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MDMA. Part II. Clinical effects, doses, studies

Brain

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Clinical effects.
In most studies on humans, doses ranged from 75 to 125 mg of pure ecstasy are used. It has been revealed that MDMA causes insignificant changes in visual and auditory perception, including changes in the brightness of the color and its saturation, changes in auditory distance perception. Visual distortions are determined. Use of ecstasy also causes changes in perception of time. Women have reported to have more intense experience with subjective effects, especially the perceptive effects. However, the latest study of Kirkpatrick 2014-Basel-Chicago-SF hasn't revealed any gender differences in subjective effects. Perceptive effects of ecstasy are more likely to be the result of direct or indirect action on 5-HT2A receptors because addition of ketanserin, which is an antagonist of these receptors, decreases the stated perceptive changes and levels the increase in the body temperature. MDMA improves mood, but increases anxiety level. There is evidence on positive mood and anxiety being dose-dependent. Ecstasy users become talkative and friendly, have pronounced euphoria and empathy depending on the dose. Almost all the studies show increased interpersonal intimacy after use of the substance. In studies on MDMA in combination with paroxetine it was found that paroxetine decreases the effects of social belonging and intimacy, which indicates a significant and important role of the serotonergic system in pro-social effects of MDMA. Also, when using MDMA, negative derealisation occurs, including increased anxiety level, associated with the loss of control over situation, experiences associated with jumping or blocking of thoughts. Ecstasy significantly improves the recognition of positive mood expressions and reduces the accuracy of recognition of negative mood expressions, which is associated with a decrease in signaling in the amygdala in response to angry faces, compared to placebo without changing the reaction to faces that visualize fear (in studies with fMRI). These studies revealed increased activity in the ventral striatum, when looking at happy faces. Generally, the obtained research results allow us to consider MDMA as a substance which helps to process visual emotions of other people and determine the appropriate reaction to them. At the moment there are a few published studies on healthy volunteers, which have identified decreased reactivity to stimulation of social exclusion, decreased negative emotional reaction to "bad" memories and increased talkativeness and increased perceived empathy of the interlocutor. In studies of Kirkpatrick and Wardle it has been proved that ecstasy administration causes positive response to any social stimuli even without social content, which implies the presence of a clear and distinctive contrast in the assessment of social and non-social emotional stimuli in terms of the study on MDMA influence on pro-social effects. So, users, who have taken low and medium doses of MDMA, prefer social activity.

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MDMA use causes sympathomimetic effects, including increased blood pressure and heart rate, reduction of respiratory sinus arrhythmia during each respiratory cycle. Cardiovascular effects appear 20-35 minutes after oral administration and reach their peak after 1-2 hours. After the peak, cardiovascular effects gradually weaken within 5-10 hours, depending on many factors. In 5-10% of cases, there is a chance of an increase in blood pressure of more than 140/90 mmHg after administration of 100 mg of ecstasy. As it was mentioned earlier, in people with a certain COMT genotype (Val158Met genotype), as well as in people with a certain SERT genotype, more pronounced cardiovascular effects occur. α1-and β-adrenergic receptor antagonist carvedilol levels the MDMA-induced increase in blood pressure, heart rate and body temperature if it is taken 1 hour before use of ecstasy. This fact indicates that norepinephrene release is responsible for cardiovascular effects of MDMA.

Norepinephrine release induced by MDMA leads to indirect activation of the AVP system, stimulating secretion of copeptin (CTproAVP), a 39-aminoacid glycopeptide that is a C-terminal part of the precursor pre-proAVP. CTproAVP is secreted into circulation from the posterior pituitary gland in equimolar amounts with AVP. CTproAVP directly reflects AVP concentration and can be used as a surrogate biomarker of AVP secretion. In many studies CTproAVP behavior represents changes in plasma osmolality, stress and various disease states (diabetes, SIADH, heart failure, renal disorders), and is an indicator of osmoregulatory function in the body. Increased CTproAVP concentration is described in several studies as a strong predictor of mortality in patients with chronic heart failure and acute heart failure. Taken together, the AVP system appears to be the main connection between MDMA and cardiovascular risk as well as hyponatremia. All studies on MDMA influence on cardiovascular system conducted so far indicate dose-dependent effect on SBP and heart rate. Though peak DBP is higher after a dose of 100 mg, there is data on a significant increase of this indicator even in case of smaller dose of ecstasy. This is presumably due to the fact that there are various adulterants in a tablet or other undesirable products in MDMA crystals. On average, cardiovascular indicators return to normal within a few hours.
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Stimulation - MDMA is popularly known for being stimulating and energetic. This encourages activities such as running, climbing and dancing in a way that makes MDMA a popular choice for musical events such as festivals and raves. The distinct style of stimulation which MDMA presents can be described as forced. This means that at higher doses, it becomes difficult or impossible to keep still as jaw clenching, involuntarily body shakes and vibrations become present, resulting in an unsteadiness of the hands and a general lack of motor control. Unlike most other stimulants, however, the stimulating effects of MDMA can also paradoxically be accompanied by persistent or wave-like feelings of deep sedation and relaxation, typically at moderate to strong doses.
Spontaneous bodily sensations - the "body high" of MDMA can be characterized as a moderate to extreme euphoric tingling sensation that encompasses the entire body. This sensation maintains a consistent presence that steadily rises with the onset and hits its limit once the peak has been reached.
Physical euphoria - physical euphoria is a prominent aspect of the MDMA experience and occurs reliably when MDMA is used responsibly (i.e. reasonable dosing and spacing between experiences) and can lead to profound feelings of social and physical disinhibition. However, euphoria is quick to fade as one builds tolerance to MDMA's effects, colloquially known as "losing the magic".
Tactile enhancement - MDMA produces distinct enhancements to tactile sensations. Users commonly report a sense of softness and fuzziness draping over their skin. Likewise, touching soft and fuzzy objects such as shag rugs can become irresistibly pleasurable and satisfying. MDMA-type tactile enhancement appears to be an effect unique to the entactogen class and may be a serotonin-related effect. More physical effects: bodily control enhancement; stamina enhancement; bronchodilation; abnormal heartbeat; increased blood pressure;increased heart rate; temperature regulation suppression; increased bodily temperature; muscle contractions; increased perspiration; dehydration; dry mouth; difficulty urinating; vibrating vision; nausea; appetite suppression; pain relief; excessive yawning; pupil dilation; orgasm suppression; temporary erectile dysfunction; vasoconstriction; teeth grinding; seizure. Visual effects: colour enhancement; pattern recognition enhancement; double vision; tracers; symmetrical texture repetition; external hallucination (autonomous entities; settings, sceneries, and landscapes; perspective hallucinations and scenarios and plots); internal hallucinations; peripheral information misinterpretation.
Cognitive effects: amnesia; anxiety suppression; disinhibition; empathy, affection, and sociability enhancement; emotion enhancement; cognitive euphoria; increased music appreciation; time compression; increased libido; creativity enhancement; motivation enhancement; focus enhancement; immersion enhancement; ego inflation; increased sense of humor; compulsive redosing; mindfulness; thought acceleration; wakefulness; delirium &confusion; rejuvenation. After effects: anxiety; appetite suppression ; brain zaps; cognitive fatigue; depression; derealization; dream suppression; sleep paralysis; irritability; motivation suppression; thought deceleration; thought disorganization; suicidal ideation; wakefulness.

Short term undesirable states during MDMA use include: heat stroke and/or serotonergic reaction, which has similar symptoms to that of serotonin syndrome to different degrees of severity both due to MDMA effect on hypothalamic area responsible for thermoregulation and its effect on other systems in the body; hyponatremia due to dehydration and consumption of large amounts of water without sufficient number of electrolytes; various allergic and cardiovascular reactions. Long term undesirable effects of ecstasy include: depressive/subdepressive state or anxiety, when MDMA is used frequently. High and/or frequent doses of MDMA have been shown to be neurotoxic in laboratory animals. However, no properly controlled studies have shown cognitive impairments in human users after a period of abstention long enough to rule out temporary effects of MDMA, polydrug use, and a partying/unhealthy lifestyle. Normal therapeutic doses of SSRI’s like Prozac, taken with MDMA or on the comedown, have been shown to be neuroprotective in animals, though we don’t recommend this due to SSRIs having their own side effects and risks. For reducing risk of neurotoxicity, limiting dose amount and taking supplements may be most important; “losing the magic” is when people who use MDMA find that over time, they get less and less of the special effects of MDMA. This is unfortunate, especially considering that MDMA is on a path to be used as a prescription medicine to assist therapy. Avoid if you have any of these contraindicated conditions: cardiovascular disease; cerebrovascular disease; uncontrolled hypertension; malignant hyperthermia; anhydrosis; central core disease or any condition that increases the risk of heat stroke or hyperthermia (this includes if you currently have a fever or if you know you are particularly heat sensitive); susceptibility to seizures; liver problems; malignant hyperthermia is a rare genetic disorder. Many individuals with the condition do not know they have it. If either of your parents have it, or if you have any first or second-degree relatives who have had an adverse reaction to anesthesia, you may have it. If this is true, you should not take MDMA. If you’ve taken any MAOIs (e.g. Nardil, Parnate, Marplan, Ayahuasca) within the last 3 weeks due to potential risk of death. There is no high-quality evidence that 5-HTP is dangerous to combine with MDMA, though there are rumors that this is a bad combination. If you know of good evidence either way, please send it to us. If you’ve recently taken St John’s wort. SJW has a high potential for drug interactions, some of which may be serious. If you’ve recently taken any CYP2D6 inhibitors. In combination with drugs that increase heart rate or blood pressure (e.g. many asthma medications, stimulants like cocaine, amphetamine, caffine), DXM (Robitussin), stomach acid mediciations, sedatives (alcohol, opioids), due to an increased risk of serious adverse effects. If you’re concerned about neurotoxicity risk, do not consume at the same time as classic psychedelics like LSD, 2C-B, or shrooms, as this combination increased neurotoxicity in rodents. SSRIs like Prozac, Paxil and Zoloft are not reported interacting dangerously with MDMA, though MDMA might make SSRIs less effective and SSRIs may make MDMA less effective. Increasing your MDMA dosage to compensate is not a good idea. Read here for more.

In terms of MDMA effect on osmoregulatory function of the body, it has been revealed that the neuroendocrine hormone copeptin is detected in women immediately after ingestion as correlating with AVP in the blood. In other studies it has been reported that even at a dose of 47.5 mg there is a rapid increase in AVP and a decrease in plasma sodium within one day, while in men no changes occur. While using ecstasy, liver function tests haven't shown any changes during a month of use, however, during the first three days there has been an increase in values of alanine aminotransferase, bilirubin and aspartate aminotransferase, which has been expected and is mainly associated with hepatic metabolism. People receiving active doses of MDMA experience euphoria, positive mood, vigor, and positively experienced derealization, consonant with early retrospective reports, but also report experiencing anxiety, tension, and dysphoria, as well as concern over losing control over the self. It is uncertain whether the increases in positive and negative mood occur simultaneously or at different times throughout the duration of MDMA effects; evidence from two different teams suggests that peaks in negative mood may precede peaks in positive mood. MDMA may have a greater impact on mood in women than in men. Women report greater elevation in negative mood despite similar plasma concentrations of MDMA and metabolites to men. A second dose of MDMA 2 hours after the first does not increase subjective effects beyond that of an initial dose, interpreted by Peiro and colleagues as indications of tolerance to these effects. When two 100 mg doses are given 4 hours apart, most subjective effects are comparable to those after a single dose, despite their being double the amount of plasma MDMA. In large sample studies on MDMA effects at a dose of 125 mg the following effects have been identified at a percentage ratio: tight jaw (63.8%); lack of appetite (50%); dizziness (50%); nausea (43.1%); sensitivity to cold (39.7%); perspiration (32.8%); thirst (29.3%); anxiety (70%); headache (51.7%); fatigue (48.3%); low mood (20.7%); insomnia (34.5%). Generally, spontaneous reactions which are observed during MDMA use, are transient, their severity decreases within 24 hours (on average) due to metabolism and elimination of the substance and its metabolites. However, some effects can remain during 5-7 days after use and level completely only after 7 days. These effects include: trism or bruxism, dizziness, anxiety, lack of appetite, dizziness, nausea, headache, dry mouth, hypersensitivity to cold.
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Methods of use and doses.
MDMA use starts a couple days prior to the act of oral administration. First of all, you should be in a state of complete physical and mental well-being, you shouldn't be in acute or critical state. It is not recommended using while having experienced recent psychological trauma. You shouldn't (ideally) be taking any course of treatment. 4-5 days before use, you should start taking drugs of the proton pump inhibitor group in preventive doses (usually 20 mg of omeprazole per day); alpha-lipic acid at a dose of 600 mg per day; start a course of multivitamins (with mandatory inclusion of vitamins B and C); omega−3 fatty acids according to the instructions; or you can purchase special mixtures that contain the above substances (including acetyl L Carnitine, CoEnzyme Q10, Vitamin C, Vitamin E); pre-stock up with enough water (preferably chloride-bicarbonate-sodium like Gatorade and so on). Meals should be eaten no later than two hours in advance; the qualitative component of the food should be moderate, without a large amount of meat and fat (for preventive purposes, it is recommended to take exogenous enzymes' amylase, protease and lipase) in order to avoid problems with the pancreas. In most cases, it is recommended to follow the algorithm of “premedication before MDMA use”: 4 h before MDMA ingestion: 2 g ginger; 3 h before 500 mg ALCAR (Acetyl-L-carnitine), 500 mg Vitamin C; 2h before nothing; 1h before 2 g ginger and optional - 1 tablet (100 mg) magnesium with MDMA, 300 mg ALA (alpha-lipoic ccid), 500 mg vitamin C; 1 h after MDMA ingestion: 300 mg ALA, 500 mg ALCAR; 2 h after 300 mg ALA, Optional - 1 tablet (100 mg) Magnesium; 3 h after 300 mg ALA, 500 mg Vitamin C; 4 h after 300 mg ALA; 5h after 300 mg ALA, 500 mg ALCAR; 6 h after 300 mg ALA, 500 mg Vitamin C; 7 h after 300 mg ALA. There are anecdotal reports that taking 5-HTP in the nights following MDMA use may help reduce a comedown. There are also anecdotal reports that taking EGCG with the 5-HTP makes it more effective at reducing the comedown. There’s no strong evidence supporting either of these recommendations. There’s some evidence that a precursor to 5-HTP may be beneficial in memory related tasks in ex-MDMA users, so if you’re a heavy user or following less safe practices (e.g. re-doses, frequent use, higher dosages) it may be worth considering taking 5-HTP for a week after using MDMA, starting the night after your MDMA session. Adding green tea catechins (i.e. EGCG and EGC) should help. For safety purposes, recommends avoiding 5-HTP within 24 hours of MDMA consumption. Only consume MDMA in a positive environment to minimize the chance of a negative experience. Being at home can be more enjoyable than being out. You can be as weird as you want without judgement, you can control the music, you can dance and then stop and sit around and talk because it’s not too loud, there are no aggressive people around to make you feel uncomfortable, etc. As a bonus, MDMA is generally safer in a house instead of a club: being at home allows you to take frequent cool off breaks, to take your supplements easily, and means you can get electrolyte-containing fluids easily. Don’t be with people that make you uncomfortable, and consider avoiding sober people that you don’t know. It can also be more enjoyable to avoid drunk people, even if you know them.

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After purchasing of an ecstasy tablet, it is necessary to check it using a special test kit (for example, https://dosetest.com) or study the source (https://www.pillreports.net/), where you can find information about the tablet. The combination of these two methods will help to avoid negative complications. Common MDMA adulterants that we want to avoid include: DXM, MDA, methamphetamine, methylone and occasionally PMA/PMMA. DXM has become substantially rarer over time. Test kit set for US users with Marquis and Simon’s reagents: USA, Elevation Chemicals, Marquis and Simon’s: $29 with free shipping, 1-2 day shipping available for $45 extra; USA, DanceSafe, Marquis and Simon’s: $51 including shipping, next day shipping available for $22 extra; USA, eBay, Marquis and Simon’s: $39 including shipping; USA, Bunk Police/Lunar Laboratories, Marquis and Simon’s: $50 including shipping, next day shipping available for $58 extra; Worldwide, ships from Europe and USA, DoseTest: $30 including shipping, 1-2 day shipping available for $40 extra.

Of course, it is not recommended to use MDMA with other substances; however, it is still necessary to study the substance interaction table. MDMA dose, in case of joint use with other psychoactive substance, should be 25-50% less than the initial. Dose calculation of MDMA should exclusively be carried out using this formula: 1.54 mg/kg, depending on the dose there can be different desirable, and undesirable effects of different severity, risk of serotonin syndrome and other complications. Minimal dose of MDMA ranges from 50-90 mg which is associated with minimum risk. Medium recommended dose for most users ranges from 75 to 125 mg. A high dose ranges from 150 to 200 mg, doses exceeding 200 mg are considered dangerous. If finger dipping powder: ideally switch to weighed doses, but if not that, use “crush, dab, wait.” If using tablets and you haven’t taken a tablet from this exact batch before, start with half, or less. Low doses may be particularly important for your first few uses, as you might unknowingly have a health condition like malignant hyperthermia that makes MDMA more dangerous. A study found that MDMA desirable effects are maximized, and undesirable effects minimized, at doses between 81-100 mg. If you’re unwilling to use these dosage guidelines, please make extra sure your friends are aware of the signs of heat stroke and heat exhaustion, and pay extra attention to keeping cool. The onset of effects after oral administration of ecstasy is within the range of 20 to 40 minutes (depending on type of ecstasy, amount of food that you ate before use and other factors). The duration of effects ranges from 3 to 5 hours, post effects can remain within 24 hours. When MDMA crystals are used intranasally, the onset of effects can occur after 5-10 minutes and reach its peak at 2 hours since use, the duration of effects is about 3 hours with a tendency to decrease after 60 minutes. While it is necessary to enjoy MDMA effects during use, you also shouldn't forget about monitoring your condition (but don't get hung up on it). During use, you should drink enough chloride-bicarbonate-sodium water, the volume should correspond to 250 ml per hour (you can drink, for example, Gatorade). In case of active physical activity, the volume of oral water intake should be about 500 ml per hour (but in no more!). However, physical activity is strictly not recommended because it significantly increases the risk of side effects and acute conditions. Take into account that the volume of oral consumption decreases after 5 hours and will be 150 ml per hour. Large amount of water can also negatively affect your general somatic condition. Your body will need rest after use. To reduce the undesirable post effects you can take low doses of tranquilizers (e.g. 1 mg of alprazolam in absence of contraindications) and low therapeutic doses of beta-blockers; it is necessary to sleep (ideally – for 8 hours at night); the other part of the day should be taken to rest, to restore and “return” to the world; it is not recommended driving a car and work both during the trip and the day after; it is not recommended consuming large amounts of food the day after, it is recommended to have light meals. While research hasn’t definitively answered whether MDMA is addictive, there are certainly still people who may be concerned about their own use of MDMA or a loved one’s use of MDMA. This may be especially relevant for MDMA use that is particularly suboptimal - e.g. high doses, using more often than 3x per month, using in particularly unsafe or hot environments, etc. It is not recommended to use MDMA more than 3 times a month (ideally no more than once in 6 months) because considering the mechanism of MDMA action it causes depletion of neurotransmitters (mostly serotonin), associated with depression symptoms and other long-term post effects. You should save ecstasy for special occasions and use it sparingly. Frequent use of this substance lowers its efficacy and can cause tolerance.​

MDMA interactions with different psychoactive substances

The most dangerous combination is MDMA+MAOIs because it increases the risk of serotonin syndrome development to varying degrees of severity, which requires urgent medical care. Also, joint use of MDMA is not recommended with such psychoactive substances as DXM, αMT, tramadol, 2C-T-x. It is recommended to use MDMA with caution (ideally, it is better not to use at all or lower the dose of ecstasy by 50% of the initial one): DOx, NBOMes, 5-MeO-xxT, MXE, cocaine, caffeine, alcohol, GHB/GBL, PCP. Minimal risk (or insignificant changes in MDMA effects) is associated with combinations of MDMA with mushrooms, LSD, DMT, mescaline, cannabis, ketamine, N2O, amphetamines, SSRls, benzodiazepines, opioids.

SSRIs are the most widely prescribed class of antidepressants. SSRIs are potent inhibitors of the metabolism via the CYP450 system and, among them, some have been evaluated in combination with MDMA, such as fluoxetine (a strong inhibitor of CYP2D6 and moderate inhibitor of CYP3A4 and CYP2C9), paroxetine (a very strong CYP2D6 inhibitor), duloxetine (a moderate CYP2D6 inhibitor), while citalopram appears to have little effect on the major CYP isoforms. The experimental administration of 125 mg of MDMA in healthy subjects that have taken pretreatment with therapeutic doses of paroxetine significantly attenuates MDMA-related physiological and psychological effects. These findings are consistent with the previous administration of intravenous citalopram. The administration of 100 mg of MDMA after 5 days of treatment with therapeutic doses of fluoxetine reduces the MDMA-induced increase in HR without reducing BP. Regarding subjective effects, both studies, concluded in significant reduction in prototypical subjective effects and mood subjective effects. MDMA dopamine release mediated by D reuptake inhibition is also amplified through the activation of postsynaptic 5-HT2 receptors, and they do not exclude the hypothesis of the potential contribution of NE on the subjective effects of psychostimulants such as MDMA. While for the other SSRIs, no pharmacokinetic (PK) interaction was tested, in the case of paroxetine, a significant increase of 30% in MDMA plasmatic concentration was detected along with a decrease of 40% in concentrations of its metabolite HMMA, thus suggesting a pharmacodynamic (PD) (5HT transporter) and also PK (CYP2D6 metabolism) DI. Evidence from experimental studies, confirm the existence of a pharmacokinetic interaction mediated by CYP2D6 metabolism between MDMA with antidepressants with CYP2D6 inhibitory actions. Overall, previous administration of all of them, produced 15–30% increase in MDMA concentrations, but decreased concentrations of its metabolite HMMA by 40–50%. Thus, the metabolic change and higher MDMA concentrations considered as a phenotyping change from extensive metabolisers (EM) to poor metabolisers (PM) have been observed when antidepressant CYP2D6 inhibitors have been administered before MDMA dosing. In subjects taking medication that inhibits CYP2D6, higher MDMA concentrations and possibly also acute effects should be expected. Contrarily to SSRIs potent inhibitors of CYP2D6, other SSRIs such as citalopram at usual therapeutic dosages are probably less likely to cause significant alterations in CYP450 status and, consequently, have less risk to develop acute toxicity.

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Regarding MDMA-antipsychotic interactions, only one experimental study has been published. Haloperidol is a typical butyrophenone antipsychotic that exhibits high affinity dopamine D2 receptor antagonism. In healthy volunteers, pretreatment with haloperidol attenuated MDMA-induced positive and mania-like behaviour, but had no other effects in reducing subjective changes or cardiovascular effects. Results are consistent with a partial dopaminergic mediation of the euphoriant effects of MDMA. Relating to MDMA-psychostimulant drug interactions, only one study has evaluated the potential interaction with methylphenidate. Methylphenidate (MPH) is a psychostimulant drug prescribed to treat ADHD, a condition that affects around 5% of young people up to 18 years of age worldwide. It is also used for nonmedical conditions as cognitive enhancers among healthy subjects. Pretreatment with MPH produced significantly higher cardiovascular and haemodynamic responses than either drug alone, although pharmacokinetics of MDMA were not altered for MPH administration. Methylphenidate did not enhance the psychoactive effects of MDMA. The results observed are in accordance with previous evidences that both drugs induce a weaker increase in NA exerting sympathomimetic properties. MPH mainly enhances DA neurotransmission, whereas MDMA mainly acts enhancing 5-HT neurotransmission. Memantine is a low-affinity N-methyl-D-aspartate receptor antagonist and alpha 7 nicotinic acetylcholine antagonist approved in some countries for the symptomatic treatment of patients with moderate to severe Alzheimer's. Memantine has been hypothesized as a potential drug to prevent and/or overcome the memory impairment caused by MDMA use in humans. In fact, some ecstasy drug-user forums and blogs reported MDMA use in combination with memantine to provide neuroprotection and to reverse deficits in learning/memory. At this respect, only one experimental study has been performed in humans in order to evaluate MDMA-memantine interaction, which had negative results. Preliminary evidence shows that memantine does not reverse MDMA-induced memory impairment and mood effects. In addition, no PK changes were detected in MDMA concentrations. Pindolol is a non-selective beta-adrenergic antagonist (beta-blocker) used as an antihypertensive agent. Pretreatment with pindolol reduced MDMA-induced tachycardia but did not reduce neither hypertensive effects nor other adverse effects related to MDMA. Furthermore, while pindolol moderately attenuated the increases in positive mood, dreaminess, derealisation and mania-like behaviour induced by MDMA, it did not have any effect on MDMA-induced cognitive performance impairment. These results could be attributed to a potential role for serotonergic 5-HT1 receptors in the mediation of the mood effects of MDMA. Carvedilol is an alfa1 (α1) and beta (β1) adrenergic antagonist indicated for the treatment of mild- to-severe chronic heart failure of ischemic or cardiomyopathic origin, usually in addition to diuretics, angiotensin-converting-enzyme inhibitors (ACE inhibitors), and digitalis. Probably, based on the evidence of the beta-blocker effect of the cocaine-induced haemodynamic response in humans, the potential existence of an interaction between carvedilol and MDMA has been evaluated. Pretreatment with carvedilol reduced MDMA-induced increases in BP, HR and T, although it did not affect the subjective effects of MDMA neither did it modify the MDMA plasma concentrations. Clonidine is a α2-adrenergic agonist used as an antihypertensive agent. Pretreatment with clonidine did not modify neither the physiological nor the subjective effects. No alteration was detected in plasma concentrations of MDMA. The coadministration of MDMA and clonidine results in a decrease in plasma concentration of norepinephrine, which has been correlated with hypotensive effects. Doxazosin is a α1-adrenergic antagonist used to treat hypertension and symptoms of benign prostatic hyperplasia. Pretreatment with doxazosin had very modest effects on HR and BP produced by MDMA but not on T. Doxazosin has been proven to attenuate mood effects of MDMA. As expected, the effects of doxazosin on the cardiovascular response of MDMA are consistent with the sympathetic effects mediated by the effects of epinephrine and NE on peripheral vasculature.Ketanserin is a 5-HT receptor antagonist antihypertensive drug, as well as an adrenergic receptor blocker and dopamine antagonist. The experimental administration of MDMA in pretreatment with ketanserin produced a reduction in anxiety, but not in memory test scores. In addition, no alterations in MDMA concentrations were observed. Ketanserin attenuated MDMA- induced perceptual changes, emotional excitation, and acute adverse responses. Evidence shows that 5-HT1 and 5-HT2 receptors contribute to the influence of MDMA on mood and impulsivity. Dextromethorphan (DEX) is an over-the-counter (OTC) antitussive found alone and in most cough and cold products, frequently in combination with antihistamines and/or pseudoephedrine. DM has a complex pharmacology with mechanisms beyond blockade of N-methyl-d-aspartate (NMDA) receptors and inhibition of glutamate excitotoxicity, likely contributing to its pharmacological activity and clinical potential. It is well-knowledge that DEX is primarily metabolized to dextrorphan by CYP2D6, which has hampered the exploration of DEX therapy separate from its metabolites. DEX has been used as probe drug to evaluate changes in CYP2D6 activity using urinary metabolic ratio of DEX and dextrorphan. MDMA administration before DEX produced a strong inhibition of CYP2D6 that reduced the metabolism of DEX, recovery to 90-100% last 10 days after MDMA exposure in both men and women. Alcohol is the most widely used licit substance worldwide and the mainly concomitant substance used among ecstasy/MDMA users. It is a CNS depressant drug that that promotes simultaneous changes in several neuronal pathways that leads to various behavioural and biological alterations.

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Alcohol exerts direct effects on several neurotransmitter receptors (gamma-aminobutyric acid [GABA], glutamate, endocannabinoids and others), indirect effects on the limbic and opioid systems, and also effects on calcium and potassium channels and on proteins regulated by GABA in the hippocampus. Four studies in experimental conditions point out that concomitant MDMA and alcohol produce an increase in MDMA concentrations ranging from 7–13% and long-lasting duration of subjective effects. Unpublished data of the same study showed that the combination produced higher and long-lasting cardiovascular effects (BP and HR) and a slight increase in body temperature. The use of both drugs increases the levels of dopamine in the brain due to dopamine’s function in the experience of reinforcement. The euphoria that occurs as a result of these drugs is reinforcing, which leads to an increase in dopamine. Cannabis (THC) is a drug of abuse frequently used among recreational ecstasy/MDMA users to reduce MDMA’s initial psychostimulant effects and to attenuate the post-MDMA comedown. Preclinical studies have shown that a combined administration of MDMA with THC induces hyperthermia and decreases hyperactivity in animal models in order to achieve neuroprotection and/or prevent toxicity. In humans, the investigation in experimental conditions is limited to one clinical trial. Results did not show alterations in MDMA plasma concentrations, but they did show a significant reduction in HR. Caffeine (1,3,7-trimethylxanthine) is the most consumed legal psychoactive substance contained in foods and beverages such as coffee, sodas, energy drinks, and shot energy among others in the world. It acts on adenosine receptor as antagonism whose actions include G-protein-coupled mainly. It exerts CNS effects mainly by antagonizing the adenosine A1 and A2A receptors. It is commonly used in combination with MDMA in order to reduce drowsiness and fatigue, primarily as energy drinks and caffeine tablets and more recently as caffeine intranasal sprays and sublingual strips. It is notable to remark that caffeine is also present as adulterant in ecstasy pills. Caffeine, similarly to DEX, has been extensively used as a probe drug to investigate CYP1A2 activity, based in the ratio of caffeine and its metabolite paraxanthine. There is only one study has monitored caffeine metabolism by CYP1A2 after MDMA administration. The results showed a modest increase in the metabolism of caffeine. In terms of CYP1A2 activity, the results shown an increase in activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females. It points out the existence of a compensatory mechanism between the CYP 450 isozymes in order to metabolically clear MDMA.

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Prospects of MDMA therapy.
MDMA therapy seems to work by helping you trust yourself and helping you accept parts of yourself. MDMA provides a feeling of safety, peacefulness, and love, that allows you to revisit both past experiences and parts of yourself that you don’t fully accept. The MDMA also enhances the bond between the client and the therapist, which also seems to help enable deeper healing.“One day, I met a therapist who recommended using MDMA to get ‘unstuck.’ From the very first session, I began making amazing breakthroughs. The split between my mind and my body began to dissolve. Being present in my body became an experience, not a concept. My heat opened. I could access blocked emotions as never before. As I continued psychedelic therapy, I discovered and worked through trauma of childhood neglect and abuse. Hidden sources of my chronic illness, anxiety, and depression were revealed. My colitis healed, my depression vanished, and my health improved. As my sexual and relationship issues healed, I was able to manifest the healthy, happy marriage I enjoy today. I spent years in cognitive and Reichian therapy before I discovered psychedelic-assisted psychotherapy. I meditated, practiced yoga, got Rolfed and rebirth. All these were helpful, but were only able to take me so far. I believe that without the help of psychedelics I would never have healed. Psychedelic therapy saved my life.” – R. Coleman in the book Psychedelic Psychotherapy: A User-friendly Guide for Psychedelic Drug-assisted Psychotherapy.

“I did MDMA therapy. It was a deeply profound and life-changing experience. I did two treatments, one in early September, another in early October. I would rank it as one of the top 3 most important things I’ve done in my life, at least in terms of my personal development. I’m writing about it because I think this therapy could help a lot of people, and more people need to know it's an option. In this piece, I’ll explain why I did it, what it was like, how it impacted me, and resources for how to seek out more info. I’m not trying to convince you to do MDMA therapy, but I won’t pretend to be objective. I do have a viewpoint: MDMA therapy fundamentally changed my life, I think it could be impactful for many people, and I believe it will become a major part of the future of therapy” – Tucker Max in What MDMA Therapy Did For Me. If you’re interested in MDMA therapy, we highly recommend looking into IFS therapy. It’s a primary method used by MAPS MDMA therapists, and you can work with it today, with or without a therapist. You may be able to get some, but not all, of the benefits of MDMA therapy just by doing IFS therapy. Here are the USA studies that are actively recruiting volunteers for MDMA research. FDA has granted MDMA “Breakthrough Therapy” status, which means that “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy”. In studies analyzed, MDMA for PTSD had a large treatment effect, and effectively cured 54% of the participants’ PTSD. “After two blinded experimental sessions, the active group had significantly greater reductions in CAPS-IV total scores from baseline than the control group [MMRM estimated mean difference (SE) between groups − 22.0, P < 0.001]. The between-group "Cohen’s effect size was 0.8, indicating a large treatment effect". It might be possible to become a legal MDMA therapist in the USA in 2019, via MAPS’ FDA Expanded Access program. To apply you need a prescribing MD or similar, a licensed therapist, and a qualified site. To begin applying, see the instructions under “how to apply” on this page: https://maps.org/training. Rent and watch the MDMA therapy documentary “Trip of Compassion”.

MDMA Therapy Playlists.
Documentaries and videos.

 
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