 - 101-120 beats/min d. 4 - > 120 beats/min • Sweating over the past 30 minutes, not caused by ambient temperature or physical activity: a. 0 - No chills or flushing b. 1 - Subjective reporting of chills or flushing c. 2 - Observed flushing or moistness on the face d. 3 – Diaphoresis on the brow or face e. 4 – Sweat streaming from the face • Restlessness: a. 0 - able to sit still b. 1 – Reports difficulty sitting still, but can do so c. 3 – Frequent shifting or extraneous movements of arms/legs • GI upset within past 30 minutes: a. 0 - No GI symptoms

53 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

b. 1 - Stomach cramps c. 2 - Nausea or loose stools d. 3 - Vomiting or diarrhea e. 5 - Multiple episodes of diarrhea or vomiting • Anxiety or irritability: a. 0 - None b. 1 - Patient reports increasing anxiousness or irritability c. 2 - Patient is obviously anxious or irritable d. 4 - Patient is anxious/irritable and difficult to assess

or aches: a. 0 - absent b. 1 - Mild, diffuse discomfort c. 2 - Patient reports severe, diffuse aching of muscles, d. 4. - Patient is rubbing joints or muscles and cannot sit still • Tremor: observation of outstretched arms a. 0 - No tremor b. 1 - Tremor can be felt but not observed c. 2 - Slight tremor observed d. 4 - Gross tremor or muscle twitching • Yawning: a. 0 - No yawning b. 1 - Yawning once or twice during assessment c. 2 - Yawning three or more times during assessment d. 4 - Yawning several times a minute • Pupils size: a. 0 - Pupils normal sized for room light or pinned b. 1 - Pupils possibly (?) than normal size for room light c. 2 - Pupils moderately dilated d. 4 - Pupils are dilated to the point that only the rim of the iris is visible • Runny nose or tearing: Not accounted for by allergy or cold: a. 0 - Not present b. 1 - Nasal stuffiness or unusually moist eyes c. 2 - Nose running or tearing d. 4 - Nose constantly running or tears streaming down cheeks • Gooseflesh skin: a. 0 - Absent b. 3 - Skin piloerection can be felt or hair standing up on arms c. 5 - Prominent piloerection

54 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

A score of 5-12 is considered mild, 13-24 is moderate, 25-36 is moderately severe, and > 36 is severe.

Benzodiazepine Withdrawal

The benzodiazepines are comparatively old drugs; they are commonly prescribed and commonly abused, and the most of the medical literature regarding sedative-hypnotic withdrawal has been about benzodiazepines. Benzodiazepine intoxication is typically mild to moderate in severity but paradoxically, withdrawal from benzodiazepines can produce severe signs and symptoms and can be life-threatening.

As with other alcohol and the other drugs discussed in this module, chronic use of a benzodiazepine changes the affinity of receptors for a specific neurotransmitter (GABA in the case of benzodiazpines), causing a compensatory change in the number, function, and activity of these receptors. When someone who has been chronically using or abusing a benzodiazepine stops taking the drug, the inhibitory effect of GABA is removed, causing excess CNS excitation.

Withdrawal from benzodiazepines occurs when use of the drug is abruptly stopped or tapering of the drug is done too quickly, but mild withdrawal can occur even if the drug is slowly tapered. The onset of signs and symptoms depends on the half-life of the particular benzodiazepine. The withdrawal syndrome may begin within 24-48 hours after cessation of the drug, but if the benzodiazepine has a long half-life (> 24 hours) it may be several weeks before signs and symptoms are observed. The severity and duration of the withdrawal syndrome appears to be related to the duration of use/abuse and how quickly the drug was stopped. However, severe withdrawal reactions can occur even after short-term use at low doses. 55 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

The benzodiazepine withdrawal syndrome is characterized by agitation, anxiety, , insomnia, irritability, muscle tremors, and restlessness. Other, less common signs and symptoms include abnormal sensory , delirium, parathesias, tinnitus, psychotic symptoms, persistent headaches, myoclonic jerks, and seizures. The prevalence of seizures has been estimated to be 2.5%-8%. They are usually self-limiting, but deaths have been reported in association with seizures caused by benzodiazepines.

The benzodiazepines that have short (< 1 hours) half-lives such as diazepam and lorazepam are more likely to cause withdrawal seizures, and seizures are more likely to occur during withdrawal if the prescribed dose is high and the duration of use is long. The risk of withdrawal seizures is also increased by other factors that are common to the population of substance abusers such a concomitant alcohol use.

Amphetamine/Stimulant Withdrawal

Compared to the amount of literature published about alcohol withdrawal and opioid withdrawal there is little data about amphetamine/stimulant withdrawal and much of the research has been on methamphetamine. The medical effects of methamphetamine withdrawal appear to be relatively benign and well tolerated, and several sources identify an acute phase and a subacute phase.

The acute phase lasts approximately 7 to 10 days and the signs and symptoms may include diaphoresis, headache, muscle and joint pain, and mild, self-limiting gastrointestinal distress. Psychological effects during the acute phase include anxiety, depression, an increased appetite and an increased need for sleep, and craving for the drug. Psychosis during the

56 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com acute phase of withdrawal is relatively common. Patients who have a long history of methamphetamine use, have more severe depressive symptoms, and are significantly older than other users, are more likely to have persistent and severe psychotic symptoms.

The subacute phase lasts approximately two weeks and is characterized by a gradual decrease in the number and intensity of symptoms. Craving may persist for up to five weeks.

Cocaine Withdrawal

Cocaine withdrawal rarely causes serious medical harm or consequences, and most patients simply have mild, self-limiting signs and symptoms such as chills, non-specific musculoskeletal pain, and tremor. However, the psychological effects of cocaine withdrawal can be intense and debilitating. Patients may experience significant levels of anxiety, depression, fatigue, inability to concentrate, insomnia, and intense drug cravings. The duration of cocaine withdrawal is typically one to two weeks.

Treatment For A Substance Use Disorder

Treatment of certain drugs and alcohol use and withdrawal has been well studied. As compared to MDMA treatment, discussed in the next section, this section highlights specific recommended treatment for common drugs and alcohol often used in combination with MDMA.13-16,45-50

Amphetamine/stimulant use and withdrawal and cocaine use and withdrawal are considered to be relatively mild and self-limiting and treated with symptomatic/supportive care. Benzodiazepine use and withdrawal is treated by slowly tapering the use of the drug, administering a long-acting

57 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com benzodiazepine, and providing symptomatic/supportive care. , anti-psychotics, beta-blockers, selective serotonin reuptake inhibitors, and tricyclic anti- have been used to treat benzodiazepine withdrawal, but they have not been shown to be superior to benzodiazepines. There has been some evidence supporting the use of to treat benzodiazepine withdrawal, but a review considered the data for its use for this purpose insufficient. The optimum rate for tapering has not been determined and it may take weeks to years to successfully withdraw a patient from a benzodiazepine.

The basic approach is to: 1) make sure the patient is undergoing alcohol withdrawal by ruling out alternative diagnoses, and; 2) provide symptomatic/supportive care. Symptomatic/supportive care should consist of frequent assessments, intravenous hydration and nutritional support, the use of benzodiazepines to control agitation, and this approach is appropriate for all patients who are undergoing alcohol withdrawal. Patients in severe withdrawal and having a serious complication such as DTs may need sedation with a long-acting barbiturate, such as phenobarbital, or a more powerful sedation with .

Assessment

One of the most widely used tools for assessing the severity of alcohol withdrawal is the Clinical Institute Withdrawal Assessment for alcohol (CIWA). The CIWA scale measures 10 symptoms: Agitation, anxiety, auditory disturbances, clouding of sensorium, headache, nausea/vomiting, paroxysmal sweats, tactile disturbances, tremor, and visual disturbances.

The presence of symptoms in the CIWA is scored on a scale of 0-7, and the total score is used to determine the severity of withdrawal, i.e., a score of 8-

58 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

15 indicates the patient is in moderate withdrawal. If the patient is determined to be in severe withdrawal and needs intravenous benzodiazepines, an assessment with the CIWA scale may be needed every 10-15 minutes. If the patient is unable to answer questions, i.e., he/she is incoherent or endotracheally intubated, another assessment tool will need to be used.

Hydration and Nutritional Support

Careful attention should be given to hydration as patients undergoing alcohol withdrawal are often dehydrated. Often intravenous fluids are initially provided to patients, containing glucose, supplemental thiamine, and multivitamins that contain folate. Serum levels of , phosphate, and potassium should be measured and replenishment given as needed.

Benzodiazepines

Benzodiazepines are the cornerstone of treating agitation in patients who are in alcohol withdrawal. Many authorities recommend a symptom-triggered approach in which benzodiazepines are given based on the result of the CIWA assessment. Benzodiazepines such as diazepam that have a long half- life are preferred, but chlodiazepoxide and lorazepam can be used, as well. The patient’s liver function should be evaluated prior to use as compromised hepatic function could cause decreased and clearance of a benzodiazepine, resulting in prolonged effects.

The treatment of opioid use and withdrawal is also well studied and the treatment approach is relatively standardized. Use of the opioid should be stopped. A long-acting drug such as methadone that is pharmacologically

59 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com similar to the used opioid should be given, and symptomatic or supportive care should be offered.

The pharmacological treatment of opioid use and withdrawal typically involves three drugs: methadone, buprenorphine/naloxone, and . Methadone is the most commonly used drug for the treatment of opioid withdrawal. It is a longer-acting opioid and it produces less central nervous system depression and euphoria than most opioids. The drug is given as a tablet or oral solution several times a day, and the amount of time a patient will need to take methadone is highly variable. Buprenorphine is a partial opioid agonist that can be used to treat opioid withdrawal. It is often combined with naloxone in the form of Suboxone® in order to discourage use. Clonidine is a centrally acting -agonist that decreases sympathetic outflow. This mechanism of action makes it useful for treating the signs and symptoms of opioid withdrawal.

Anxiolytics and hypnotics can also be used for symptomatic care. Long- acting opioid antagonists such as have been used to treat opioid use and withdrawal but without a significant degree of success.

Psychological Treatment

There is a vast and bewildering array of psychological approaches for treating chemical dependency, and given the diverse multitude of treatments, it is not surprising that there is no consensus as to what is the “best” psychological approach for treating chemical dependency. Also, there are many methods that are widely used that have little supporting scientific evidence.

60 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Add to the above the fact that research has indicated that many of the therapeutic approaches have similar success rates and the selection of treatment becomes confusing. However, there are common aspects of successful treatments. The best ones are evidence-based treatments, and where the practitioners have received extensive training. For example, there is an organization of physicians who specialize in treating chemical dependency, the American Society of .

But although there are many ways to address the psychological needs of the chemically dependent patient, behavioral therapies are most often used. Behavioral therapies are a group of approaches characterized by a concern with the patient’s behavior. The therapist focuses not on past events that may have led to chemical dependency, but on what is currently occurring in the patient’s life. There are different behavioral therapies. Cognitive behavioral therapy has been proven to work, has been thoroughly tested and there is empirical evidence for its success.

Cognitive Behavioral Therapy

Cognitive behavioral therapy (CBT) is grounded in social learning theories and operant conditioning. In this process, the patient identifies feelings, thoughts, and situations that are associated with using a substance. The patient sees the thinking – the distorted, inaccurate, maladaptive thinking – that is the underpinning of negative emotions that lead to his/her chemical dependency behaviors, and the therapist helps him/her to replace these with realistic, life-affirming beliefs. Thus, cognitive behavioral therapy has two parts. The first is a functional analysis, and the second is skills training. It provides the chemically dependent patient with motivation for abstinence, teaches coping skills, changes reinforcing contingencies, and trains interpersonal skills that allow the patient to build a support network.

61 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

The treatment is a one-on-one encounter with a trained therapist and 12-16 weekly sessions are typically scheduled. It is done on an outpatient basis (typically) because chemical dependency is intimately connected with the circumstances of the patient’s life, and this gives the patient an immediate chance to try new coping skills and get immediate feedback on their effectiveness. Cognitive behavioral therapy can be successfully combined with pharmacological treatment and group, family, and/or couples’ therapy. It is unique in that it provides a functional analysis of chemical dependency and concrete coping skills are taught and practiced during sessions. Of course, cognitive behavioral therapy is not the only way to address the psychological and emotional concerns of the patient with chemical dependency. may be valuable. In this technique, patients receive rewards for specific behavioral goals, and there is a lot of very good empirical support for its effectiveness. However, it should also be noted that there is evidence that the effects tend to lessen when the contingencies are removed, and that this approach involves a lot of time and money.

Motivational interviewing is a focused, goal-directed technique that helps patients explore and resolve ambivalence and helps the patient towards an acceptable goal. It has been successfully used in treating chemical dependency on alcohol and research has shown significant effects, which are very durable. The therapist tries to understand the patient’s frame of reference, expresses acceptance and affirmation, and reinforces the patient’s own concerns, desires, and intentions for change. Finally, couples and family therapy can be used. There is much research that indicates these psychological treatments can be effective in adult and adolescent patients with chemical dependency.

62 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Care Of The Chemically Dependent Patient

Care of the patient who is chemically dependent is complex. Health teams specialized on chemical dependency may encounter these patients during acute intoxication, the withdrawal phase, or during the process of rehabilitation and the patient’s ongoing attempts to maintain a drug-free state. During these specific periods, the goals of clinical care will be very different and the needs of the patient will be very different, so it is difficult to provide a “one size fits all” approach.

Health care personnel frequently report that they do not like caring for the patient with chemical dependency, and they have negative attitudes towards them. This is not surprising. The typical heath care paradigm is that the patient seeks help for a health problem that is out of his/her control and is willing to cooperate willingly with the recommendations of caregivers. However, many patients with chemical dependency do not fit this paradigm: quite the opposite. As a result, clinicians caring for them experience impatience, resentment, anger, and the feeling that other patients with “legitimate” health care concerns are being neglected.

Chemical dependency carries a large negative stigma in our society, and clinicians may feel that the patient with chemical dependency is simply a “bad person.” Clinicians often wonder: why can’t they just stop? The solution is education. Clinicians must be taught that chemical dependency is a chronic disease, and that the health issues of these patients are legitimate, albeit at times confusing and unfamiliar.

All health professionals, not just those specifically trained in chemical dependency treatment, need specific information about drug use and 63 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com treatments. They must familiarize themselves with specific diagnoses (i.e., ineffective health maintenance, anxiety, risk for injury, etc.) that will be used when caring for these patients. In addition, clinicians must also cultivate the following characteristics that have been found to be important for successful care of someone with a chemical dependency.

• Hope and optimism: Given the seemingly self-inflicted nature of chemical dependency and the high relapse rate, it can be a challenge to remain hopeful and optimistic, but these attitudes are essential.

• A non-judgmental attitude: It is very easy to form judgments about the patient with chemical dependency, to view them as weak or lacking in morals and/or self- control.

• A low need to control the patient.

• The ability to engage the patient, but still detach.

• Patience and tolerance: Chemical dependency is a chronic disease and are very common.

• Flexibility.

• Recognize that people with chemical dependency often have co- occurring psychiatric disorders that must be treated.

64 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

A substance use disorder involves a wide variety of legal and illicit substances but the essential feature of a substance use disorder is a cluster of cognitive, behavioral, and physiological symptoms indicating that the individual continues using the substance despite significant substance- related problems. In simpler terms, the person who has a substance use disorder will continue to acquire and use alcohol or drugs despite very serious consequences. This is further illustrated by the diagnostic criteria of a substance use disorder, i.e., the person who has a substance use disorder has impaired control, exhibits risky behavior regarding acquisition and use, and his/her substance abuse disorder and its associated behaviors causes social impairment.

The causes of a substance use disorder are many and varied, but it is believed that one of the primary effects of continued use of alcohol or drugs is a significant increase and/or decrease in the activity and function of inhibitory and excitatory neurotransmitters. This effect produces tolerance and withdrawal. The central nervous system responds by needing larger amounts of alcohol or drugs to produce the desired effect (tolerance), and if the alcohol or drug is discontinued the inhibitory effect of the drug or alcohol is removed and the excitatory effect of these neurotransmitters is greatly increased, resulting in withdrawal.

Treatment of substance use requires specific interventions and long-term commitment. It involves cessation of alcohol or the drug, identification and treatment of complications of withdrawal, and, the use of specific drugs that can help to decrease craving and treat the signs and symptoms of withdrawal.

65 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

Withdrawal is most often a benign and self-limiting process, albeit physically and psychologically quite uncomfortable. Follow-up care that involves social and psychological support is crucial after the withdrawal period is complete. A substance use disorder certainly has a physical basis but there are emotional and psychological aspects that cause and reinforce substance use that must be addressed.

MDMA Use And Addiction Treatment

There are no specific medical treatments for MDMA use and addiction. However, treatment that is effective for drug use and addiction in general, as noted in the section above, can apply and include cognitive behavioral interventions. These are designed to modify the thinking of the patient and their expectancies and behaviors. The therapy increases skills for coping with stressors of life. Support groups can also help in combination with behavioral interventions to support recovery that is long-term and drug-free. There are no specific to treat MDMA use. There are also no FDA approved medical or drug-based therapies to treat cocaine/MDMA use. There are possible new approaches and developments that could be promising, which are outlined in this section.19,38-44

Clinical trials have shown that certain medications can help with decreasing cocaine use. The medications are used for treatment of other conditions too. Some of the drugs that could help are , , tiagabine, disulfiram and vigabatrin. They have the potential to decrease cocaine use. They could potentially be useful for MDMA use also.

While some patients who use cocaine respond to drug counselling, others do not respond. Development of medication for cocaine use should be explored

66 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com and is a research priority. No one medication has yet emerged as consistently and predictably effective to treat cocaine use. For a severely addicted patient, propranolol could help with the initial period of abstinence that is stable. To prevent a relapse what could work is a medication that blocks the euphoria from cocaine or reduces craving for cocaine. This is where GABAergic medications, such as , tiagabine, and topiramate, and the glutamatergic medication modafinil could help.

Disulfiram is a treatment for an alcohol use disorder. It could also be effective for cocaine relapse prevention. A could also help. It could stimulate the production of cocaine specific antibodies, and could help with prevention of relapse for cocaine use. Other medications that could help include those to treat acute overdose emergencies.

Psychosocial Treatment

While there is no specific psychosocial treatment for concurrent use of Ecstasy and cocaine, those suffering from addiction can find help with the Matrix Model. This model is helpful for those who have an addiction to a stimulant. It is an intensive outpatient program that lasts 16 weeks, and is specifically for helping a stimulant addict maintain abstinence. This is an outpatient rehab program that includes relapse prevention, urine testing, self-help, family education, social support, and recovery skills. A therapist plays the role of coach and therapist, and fosters a positive and encouraging environment. The focus is on the self-worth of the patient.

Cognitive behavioral therapy (CBT) is another possible useful psychosocial therapy that could apply to treatment for MDMA use. This therapy is based

67 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com on the idea that human behaviors, thoughts, and feelings interconnect. The therapy evaluates how they influence each other in the context of drug use. A therapist uses CBT to identify maladaptive behavior. The approach is to rectify unwanted behavior and develop coping strategies and self-monitoring tactics. CBT teaches a patient to recognize a craving and avoid a trigger situation. The patient also acknowledges the negative consequence of drug use.

Inpatient Hospitalization and Residential Treatment

A patient could benefit from a stay in a hospital and/or other facility to receive treatment for stimulant drug use. This inpatient hospitalization and treatment depends on the facility.

Residential treatment could help some patients. These are treatments that require a patient stay at a center for the duration of the treatment. The patient moves into a residential facility. The facility is adapted to avoid drug use environmental factors that could influence a person to use a drug. This can include psychological services, group therapy, yoga or access to nature.

Outpatient Treatment

Outpatient treatment could take place at a hospital, clinic, or other facility where stimulant drug use treatment is an option. The patient agrees to attend treatment sessions. These could include evaluations and assessments with healthcare professionals. Outpatient treatment can be a good option if someone has gone through a recovery program. The person could also have a less severe addiction or mental health disorder, as well as a family or work obligation where inpatient treatment is not a good option.

68 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

A Vaccine for Drug Addiction

Drug use and addiction is an ongoing and serious problem. It has contributed to the growth of a criminal enterprise especially in America and Europe. The idea that a vaccine could help with the problem of drug addiction has been considered. Some information about cocaine and a vaccine has been suggested with the hope such an approach for MDMA/Ecstasy exists too.

There are currently no effective pharmacological agents available to treat addiction by blocking cocaine or reversing its effects. To motivate addicts to conquer their addiction, there is development of in progress as well as clinical trials. Consider some of the vaccine approaches in how to deal with drug use and addiction. The addicting qualities of drugs such as cocaine are well known as are the adverse effects. There is a need to develop new treatments for these types of drug addiction as there currently are no pharmacological interventions that are effective except for methadone used for morphine/heroin addiction.

Development of Anti-drug Vaccine

For at least fifty years it has been known that small molecules called haptens will not typically elicit an immune response. This is unless they are attached to an immunogenic . This means the body has tolerance for most medications and chemical exposures with no harmful immune reaction. An allergic reaction happens when, for example with penicillin, the immune system recognizes the chemical and its metabolic products after they bind to a native protein. This allows for antigen presentation and the start of an immune response. To produce an anti-drug vaccine, the hapten must

69 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com covalently attach to a foreign carrier protein. This permits both cross linking of the antibody molecules expressed on B cells to activate them.

The first effort to create an anti-drug vaccine was published in the 1970s. Three vaccines were prepared from derivatives of morphine. Discussion was about whether the antibodies produced bound to other morphine-like molecules. Work on vaccines stopped, possibly because of the availability of methadone for heroin addiction, which appeared to help addicts stop using the drug. Methadone itself is addicting because it calms the craving for heroin and has few side effects. It has been used successfully for more than thirty years.

In 1992, an interest in vaccines restarted when there were reports of an anti-cocaine vaccine. In 2001, a hapten for use in making anti-nicotine vaccines was prepared. Other nicotine vaccines followed. Some went into clinical trials with modest results. Methamphetamine vaccines were also produced. Their use in rodents provided positive results. Clinical trials for anti-methamphetamine vaccines may not be far away.

Anti-cocaine Vaccines and Catalytic Antibodies

There was interest in the 1990s in creating catalytic antibodies to act in a way similar to HBC. Chemistry was used to create haptens known to be transition state analogs to mimic the intermediate chemical structures leading to the hydrolysis reaction. This was so antibodies produced would act as enzymes, and were expected to catalyze the release of the benzoyl group from cocaine. It should be noted that the methyl ester of cocaine can spontaneously hydrolyze in serum; it gives benzoyl . In tissues there are also esterases that perform this hydrolysis. The phenyl ester can be hydrolyzed by human butyryl cholinesterase (HBC); this will give 70 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ecgonine methyl ester and . These metabolites have little or no pharmacological activity.

One researcher reported on the effect of polyclonal antibodies in the sera of vaccinated mice. Through a chemical synthesis a hapten was prepared that was reported to be stable and long-lived, conjugating it to keyhole limpet hemocyanin. Mice were given the vaccine. The monoclonal antibodies generated were identified by a high throughput method. At this time, the position of the link in the cocaine transition state hapten was reported to be important. A link was attached in the methyl ester position rather than the tropane which gave better results. Having an amide group in the carbon chain of the link was more effective.

This catalytic antibody idea is attractive because in a relative small number of antibodies produced through a vaccine, cocaine molecules may be destroyed. The impact, however, of such findings is that users could take on more.

There are still questions about quantity, efficacy, and affinity of these antibodies. None of the studies had the vaccinated mice tested for the behavioral outcomes of cocaine dosing. Anti-cocaine catalytic antibodies are still being studied. No related clinical trials are in progress.

MDMA’s Potential Use As A Therapeutic Agent

The research in humans and clinical use of MDMA was severely limited when MDMA was made illegal. Data was gathered regarding the neurotoxicity and effects of MDMA in animals. Besides the animal studies, over 1000 humans were administered the drug for research purposes in several clinical trials

71 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com without adverse effects seen. The use of MDMA and its neurotoxic effects, including effects on cognitive function in humans, is discussed here as the possible therapeutic use in the treatment of anxiety disorders. Studies are evaluating MDMA for PTSD patients. MDMA could also be a treatment for the powerful anxiety associated with an illness like cancer or as a new treatment for social anxiety in adults with autism. The following discussion highlights aspects of the research and discussion relative to findings and the potential therapeutic use of MDMA.20,34-44

Post-traumatic Stress Disorder

Clinical studies addressed the possible role for drug assisted psychotherapy with MDMA as a treatment. This could be particularly useful for individuals diagnosed with post-traumatic stress disorder (PTSD). In recent trials on a therapeutic application, MDMA showed benefits in drug-assisted psychotherapy for PTSD patients with bearable (short-term) side effects. Two randomized controlled trials were completed. They showed a better outcome for psychotherapy using MDMA than using a placebo.37 Another researcher found MDMA having a larger effect when compared to common psychotherapeutic treatment. Further studies of a similar nature are now being conducted.

In the meantime, anecdotal reports are coming from people with post- traumatic stress disorder. They discuss their experiences with standard therapy and . Some therapy had been dependent on medications used in standard therapy; yet nothing was working. Some joined to test MDMA to help patients not responding to standard therapy. Some reported that MDMA helped to reconnect, and felt a weight was lifted off their shoulders. The MDMA administered to some study participants was

72 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com the pure form of the party drug known as Ecstasy. Researchers note that the majority of non-research Ecstasy is not pure MDMA.

In one trial, participants in the study eliminated symptoms of PTSD in two months after treatment. Four years later the MDMA therapy had lasting effects. Another sample of people showed promise during a trial. This group was going into Phase 2 of the clinical trials. Phase 2 is the second of three steps of human trials needed for the Food and Drug Administration to consider approving a new drug. In the Phase 2 , 136 people were treated using MDMA-assisted therapy for PTSD. They compared MDMA- assisted psychotherapy with current treatments and a placebo. The results of Phase 2 have not been published. After Phase 2 results are published, the clinical trials could move to Phase 3. This would involve more people and it may be a final test before the FDA decides whether to approve MDMA as a new medication. Phase 3 could start in 2017. The trial would take four to five years. This means that an FDA decision could come as soon as 2021.

MDMA Assisted Therapy for Autism

Another study investigated a new treatment model using MDMA for social anxiety in adults with autism. It is a controversial area but one to consider understanding the full picture on MDMA use. In 2014, the first study of using MDMA-assisted therapy for treating social anxiety in autistic adults occurred. Consideration of psychotherapeutic options for those with autism is important as there is a lack of effective conventional treatment for mental health issues that are common with those who have autism.

A paper recently explained a study concerning MDMA-assisted therapy for the treatment of social anxiety in autistic adults. The report points out that

73 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com areas of investigation of autism research have paralleled MDMA research. This includes neurobiological studies and the effects of the neuropeptides oxytocin (OT) and vasopressin. These are believed to play a role in interpersonal connection and bonding. It also includes the study of the neurotransmitter serotonin. Another area that appears in the literature of both autism and MDMA research is cognitive study such as investigation of the mechanisms of face recognition. Functional brain imaging suggests that in autistic individuals the amygdala may be differentially activated, with greater activation in the anterior cingulate gyrus and superior temporal cortex, with less activation occurring in the left amygdala and left orbitofrontal cortex. Or, it may signal an atypical way to the fusiform gyrus, a key brain region involved in facial recognition. The results involve differences in social perception between autistic and non-autistic individuals.

In a healthy volunteer, MDMA decreases activity in the left amygdala, which is a brain region involved in interpreting negative cues and attenuates amygdala response and emotional reaction to an angry face. This action of MDMA is compatible with its reduction of fear of emotional injury of defensiveness. The effect is multilevel on brain circuits, neurotransmitters, and neuro hormones that are studied extensively in autistic individuals.

Other Studies on MDMA’s Therapeutic Use

The continuation of ongoing studies is seen as a reflection of increasing interest in MDMA as a therapeutic agent. If it is to be a therapeutic agent, there needs to be a better understanding of the consequences of its use. In clinical trials that administer MDMA, the incidence of serious adverse events is rare and non-life threatening. Given the absence of adverse effects

74 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com in past studies, the potential of using MDMA as a therapeutic drug has not subsided.

As with other hallucinogenic and psychedelic drugs, MDMA catalyzes and shifts toward and openness. A patient does not need ongoing administration to get lasting results. An infrequent dose mitigates adverse event frequency. It also improves the risk/benefit ratio of the drug. This could provide a significant advantage over medications requiring a daily dose. Clinicians could use new treatment approaches for social anxiety. The approaches could also help with similar types of distress administering MDMA. This could be on one or several occasions. It would also be within a supportive and integrative protocol of psychotherapy.

Some studies suggest it is a possible therapeutic agent for humans, and should be given in moderate dosages and under controlled conditions in a medical setting. However, MDMA’s potential effects on decision-making are something medical researchers need to understand before recommending MDMA use therapeutically. Moreover, if it is intended to be applied periodically, the long-term effects must be thoroughly studied in order to evaluate a cost-benefit ratio of MDMA in a therapeutic setting.

To draw more precise conclusions about the long-term effects of MDMA, longitudinal studies are required. These would allow for some insight into the time course of alterations in decision-making and other cognitive functions after MDMA use. Further, these studies should take relevant factors of MDMA use, like preexisting comorbidities and polydrug use, into account and employ additional methodological approaches, such as neurochemical and imaging methods.

75 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

MDMA: Federal Restrictions and Penalties

Researchers believe MDMA could help with PTSD but MDMA has been an illegal substance in the United States since 1985. As a Schedule I controlled substance, stiff federal penalties apply to the use of MDMA (Ecstasy/Molly). This includes anyone who is caught manufacturing, distributing, or using MDMA. Unless MDMA is approved for medicinal uses, its possession is a felony. This may result in fines, probation, and/or a prison sentence. Summary

MDMA — also known as Ecstasy or Molly — remains an illegal and dangerous drug that is often mixed with other substances that increase the potentially harmful effects. It is a stimulant with psychedelic effects. It causes a sense of euphoria and increased energy in the short-term. can have a significant and damaging short-term and long-term effect on the body and brain. Drug use can be particularly risky especially if taken in a high dose and combined with other drugs and alcohol, as is often the practice with MDMA. MDMA causes dehydration, electrolyte imbalance, and complications such as seizures. Long-term MDMA use can lead to fatigue and depression damage the brain.

Health clinicians should be aware of the effects of MDMA use in patients. They also need to know of the tendency to use it in conjunction with other drugs and alcohol to heighten the short-term and long-term impact on the user. On the other hand, clinical studies addressed the possible role for drug-assisted psychotherapy with MDMA as a treatment. This could be particularly useful for individuals diagnosed with post-traumatic stress disorder (PTSD) or for social anxiety in adults with autism. More research is needed to determine future benefit of MDMA as a treatment option.

76 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

References Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading.

1. National Institute on Drug Abuse. (2013). MDMA (Ecstasy, Molly). Retrieved online from https://www.drugabuse.gov/drugs- abuse/mdma-EcstasyMolly 2. Hoffman R. (2016). MDMA (Ecstasy) intoxication. Retrieved online from http://www.uptodate.com/contents/mdma-Ecstasy- intoxication?source=search_result&search=MDMA+epidemiology&selec tedTitle=1%7E88 3. Palamar, J., Kamboukos, D. (2014). An examination of sociodemographic correlates of Ecstasy use among high school seniors in the United States. 4. Armenian, P., Mamantov, T. (2013). Multiple MDMA (Ecstasy) overdoses at a rave event: a case series. J Intensive Care Med 2013; 28:252. Retrieved online from http://journals.sagepub.com/doi/10.1177/0885066612445982 5. Amoroso, T. (2015). The of + - 3,2 Methylenedioxymetharmphetamine and its role in the treatment of posttraumatic stress disorder. J Psychoactive Drugs 2015; 47:337. Retrieved online from http://www.tandfonline.com/doi/full/10.1080/02791072.2015.109415 6 6. National Institute on Drug Abuse. (2013). MDMA (Ecstasy, Molly). Retrieved from https://www.drugabuse.gov/drugs-abuse/mdma- EcstasyMolly 7. United States Department of Justice. (2015). Advisories to the public. Retrieved from https://www.deadiversion.usdoj.gov/chem_prog/advisories/safrole.ht m

77 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

8. American Academy of Pediatrics. (2015). Understanding drug schedules. Retrieved from https://www.healthychildren.org/English/ages-stages/teen/substance- abuse/Pages/Controlled-Substances-Not-Just-Street-Drugs.aspx 9. Iversen, L. (2013). Handbook of Psychopharmacology: Volume 14 Affective Disorders: Drug Actions in Animals and Man. Springer Science & Business Media. pp. 132–. ISBN 978-1-4613-4045-4. 10. Biological Research on Addiction: Comprehensive Addictive Behaviors and Disorders. (2013). Academic Press. 17 May 2013. pp. 632. ISBN 978-0-12-398360-2. 11. Ericson, J. (2013) Ecstasy related emergency room visits more than doubled in 2005 to 2011. Retrieved online from http://www.medicaldaily.com/Ecstasy-related-emergency-room-visits- more-doubled-2005-2011-mdma-increasingly-popular-among-young 12. United States Department of Justice. (2017). Drugs of Abuse. Retrieved from https://www.dea.gov/pr/multimedia- library/publications/drug_of_abuse.pdf#page=66 13. Mortality and Causes of Death. (2014). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.". Lancet. 385: 117–71. PMC 4340604 . PMID 25530442. doi:10.1016/S0140-6736(14)61682-2. 14. ICD10data.com. (2017) Hallucinogen related disorders. Retrieved online from http://www.icd10data.com/ICD10CM/Codes/F01-F99/F10- F19/F16- 15. APA Practice Organization. (2015). Substance Use Disorders and ICD- 10 Coding. Retrieved from http://www.apapracticecentral.org/update/2015/09-10/substance- disorders.aspx 16. Centers for Disease Control and Prevention. (2017). Retrieved from https://www.cdc.gov/nchs/icd/icd10cm.htm 17. Samanez-Larkin, G.R. & Knutson, B. (2015) Decision-making in the ageing brain: changes in affective and motivational circuits. Nat. Rev. Neurosci., 16, 278–289. 18. Garg, A., Kapoor, S., Goel, M., et al (2015). "Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review". Curr. Drug Abuse Rev. 8 (1): 15–25. PMID 25731754. doi:10.2174/1874473708666150303115833. 19. Danforth, A., et al. (2015) MDMA-assisted therapy: A new treatment model for social anxiety in autistic adults, Prog Neuro- Psychopharmacol Biol http://www.maps.org/research- archive/mdma/danforth-et-al-2015-mdma-autism.pdf

78 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

20. Mueller, F., Lenz, C., et al. (2016). "Neuroimaging in moderate MDMA use: A ". Neurosci. Biobehav. Rev. 62: 21–34. PMID 26746590. doi:10.1016/j.neubiorev.2015.12.010. 21. Halpin, L., Collins, S., Yamamoto, B. (2014). "Neurotoxicity of methamphetamine and 3,4-methylenedioxymethamphetamine". Life Sci. 97 (1): 37–44. PMC 3870191 . PMID 23892199. doi:10.1016/j.lfs.2013.07.014. 22. Garg A., Kapoor S., et al. (2015). "Functional Magnetic Resonance Imaging in Abstinent MDMA Users: A Review". Curr. Drug Abuse Rev. 8 (1): 15–25. PMID 25731754. doi:10.2174/1874473708666150303115833. 23. Carvalho, M., Carmo, H., et al. (2012). "Toxicity of amphetamines: an update". Arch. Toxicol. 86 (8): 1167–1231. PMID 22392347. doi:10.1007/s00204-012-0815-5. 24. Roberts, C., Jones, A., Montgomery, C. (2016). "Meta-analysis of molecular imaging of serotonin transporters in Ecstasy/polydrug users". Neuroscience and biobehavioral reviews. 63: 158–67. ISSN 1873-7528. PMID 26855234. doi:10.1016/j.neubiorev.2016.02.003. 25. Betzler, F., Viohl, L., et al. (2017, Jan.). "Decision-making in chronic Ecstasy users: a systematic review". European Journal of Neuroscience. 45 (1): 34–44. PMID 27859780. doi:10.1111/ejn.13480. “...the addictive potential of MDMA itself is relatively small.” 26. Kousik, S., Napier, T., Carvey, P. (2012). "The effects of psychostimulant drugs on blood brain barrier function and neuroinflammation". Front Pharmacol. 3: 121. PMC 3386512. PMID 22754527. doi:10.3389/fphar.2012.00121. 27. McMillan, B., Starr, C. (2014). Human biology (10th ed.). Belmont, CA: Brooks/Cole Cengage Learning. ISBN 9781133599166. 28. Boyle NT, Connor TJ (2010). "Methylenedioxymethamphetamine ('Ecstasy')-induced immunosuppression: a cause for concern?" (PDF). British Journal of . 161 (1): 17–32. PMC 2962814. PMID 20718737. doi:10.1111/J.1476-5381.2010.00899.X. 29. Sessa, B., Nutt, D. (2015). "Making a medicine out of MDMA". The British Journal of Psychiatry. 206 (1): 4–6. PMID 25561485. doi:10.1192/bjp.bp.114.152751.

79 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

30. Betzler, F., Viohl, L., et al. (2017). "Decision-making in chronic Ecstasy users: a systematic review". European Journal of Neuroscience. 45 (1): 34–44. PMID 27859780. doi:10.1111/ejn.13480. 31. Kinsey, B., Kosten, T., Orson, F. (2010). Anti-cocaine vaccine development. Expert Rev Vaccines. 9(9). 1109-1114. Retrieved fromhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936703/ 32. National Institute of Drug Abuse. (2012). The Matrix Model (stimulants) Retrieved fromhttps://www.drugabuse.gov/publications/principles-drug- addiction-treatment-research-based-guide-third-edition/evidence- based-approaches-to-drug-addiction-treatment/behavioral-3 33. Betzler, F., Viohl, L., et al. (2017). "Decision-making in chronic Ecstasy users: a systematic review". European Journal of Neuroscience. 45 (1): 34–44. PMID 27859780. doi:10.1111/ejn.13480. 34. Meyer, P., King, C., and Ferrario, C. (2016) Motivational processes underlying substance abuse disorder. Curr. Top Behav. Neurosci., 27, 473–506. 35. Heinz, A., Schlagenhauf, F., Beck, A. and Wackerhagen, C. (2016) Dimensional psychiatry: mental disorders as dysfunctions of basic learning mechanisms. J. Neural. Transm., 123, 809–821. 36. Mithoefer, M., Grob, C., and Brewerton, T. (2016) Novel psychopharmacological therapies for psychiatric disorders: and MDMA. Lancet Psychiatry, 3, 481–488. 37. Oehen, P., Traber, R., Widmer, V., and Schnyder, U. (2013) A randomized, controlled pilot study of MDMA (+/− 3,4- methylenedioxymethamphetamine)-assisted psychotherapy for treatment of resistant, chronic post-traumatic stress disorder (PTSD). J. Psychopharmacol., 27, 40–52. 38. Amoroso, T. and Workman, M. (2016) Treating posttraumatic stress disorder with MDMA-assisted psychotherapy: a preliminary meta- analysis and comparison to prolonged exposure therapy. J. Psychopharmacol., 30, 595–600. 39. Danforth, A., Struble, C., Yazar-Klosinski, B., and Grob, C. (2016) MDMA-assisted therapy: a new treatment model for social anxiety in autistic adults. Prog. Neuro-Psychoph., 64, 237–249. 40. Oehen, P., Traber, R., Widmer, V., and Schnyder, U. (2013) A randomized, controlled pilot study of MDMA (+/− 3,4- methylenedioxymethamphetamine)-assisted psychotherapy for

80 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com

treatment of resistant, chronic post-traumatic stress disorder (PTSD). J. Psychopharmacol., 27, 40–52. 41. Mithoefer, M., Grob, C., and Brewerton, T. (2016) Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry, 3, 481–488. 42. Wagner, D., Becker, B., Koester, P., Gouzoulis-Mayfrank, E., and Daumann, J. (2013) A prospective study of learning, memory, and executive function in new MDMA users. Addiction, 108, 136–145. 43. Wagner, D., Tkotz, S., Koester, P., Becker, B., Gouzoulis-Mayfrank, E., and Daumann, J. (2015) Learning, memory, and executive function in new MDMA users: a 2-year follow-up study. Front. Neurosci., 9, 445. 44. Berma, M., Kinsey,T., et al. (2010). Anti-cocaine vaccine development. Expert Rev Vaccines. 2010 Sep; 9(9): 1109–1114. doi: 10.1586/erv.10.102 45. American Psychiatric Association (2013). Substance-related and Addictive Disorders. Retrieved from APA_DSM-5-Substance-Use- Disorder.pdf. 46. Hoffman, R. (2017). Testing for drugs of abuse (DOA). UpToDate. Retrieved online at https://www.uptodate.com/contents/testing-for- drugs-of-abuse- doa?source=search_result&search=mDMA%20and%20other%20drug %20use&selectedTitle=2~150. 47. Stehman CR, Mycyk MB (2013). A rational approach to treatment of alcohol withdrawal in the ED. American Journal of Emergency Medicine. 2013;31:734-742. 48. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA; American Psychiatric Publishing: 2013. 49. Hopper JA. Opioids. In: McKean SC, Ross JJ, Dressler DD, Brotman DJ, Ginsberg JS, eds. Principles and Practices of Hospital Medicine. New York, NY: McGraw-Hill; 2012. 50. Stone, DM., et al (2017). Deciphering Suicide and Other Manners of Death Associated with Drug Intoxication: A Centers for Disease Control and Prevention Consultation Meeting Summary. American Journal of Public Health; 2017 Aug;107(8):1233-1239.

81 ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com ce4less.com