Of mice and men on MDMA: A translational comparison of the neuropsychobiological effects of 3,4-methylenedioxymethamphetamine ('Ecstasy').

MDMA (3,4-methylendioxymethamphetamine), also known as Ecstasy, is a stimulant drug recreationally used by young adults usually in dance clubs and raves. Acute MDMA administration increases serotonin, dopamine and noradrenaline by reversing the action of the monoamine transporters. In this work, we review the studies carried out over the last 30 years on the neuropsychobiological effects of MDMA in humans and mice and summarise the current knowledge. The two species differ with respect to the neurochemical consequences of chronic MDMA, since it preferentially induces serotonergic dysfunction in humans and dopaminergic neurotoxicity in mice. However, MDMA alters brain structure and function and induces hormonal, psychomotor, neurocognitive, psychosocial and psychiatric outcomes in both species, as well as physically damaging and teratogen effects. Pharmacological and genetic studies in mice have increased our knowledge of the neurochemical substrate of the multiple effects of MDMA. Future work in this area may contribute to developing pharmacological treatments for MDMA-related disorders.

Substance usage intention does not affect attentional bias: implications from Ecstasy/MDMA users and alcohol drinkers.

BACKGROUND: An attentional bias towards substance-related stimuli has been demonstrated with alcohol drinkers and many other types of substance user. There is evidence to suggest that the strength of an attentional bias may vary as a result of context (or use intention), especially within Ecstasy/MDMA users. OBJECTIVE: Our aim was to empirically investigate attentional biases by observing the affect that use intention plays in recreational MDMA users and compare the findings with that of alcohol users. METHOD: Regular alcohol drinkers were compared with MDMA users. Performance was assessed for each group separately using two versions of an eye-tracking attentional bias task with pairs of matched neutral, and alcohol or MDMA-related visual stimuli. Dwell time was recorded for alcohol or MDMA. Participants were tested twice, when intending and not intending to use MDMA or alcohol. Note, participants in the alcohol group did not complete any tasks which involved MDMA-related stimuli and vice versa. RESULTS: Significant attentional biases were found with both MDMA and alcohol users for respective substance-related stimuli, but not control stimuli. Critically, use intention did not affect attentional biases. Attentional biases were demonstrated with both MDMA users and alcohol drinkers when usage was and was not intended. CONCLUSIONS: These findings demonstrate the robust nature of attentional biases i.e. once an attentional bias has developed, it is not readily affected by intention.

Mood Fluctuation and Psychobiological Instability: The Same Core Functions Are Disrupted by Novel Psychoactive Substances and Established Recreational Drugs.

Many novel psychoactive substances (NPS) have entered the recreational drug scene in recent years, yet the problems they cause are similar to those found with established drugs. This article will debate the psychobiological effects of these newer and more traditional substances. It will show how they disrupt the same core psychobiological functions, so damaging well-being in similar ways. Every psychoactive drug causes mood states to fluctuate. Users feel better on-drug, then feel worse off-drug. The strength of these mood fluctuations is closely related to their addiction potential. Cyclical changes can occur with many other core psychobiological functions, such as information processing and psychomotor speed. Hence the list of drug-related impairments can include: homeostatic imbalance, HPA axis disruption, increased stress, altered sleep patterns, neurohormonal changes, modified brain rhythms, neurocognitive impairments, and greater psychiatric vulnerability. Similar patterns of deficit are found with older drugs such as cocaine, nicotine and cannabis, and newer substances such as 3,4-methylenedioxymethamphetamine (MDMA), mephedrone and spice. All psychoactive drugs damage human well-being through similar basic neuropsychobiological mechanisms.

MDMA and brain activity during neurocognitive performance: An overview of neuroimaging studies with abstinent 'Ecstasy' users.

MDMA/Ecstasy has had a resurgence in popularity, with recent supplies comprising higher strength MDMA, potentially leading to increased drug-related harm. Neurocognitive problems have been widely reported in ecstasy users, equally some studies report null findings, and it remains unclear which factors underlie the development of neurocognitive impairments. This review covers the empirical research into brain activity during neurocognitive performance, using fMRI, fNIRS, and EEG. Our main conclusion is that chronic repeated use of recreational ecstasy can result in haemodynamic and electrophysiological changes that reflect recruitment of additional resources to perform cognitive tasks. Findings are consistent with serotonergic system changes, although whether this reflects neurotoxicity or neuroadaptation, cannot be answered from these data. There is a degree of heterogeneity in the methodologies and findings, limiting the strengths of current conclusions. Future research with functional neuroimaging paired with molecular imaging, genetics or pharmacological challenges of the serotonin system may help to decipher the link between serotonergic and cognitive changes in ecstasy users.

Cannabis: An Overview of its Adverse Acute and Chronic Effects and its Implications.

In many communities, cannabis is perceived as a low-risk drug, leading to political lobbying to decriminalise its use. Acute and chronic cannabis use has been shown to be harmful to several aspects of psychological and physical health, such as mood states, psychiatric outcomes, neurocognition, driving and general health. Furthermore, cannabis is highly addictive, and the adverse effects of withdrawal can lead to regular use. These in turn have adverse implications for public safety and health expenditure. Although the cannabinoid cannabidiol (CBD) has been shown to have positive health outcomes with its antioxidant, anticonvulsant, anti-inflammatory and neuroprotective properties, high-potency cannabis is particularly damaging due to its high tetrahydrocannabinol (THC), low CDB concentration. It is this high-potency substance that is readily available recreationally. While pharmaceutical initiatives continue to investigate the medical benefits of CDB, "medicinal cannabis" still contains damaging levels of THC. Altogether, we argue there is insufficient evidence to support the safety of cannabis and its subsequent legalisation for recreational use. Furthermore, its use for medicinal purposes should be done with care. We argue that the public conversation for the legalisation of cannabis must include scientific evidence for its adverse effects.

Recreational 3,4-methylenedioxymethamphetamine or 'ecstasy': Current perspective and future research prospects.

AIMS: The purpose of this article is to debate current understandings about the psychobiological effects of recreational 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy'), and recommend theoretically-driven topics for future research. METHODS: Recent empirical findings, especially those from novel topic areas were reviewed. Potential causes for the high variance often found in group findings were also examined. RESULTS AND CONCLUSIONS: The first empirical reports into psychobiological and psychiatric aspects from the early 1990s concluded that regular users demonstrated some selective psychobiological deficits, for instance worse declarative memory, or heightened depression. More recent research has covered a far wider range of psychobiological functions, and deficits have emerged in aspects of vision, higher cognitive skill, neurohormonal functioning, and foetal developmental outcomes. However, variance levels are often high, indicating that while some recreational users develop problems, others are less affected. Potential reasons for this high variance are debated. An explanatory model based on multi-factorial causation is then proposed. FUTURE DIRECTIONS: A number of theoretically driven research topics are suggested, in order to empirically investigate the potential causes for these diverse psychobiological deficits. Future neuroimaging studies should study the practical implications of any serotonergic and/or neurohormonal changes, using a wide range of functional measures.

Recreational stimulants, herbal, and spice cannabis: The core psychobiological processes that underlie their damaging effects.

AIMS: Recreational drugs are taken for their positive mood effects, yet their regular usage damages well-being. The psychobiological mechanisms underlying these damaging effects will be debated. METHODS: The empirical literature on recreational cannabinoids and stimulant drugs is reviewed. A theoretical explanation for how they cause similar types of damage is outlined. RESULTS: All psychoactive drugs cause moods and psychological states to fluctuate. The acute mood gains underlie their recreational usage, while the mood deficits on withdrawal explain their addictiveness. Cyclical mood changes are found with every central nervous system stimulant and also occur with cannabis. These mood state changes provide a surface index for more profound psychobiological fluctuations. Homeostatic balance is altered, with repetitive disturbances of the hypothalamic-pituitary-adrenal axis, and disrupted cortisol-neurohormonal secretions. Hence, these drugs cause increased stress, disturbed sleep, neurocognitive impairments, altered brain activity, and psychiatric vulnerability. Equivalent deficits occur with novel psychoactive stimulants such as mephedrone and artificial "spice" cannabinoids. These psychobiological fluctuations underlie drug dependency and make cessation difficult. Psychobiological stability and homeostatic balance are optimally restored by quitting psychoactive drugs. CONCLUSIONS: Recreational stimulants such as cocaine or MDMA (3.4-methylenedioxymethamphetamine) and sedative drugs such as cannabis damage human homeostasis and well-being through similar core psychobiological mechanisms.

Psychomotor Tremor and Proprioceptive Control Problems in Current and Former Stimulant Drug Users: An Accelerometer Study of Heavy Users of Amphetamine, MDMA, and Other Recreational Stimulants.

The recreational use of various stimulant drugs has been implicated in the development of movement disorders through dysregulation of the dopaminergic and serotoninergic neurotransmitter systems. The present study investigated psychomotor differences in current and former recreational stimulant drug users compared with nonusing controls. Sixty participants comprised 3 groups: 20 current stimulant drug users (CSUs; 11 men, aged 31.4 ± 9.1 years), 20 former stimulant drug users (FSUs; 5 men, aged 39.1 ± 8.5 years), and 20 nonuser controls (NUCs; 5 men, aged 35.7 ± 6.4 years). Psychomotor arm steadiness for each participant was assessed with a wrist-attached accelerometer during 5 arm positions with eyes open and then eyes closed. Arm-drop of arm position was indicated by the arm longitudinal rotation axis (ALoRA), and tremor was indicated by the overall vector of dynamic body acceleration (VeDBA). Overall, CSUs performed the most poorly on ALoRA (P < .05) and VeDBA indices (P < .05), and FSUs perform almost as poorly on VeDBA indices (P < .05) compared with NUCs. It was concluded that stimulant drug use, primarily MDMA and amphetamines, may result in acute stimulant-induced tremor as well as long-term proprioceptive deficits in terms of arm-droop.

Oxytocin, cortisol and 3,4-methylenedioxymethamphetamine: neurohormonal aspects of recreational 'ecstasy'.

Most research into 3,4-methylenedioxymethamphetamine (MDMA) has debated its psychobiological effects in relation to neurotransmission. This article debates the contributory roles of the neurohormones oxytocin and cortisol for their psychobiological effects in humans. The empirical literature on these neurohormones is reviewed and suggestions for future research outlined. Acute MDMA or 'ecstasy' can generate increased levels of oxytocin and cortisol, and these neurohormonal changes may be important for its mood-enhancing and energy-activation effects in humans. However, an initial finding of enhanced sociability correlating with oxytocin levels has not been replicated. Potential reasons are debated. There may be dynamic interactions between the two neurohormones, with greater activation under cortisol, facilitating stronger positive feelings under oxytocin. Chronic regular use of MDMA can adversely affect cortisol in several ways. Regular users show increased cortisol in 3-month hair samples, changes to the cortisol awakening response, and indications of greater daily stress. Furthermore, these cortisol findings suggest changes to the hypothalamic-pituitary-adrenal axis. The effects of chronic MDMA usage on oxytocin still need to be investigated. It is concluded that the neurohormones oxytocin and cortisol contribute in various ways to the psychobiological effects of recreational ecstasy/MDMA.

Motor delays in MDMA (ecstasy) exposed infants persist to 2 years.

BACKGROUND: Recreational use of 3,4 methylenedioxymethamphetamine (ecstasy, MDMA) is increasing worldwide. Its use by pregnant women causes concern due to potentially harmful effects on the developing fetus. MDMA, an indirect monoaminergic agonist and reuptake inhibitor, affects the serotonin and dopamine systems. Preclinical studies of fetal exposure demonstrate effects on learning, motor behavior, and memory. In the first human studies, we found prenatal MDMA exposure related to poorer motor development in the first year of life. In the present study we assessed the effects of prenatal exposure to MDMA on the trajectory of child development through 2 years of age. We hypothesized that exposure would be associated with poorer mental and motor outcomes. MATERIALS AND METHODS: The DAISY (Drugs and Infancy Study, 2003-2008) employed a prospective longitudinal cohort design to assess recreational drug use during pregnancy and child outcomes in the United Kingdom. Examiners masked to drug exposures followed infants from birth to 4, 12, 18, and 24 months of age. MDMA, cocaine, alcohol, tobacco, cannabis, and other drugs were quantified through a standardized clinical interview. The Bayley Scales (III) of Mental (MDI) and Motor (PDI) Development and the Behavior Rating Scales (BRS) were primary outcome measures. Statistical analyses included a repeated measures mixed model approach controlling for multiple confounders. RESULTS: Participants were pregnant women volunteers, primarily white, of middle class socioeconomic status, average IQ, with some college education, in stable partner relationships. Of 96 women enrolled, children of 93 had at least one follow-up assessment and 81 (87%) had ≥ two assessments. Heavier MDMA exposure (M=1.3±1.4 tablets per week) predicted lower PDI (p<.002), and poorer BRS motor quality from 4 to 24 months of age, but did not affect MDI, orientation, or emotional regulation. Children with heavier exposure were twice as likely to demonstrate poorer motor quality as lighter and non-exposed children (O.R.=2.2, 95%, CI=1.02-4.70, p<.05). DISCUSSION: Infants whose mothers reported heavier MDMA use during pregnancy had motor delays from 4 months to two years of age that were not attributable to other drug or lifestyle factors. Women of child bearing age should be cautioned about the use of MDMA and MDMA-exposed infants should be screened for motor delays and possible intervention.

Why all stimulant drugs are damaging to recreational users: an empirical overview and psychobiological explanation.

AIMS: Stimulant drugs such as nicotine and Ecstasy/3, 4-methylenedioxymethamphetamine (MDMA) are taken for positive reasons, yet their regular use leads to deficits rather than gains. This article outlines the psychobiological rationale for this paradox. METHODS: The empirical literature on nicotine, cocaine, amphetamine, Ecstasy/MDMA, and mephedrone are reviewed. A theoretical explanation for why they are problematic to humans is then described. RESULTS: The acute effects of central nervous system (CNS) stimulants are typically positive, with greater alertness and emotional intensity. However, in the post-drug recovery period, the opposite feelings develop, with lethargy and low moods. All recreational stimulants cause mood fluctuation, although it is most pronounced in drugs with rapid onset and comedown (e.g. nicotine and cocaine), explaining why they are the most addictive. Parallel fluctuations occur across many psychological and neurocognitive functions, with users suffering various off-drug deficits. CNS stimulants also affect the hypothalamic-pituitary-adrenal axis, impairing sleep, disrupting homeostasis, and exacerbating psychiatric distress. Neuroimaging studies reveal altered brain activity patterns in regular users. These problems are related to lifetime usage but commence in novice users. CONCLUSIONS: Repetitive CNS stimulation is potentially damaging to the organism, both acutely and chronically. The review describes the various psychobiological systems through which recreational stimulant drugs impair human well-being.

Greater sexual risk-taking in female and male recreational MDMA/ecstasy users compared with alcohol drinkers: a questionnaire study.

AIMS: Previous studies have shown increased sexual risk-taking in experienced MDMA/ecstasy users. The main objectives of this study were to compare levels of sexual risk-taking between a young student sample of predominantly heterosexual MDMA users and alcohol-drinker controls and investigate potential gender differences. METHODS: Recreational drug use and sexual risk questionnaires were completed by 20 MDMA users (10 females, 10 males) and 20 non-user controls (10 females, 10 males). They were predominantly university students, aged between 20-22 years, mainly heterosexual (n = 37), with three bisexual participants. RESULTS: MDMA users displayed significantly greater levels of sexual risk-taking than the alcohol-drinker controls. It involved significantly higher rates of casual sex, non-condom use during sex, and penetrative sexual risks. This increase in sexual riskiness occurred to a similar extent in males and females. CONCLUSIONS: These findings indicate that both female and male ecstasy/MDMA users reported more risky sexual behaviours, than the non-user controls. Further research into the sexual behaviour and sexual risk-taking of heterosexual MDMA users should be conducted because much of the past literature has focused on homosexual participants.

Developmental outcomes of 3,4-methylenedioxymethamphetamine (ecstasy)-exposed infants in the UK.

OBJECTIVE: This paper aims to review findings from a longitudinal study of prenatal methylenedioxymethamphetamine (MDMA, "ecstasy") on infant development. METHODS: In a prospective, longitudinal cohort design, we followed 28 MDMA-exposed and 68 non-MDMA-exposed infants from birth to 2 years of age. Women recruited voluntarily into a study of recreational drug use during pregnancy were interviewed to obtain type, frequency, and amount of recreational drug use. Their children were followed for a 2-year period after birth. A large number of drug and environmental covariates were controlled. Infants were seen at 1, 4, 12, 18, and 24 months using standardized normative tests of mental and motor development. RESULTS: There were no differences between MDMA-exposed and non-MDMA-exposed infants at birth except that MDMA-exposed infants were more likely to be male. Motor delays were evident in MDMA infants at each age and amount of MDMA exposure predicted motor deficits at 12 months in a dose-dependent fashion. CONCLUSIONS: Prenatal MDMA exposure is related to fine and gross motor delays in the first 2 years of life. Follow-up studies are needed to determine long-term effects.

Reduced memory skills and increased hair cortisol levels in recent Ecstasy/MDMA users: significant but independent neurocognitive and neurohormonal deficits.

OBJECTIVES: The goals of this study were to measure the neurocognitive performance of recent users of recreational Ecstasy and investigate whether it was associated with the stress hormone cortisol. METHODS: The 101 participants included 27 recent light users of Ecstasy (one to four times in the last 3 months), 23 recent heavier Ecstasy users (five or more times) and 51 non-users. Rivermead paragraph recall provided an objective measure for immediate and delayed recall. The prospective and retrospective memory questionnaire provided a subjective index of memory deficits. Cortisol levels were taken from near-scalp 3-month hair samples. RESULTS: Cortisol was significantly raised in recent heavy Ecstasy users compared with controls, whereas hair cortisol in light Ecstasy users was not raised. Both Ecstasy groups were significantly impaired on the Rivermead delayed word recall, and both groups reported significantly more retrospective and prospective memory problems. Stepwise regression confirmed that lifetime Ecstasy predicted the extent of these memory deficits. CONCLUSIONS: Recreational Ecstasy is associated with increased levels of the bio-energetic stress hormone cortisol and significant memory impairments. No significant relationship between cortisol and the cognitive deficits was observed. Ecstasy users did display evidence of a metacognitive deficit, with the strength of the correlations between objective and subjective memory performances being significantly lower in the Ecstasy users.

MDMA, cortisol, and heightened stress in recreational ecstasy users.

Stress develops when an organism requires additional metabolic resources to cope with demanding situations. This review will debate how recreational 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') can increase some aspects of acute and chronic stress in humans. Laboratory studies on the acute effects of MDMA on cortisol release and neurohormone levels in drug-free regular ecstasy/MDMA users have been reviewed, and the role of the hypothalamic-pituitary-adrenal (HPA) axis in chronic changes in anxiety, stress, and cognitive coping is debated. In the laboratory, acute ecstasy/MDMA use can increase cortisol levels by 100-200%, whereas ecstasy/MDMA-using dance clubbers experience an 800% increase in cortisol levels, because of the combined effects of the stimulant drug and dancing. Three-month hair samples of abstinent users revealed cortisol levels 400% higher than those in controls. Chronic users show heightened cortisol release in stressful environments and deficits in complex neurocognitive tasks. Event-related evoked response potential studies show altered patterns of brain activation, suggestive of increased mental effort, during basic information processing. Chronic mood deficits include more daily stress and higher depression in susceptible individuals. We conclude that ecstasy/MDMA increases cortisol levels acutely and subchronically and that changes in the HPA axis may explain why recreational ecstasy/MDMA users show various aspects of neuropsychobiological stress.

The potential dangers of using MDMA for psychotherapy.

MDMA has properties that may make it attractive for psychotherapy, although many of its effects are potentially problematic. These contrasting effects will be critically reviewed in order to assess whether MDMA could be safe for clinical usage. Early studies from the 1980s noted that MDMA was an entactogen, engendering feelings of love and warmth. However, negative experiences can also occur with MDMA since it is not selective in the thoughts or emotions it releases. This unpredictability in the psychological material released is similar to another serotonergic drug, LSD. Acute MDMA has powerful neurohormonal effects, increasing cortisol, oxytocin, testosterone, and other hormone levels. The release of oxytocin may facilitate psychotherapy, whereas cortisol may increase stress and be counterproductive. MDMA administration is followed by a period of neurochemical recovery, when low serotonin levels are often accompanied by lethargy and depression. Regular usage can also lead to serotonergic neurotoxicity, memory problems, and other psychobiological problems. Proponents of MDMA-assisted therapy state that it should only be used for reactive disorders (such as PTSD) since it can exacerbate distress in those with a prior psychiatric history. Overall, many issues need to be considered when debating the relative benefits and dangers of using MDMA for psychotherapy.

MDMA is certainly damaging after 25 years of empirical research: a reply and refutation of Doblin et al. (2014).

Human Psychopharmacology recently published my review into the increase in empirical knowledge about the human psychobiology of MDMA over the past 25 years (Parrott, 2013a). Deficits have been demonstrated in retrospective memory, prospective memory, higher cognition, complex visual processing, sleep architecture, sleep apnoea, pain, neurohormonal activity, and psychiatric status. Neuroimaging studies have shown serotonergic deficits, which are associated with lifetime Ecstasy/MDMA usage, and degree of neurocognitive impairment. Basic psychological skills remain intact. Ecstasy/MDMA use by pregnant mothers leads to psychomotor impairments in the children. Hence, the damaging effects of Ecstasy/MDMA were far more widespread than was realized a few years ago. In their critique of my review, Doblin et al. (2014) argued that my review contained misstatements, omitted contrary findings, and recited dated misconceptions. In this reply, I have answered all the points they raised. I have been able to refute each of their criticisms by citing the relevant empirical data, since many of their points were based on inaccurate summaries of the actual research findings. Doblin and colleagues are proponents of the use of MDMA for drug-assisted psychotherapy, and their strongest criticisms were focused on my concerns about this proposal. However, again all the issues I raised were based on sound empirical evidence or theoretical understanding. Indeed I would recommend potentially far safer co-drugs such as D-cycloserine or oxytocin. In summary, MDMA can induce a wide range of neuropsychobiological changes, many of which are damaging to humans.

MDMA and heightened cortisol: a neurohormonal perspective on the pregnancy outcomes of mothers used 'Ecstasy' during pregnancy.

OBJECTIVE: The illicit recreational drug 3,4-methylenedioxymethamphetamine (MDMA) or Ecstasy has strong neurohormonal effects. When taken by recreational users at dance clubs and raves, it can generate an 800% increase in the stress hormone cortisol, whereas drug-free users show chronically raised levels of cortisol. The aim here is to critically debate this neurohormonal influence for the children of pregnant MDMA-using mothers. METHODS: High levels of cortisol are known to be damaging for neuropsychobiological well-being in adult humans. MDMA can damage foetal development in laboratory animals, and the prospective Drugs and Infancy Study was established to monitor the effects of MDMA taken recreationally by pregnant women. RESULTS: The Drugs and Infancy Study revealed that young mothers, who took MDMA during the first trimester of pregnancy, gave birth to babies with significant gross psychomotor retardation. These mothers would have experienced high levels of cortisol due to Ecstasy/MDMA use, and since cortisol can cross the placenta, this is likely to have also occurred in the foetus. CONCLUSIONS: In terms of causation, the developmental problems may reflect a combination of neurotransmitter and neurohormonal effects on the hypothalamic-pituitary-adrenal axis, with serotonergic activity being influenced by the high levels of cortisol.