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MDMA and PTSD
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2
Drafted by
Amanda Feilding - Beckley Foundation
Mendel Kaelen - Imperial College London
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1. Introduction
1.1 Treatments for PTSD.
1.2 The Beckley-Imperial research program and the aim of this document.
2. Post-traumatic stress disorder
2.1 Neurophysiology of PTSD.
2.2 The role of serotonin in anxiety regulation.
2.3 The neurophysiology of PTSD: A summary.
3. Brain mechanisms of MDMA
3.1 Pharmacology and subjective effects.
3.2 Neuropharmacology.
3.3 Neuroimaging studies to the acute effects of MDMA in humans.
4. Therapeutic mechanisms of MDMA
4.1 MDMA’s effects on the 5-HT1A receptor system.
4.2 MDMA’s effect on brain circuitry involved in anxiety regulation.
4.3 MDMA’s effect on therapeutic alliance.
4.4 Potential mechanisms explaining MDMA’s long term therapeutic effects.
5. Safety of MDMA
5.1 Animal studies.
5.2 Human studies.
5.3 How safe is MDMA in the treatment for PTSD.
6. Conclusions and recommendations for future research
6.1 Document summary.
6.2 Future research.
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Glossary
5-HT: Serotonin
ACTH: adrenocorticotropic hormone
CRF: corticotropin-releasing factor
CSF: cerebrospinal fluid
DA: dopamine
DAT: Dopamine transporter
FDA: Food and Drug Administration
fMRI: Functional Magnetic Resonance Imaging
GR: glucorticoid receptors
HPA-axis: hypothalamic pituitary-adrenocortical axis
MDMA: 3,4-methylenedioxymethamphetamine
MEG: Magnetoencephalography
NE: norepinephrine
NET: Norepinephrine transporter
PET: Positron emission tomography
PFC: Prefrontal cortex
PTSD: Post-traumatic stress disorder
PVN: paraventricular nucleus of the hypothalamus
rCBF: region cerebral blood flow
SERT: Serotonin transporter
SSRI: Selective serotonin reuptake inhibitor
World Health Organization (WHO)
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1 Introduction
Although the development of modern medicine has yielded a variety of successful treatments
of many serious medical conditions, many illnesses are still difficult to treat and impose a significant
burden on individuals, families and society. An estimated 26% of Americans aged 18 and older suffer
from a diagnosable mental disorder in a given year (Kessler et al 2006), which translates to 57.7
million people. In 2011 the World Health Organization (WHO) reported that mental illnesses are the
leading causes of disability adjusted life years worldwide, accounting for 37% of lost healthy years
(WHO, 2011). The annual global costs of mental illnesses were estimated at nearly $2.5 trillion in 2010,
and expected to increase to over $6 trillion a year by 2030 (WHO, 2011). One third of these costs can
be contributed as indirect consequences of mental illness. For example, severe mental illness is
associated with an unemployment rate of up to 90% (Latimer et al 2009).
The pressing need to redesign health care systems and to invest in research, training,
treatment and prevention is widely recognized (Colins et al 2011). In this light, more recent attention
has been drawn to novel treatments for post-traumatic stress disorder (PTSD) - a highly prevalent and
severely disabling anxiety disorder. The traumatic events that most often give rise to PTSD include
assault, combat and rape, but also natural disaster and man-made accidents (Yehuda and LeDoux,
2007a). Although lifetime exposure to a traumatic event varies between 40% to 90%, only about 10%
of these people develop PTSD as a consequence (Breslau, 2002). Prevalence in the overall population
is estimated to range from 5% to 6% in men and 10% to 14% in women (Breslau, 2002). Those who are
exposed to warfare are especially prone to PTSD. About 19% of Vietnam veterans (Dohrenwend et al
2006) and 21.8% of Iraq/Afghanistan veterans (Seal et al . 2009) experienced Post-traumatic Stress-
Disorder (PTSD) at some point after the war, with a two- to three-fold increase of suicide in military
men aged 24 years old or younger after.
The clinical condition of PTSD is characterized by a re-living of the traumatic event in the
form of anxiety, panic and nightmares, accompanied by high rates of medical and psychiatric co-
morbidity and increased disability, drug abuse and suicide (Perkonigg et al., 2000; Breslau, 2001;
Kessler et al., 2005; Seal et al., 2010). In addition to anxiety, patients often suffer from depressive
thoughts, emotional instability, insomnia and diverse somatic symptoms (Yehuda and LeDoux,
2007b;van Praag, 2004). What is typical for PTSD and what makes it distinguishable from other
anxiety disorders are the involuntary nature and the intense distress of the reliving. Typically,
patients cope with these symptoms by emotional and social withdrawal, and develop an increased
defensiveness against the trauma-related content.
1.1 Treatments for PTSD. The only pharmacological treatments for PTSD that are currently
approved by the Food and Drug Administration (FDA) are the selective serotonin reuptake inhibitor
(SSRIs) sertraline and paroxetine (Marshall et al 2001). Meta-analyses show a treatment-effect of these
drugs that is 20-22% greater than placebo (Stein et al., 2009; Van Etten et al., 1998), and that only 30%
of the subjects show complete remission of PTSD symptoms after 12 weeks of treatment. Low
remission rates, high prevalence of relapse and serious side-effects accompanied by chronic use of
these medications raise concern by many clinicians (Scott, 2008). The introduction of
psychotherapeutic methods for PTSD like cognitive–behavioral therapy (CBT) and exposure based
psychotherapies for severe PTSD created renewed optimism. These treatments were found to produce
similar or sometimes even significantly better clinical outcomes, but with fewer side-effects.
Interestingly, the effects of psychotherapy on PTSD is found to be strongest in patients with severe
PTSD (Mueser et al., 2008). (Resick et al., 2008;Davidson et al., 2006;van Emmerik et al., 2008), with
success rates of up to 60% and 95% for patients who completed the treatment (Asnis et al., 2004;
Rothbaum et al. 2006 Cloitre et al. 2009).
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These studies indicate that overall in between 25% to 50% of patients with PTSD remain non-
responsive to current existing therapies and suffer chronically from their symptoms. Together with
the high incidence of PTSD, these numbers illustrate the urgent need for better treatments, which has
been stressed by experts worldwide (Fovea et al. 2009). Recently, interest in the psychiatric
community for the putative therapeutic qualities of 3,4-methylenedioxymethamphetamine (MDMA)
for the treatment of PTSD has shown a steep increase. The defensiveness and enhances fear responses
that are typical for PTSD make it difficult for patients to engage in the psychotherapeutic process,
which relies on re-visitation of the traumatic material within tolerable levels of emotional arousal. In a
psychotherapeutic context MDMA is theorized to reduce the patients’ defensiveness and fear
response to the traumatic material, to increase the therapeutic alliance, and thereby catalyze the
therapeutic process (Doblin 2009, Mithoefer et al. 2011, Passie 2012). In contrast to conventional
pharmacotherapy, MDMA is administered only on a small number of occasions and is considered as
an adjunct to psychotherapy rather that a pharmacological treatment in itself. The first double-blind
placebo-controlled clinical trial on the effectiveness and safety of MDMA in the treatment of PTSD
showed that two months after the last (second or third) administration of MDMA, 83.3% showed
remission after MDMA versus 25% after placebo. The second phase (open-label cross-over) of the
study showed a 100% remission rate (Mithoefer et al. 2001). A long term follow up with an average 3.5
years after study exit by the patients showed that 11% (2 out of 19) showed relapse, while the other
89% showed persistent remission of PTSD symptoms. Importantly, one of four subjects with disability
and three who were fit for limited employment before the treatment, had been able to return to work
full-time after MDMA (Mithoefer et al 2011). More clinical trials where MDMA is used in the
treatment for PTSD are currently underway in the USA, in Canada, Australia, Israel and Switzerland.
1.2 The Beckley-Imperial research program and the aim of this document. The results of the
recent clinical studies on MDMA (Mithoefer et al 2011) can yield important implications for scientists
and clinicians with regard to our understanding of PTSD and mental health. In addition, being
informed about these recent developments is significant for policy makers and funding-agencies with
regard to their strategic interests. If scientists and clinicians gain a better understanding of the
mechanisms underlying the remission of treatment-resistant patients with PTSD after MDMA, the
development and improvement of novel treatments can be significantly furthered. Furthermore, this
will contribute to the development of new theoretical frameworks about what constitutes mental
health and effective treatments for mental illness in general.
The Beckley-Imperial’s research program has been internationally recognized for their
expertise in bringing together leading academics and clinicians to initiate pioneering research into
psychoactive drugs. The program performed the very first fMRI- and MEG-studies to the acute effects
of the classic psychedelic drug psilocybin (Carhart-Harris et al 2011a, 2011b). This work resulted in
new insights into the treatment of depression and consequently the funding of the scientific team by
the Medical Research Council. Most recently the Beckley-Imperial program initiated the first-ever
neuroimaging study to the psychedelic drug LSD. By funding small-scale research projects, the
program aims to open up new avenues of research that have previously been neglected, but are of
significant importance to the academic and political community. By developing empirically guided
frameworks about psychoactive substances the Beckley-Imperial program aims to further advance
progress in science, medicine, policy and society.
In this light, the literature review presented here aims to guide research and strategic
interests of scientists, policy-makers and funding-agencies with regard to the therapeutic use and
mechanisms of MDMA in the treatment of PTSD. It will provide an overview of the current
understanding of the neurophysiology of PTSD, the neuropharmacology of MDMA, animal and
human studies on MDMA’s neurotoxicity, clinical research, the putative therapeutic mechanisms of
MDMA, and recommendations for future research.
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2 Post-Traumatic Stress Disorder
This chapter will provide a brief review on the neurophysiology underlying PTSD. By
understanding the brain systems involved and how these relate to the symptomatology of PTSD, we
can discuss how the actions of MDMA on the brain could have therapeutic effects for patients with
PTSD.
2.1 Neurophysiology underlying PTSD symptoms. Studies have shown alterations in brain
structure and brain function in patients with PTSD, dysregulation in the neuro-endocrine system and
increased somatic symptoms (Olff et al., 2005). Dysregulations in systems involved in regulating the
stress response and maintaining neuro-endocrine homeostasis have been demonstrated in many
studies to be a fundamental feature of PTSD.
One of the major systems involved in stress regulation is the hypothalamic pituitary-
adrenocortical (HPA) axis. Under conditions of physical, emotional or psychological stress, a cascade
of biochemical activity is initiated. The release of corticotropin-releasing factor (CRF) from the
paraventricular nucleus of the hypothalamus (PVN) promotes the release of adrenocorticotropic
hormone (ACTH or corticotropin) from the pituitary in the blood stream. ACTH in turn stimulates
the release of cortisol from the adrenal glands. Activity of the HPA-axis is suppressed via negative
BOX 1. MDMA was first synthesized and patented by Merck in 1914, but considered as an
unimportant precursor in the search for new haemostatic substances (Freudenmann et al., 2006b). In
1950 MDMA was explored –unsuccessfully- as a truth serum by the US army for the interrogation of
enemies. It was the chemist Alexander Shulgin who after many years rediscovered the drug and
tested it on himself. He described that MDMA produces an “easily controlled altered state of
consciousness with emotional and sensual overtones” (Shulgin, 1986). Shulgin introduced the drug to a
friend who was a psychotherapist, and soon MDMA was used increasingly as an adjunct in
psychotherapeutic treatment of anxiety disorders, depression and in couple therapy (Greer and
Tolbert, 1986). MDMA was of great interest because the experiences with it were almost always
described as positive, and lacking the perceptual changes and ego-disturbances that are common
during experiences with classical psychedelics (Vollenweider et al., 2002;Greer and Tolbert, 1986).
MDMA was referred to as an ‘entactogen’ and an ‘empathogen’, for its major psychological effects
include increased sociability and openness (Sessa, 2007;Vollenweider et al., 1998; Passie 2012). In the
mid-1980s MDMA leaked out of the scientific community and became a popular recreational drug
among young people. It became especially popular among those involved in the dance music scene,
and was dubbed ‘ecstasy’ in 1981 by a distribution network of the drug in Los Angeles. Along with
the quick rise of ecstasy’s popularity, so did the concerns for public health. Although there was no
evidence that MDMA causes brain damage in animals or humans, the American Drug Enforcement
Agency (DEA) effectively called for a ban of the drug. Clinicians who used the drug for over almost
10 years requested the recognition of the medical values and applications of the drug by suing the
DEA, and thus preventing a ban for research into its psychotherapeutic potentials. This caused an
official recommendation by the judge for MDMA to be scheduled in a less restrictive category, in
order to stay available for prescription and research (Passie 2012, Iversen 2009). This was ignored by
the DEA, leading MDMA being classified as a schedule I drug until today, and causing all further
research into its therapeutic properties to be ended abruptly (Greer and Tolbert, 1986;Parrott,
2007;Sessa and Nutt, 2007;Sessa, 2007). Despite the complete halt in academic research towards the
therapeutic potential of MDMA as a result of this legislation, the drug’s recreational popularity kept
rising steadily, with large MDMA-fueled “rave-parties” emerging globally during the 80s and 90s. In
2003, a report by the United Nations estimated 8 million users worldwide with an annual
manufacturing of 125 tonnes of MDMA worldwide (United Nations 2003).
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feedback inhibition by interaction of cortisol with glucorticoid receptors (GR) in the pituitary, the
hypothalamus, the amygdala, the hippocampus and other sites in the brain (M.F.Bear, 2006).
While the PVN is considered as the neural control center for the HPA-axis, and ultimately
cortisol release from the adrenal glands, other higher cortical structures are involved in either
facilitating the stress response or providing necessary feedback control. Important cortical brain
regions involved in stress regulation include the hippocampus, the amygdala, and the prefrontal
cortex. These three structures are highly interconnected and influence each other via direct and
indirect neural activity (Yehuda, 2001;Yehuda and LeDoux, 2007a). In particular the hippocampus is
thought to play a prominent role in the neuro-endocrine stress response by inhibiting HPA-axis
activity. Damage or atrophy of the hippocampus is shown to lead to a more prolonged HPA response
to psychological stressors (McEwen, 2007;Pavlides et al., 2002).
From all brain structures, the hippocampus in particular shows high plasticity in adaptation
to stress due its high density of GR (McEwen, 2007). Chronic elevations in cortisol levels after a
stressor have therefore hypothesized to underlie atrophy of hippocampal neurons, and by this
decreasing the hippocampal volume (Joels et al., 2008). Many studies demonstrated smaller volume
(Yehuda, 2001) and increased expression of GR in the hippocampus of patients with PTSD in
comparison with non-traumatized subjects without psychiatric disorders (Asnis et al., 2004;Yehuda,
2001).
It is important to underline is that the hippocampus is a critical mediator in the regulation of
the fear response, HPA-axis activity and cognitive flexibility, and plays a key role in the neurobiology
of PTSD (McEwen, 2007;Yehuda and LeDoux, 2007a). One of the major functions of the hippocampus
is the formation of declarative types of memories (McEwen, 2007). Persons with smaller hippocampal
volumes are therefore theorized to have more difficulties to contextualize and reinterpret the
experience of trauma in a way that facilitates the process of recovery, resulting in a decreased ability
to control the fear-response (Van Praag 2004).
The hippocampus shows high density of neural connections with the amygdala, which is
involved in the regulation of fear and the formation of emotional memory. The amygdala mediates
both simple reflexive and more complex adaptive behavioral and physiologic responses to
environmental challenges (Richter-Levin, 2004). Variability in functional dynamics of the amygdala
has been associated with a broad range of individual differences in mood and temperament, as well
as pathological states such as depression disorders (Bigos et al., 2008). Important in this context,
studies in PTSD patients have demonstrated significant increased amygdala activity compared to a
healthy control group (Yehuda, 2001).
The ventral amygdala receives also strong feedback projections from the prefrontal cortex
(PFC) (Gilboa et al., 2004). The PFC exerts an important modulatory role on amygdala activity. It is
demonstrated that cognitive inhibition of negative emotion increases activity in the PFC (Hariri et al.,
2000). For this reason, reduced projections from the PFC to the amygdala can cause significant
disruptions the ability to inhibit amygdala activity (Williams et al., 2006). Relative to non-traumatized
subjects, individuals with PTSD show a marked reduction in activity in the medial prefrontal cortex
(mPFC) in response to presented fearful stimuli (Williams et al., 2006). The mPFC is primary
concerned with the conscious processing of fear signals, and is engaged in the formation of cognitive-
emotional associations between amygdala-mediated emotional responses and knowledge of the fear
stimulus (Bechara et al., 1999). Decreased activity in the mPFC is therefore also thought to decrease
the ability to regulate and control emotional arousal such as increased fear and anxiety.
2.2 The role of serotonin in anxiety regulation. Serotonin (5-HT) was first reported in 1937,
but only later identified as an important neurotransmitter in the brain for the regulation of numerous
physiological and behavioral processes, including mood- and anxiety-related behavior, sleep, pain,
sex, food in-take, body temperature, and others. Serotonergic neurons have their cell bodies lying in
9
Figure 1 (Yehuda and LeDoux, 2007a): The amygdala’s
ability to control fear responses is regulated by the medial
Prefrontal Cortex and the Hipoocampus. The medial
prefrontal cortex modulates the amygdala’s activity by
regulating the degree of fear expression, while the
hippocampus provides contextual regulation.
the raphe nuclei of the brain stem, with long axons projecting to almost the entire brain. At least 14
different receptors are now known to mediate the effects of 5-HT, with a heterogeneous functionality
and expression through the brain. The 5-HT1A and the 5-HT2C receptors are found to play a key role in
the regulation of anxiety. Generally speaking, their effects are regarded as being the opposite of each
other, with 5-HT1A receptors exerting anxiolytic effects and 5-HT2C receptors exerting anxiogenic
effects (van Praag, 2004). Also, both receptor types show a reciprocal relationship: downregulation of
one causes upregulation of the other, and vice versa. 5-HT1A receptors are expressed presynaptically
(auto-receptor) on the raphe nuclei, or postsynaptically (heteroreceptor) on non-serotonergic cell
bodies (Altieri et al 2013).
Different kinds of stressors are found to down-regulate hippocampal 5-HT1A presynaptic
receptors, possibly through glucocorticoid regulation of transcriptional mechanisms (Joca et al., 2003).
Downregulation of the 5-HT1A system diminishes the release of ACTH and cortisol and thus
neutralizes the effect of CRH and the ability for negative feedback of the stress-response (van Praag,
2004, McEwen, 2007). 5-HT1A receptor down-regulation has therefore been related to increased
fearfulness and hyperexcitability (van Praag, 2004). In PTSD patients the 5-HT1A receptors may be
underresponsive, while the 5-HT2c receptor system may be overresponsive (Van Praag 2004). Studies
using positron emission tomography (PET) indicated altered expression of the 5-HT1A receptor in
patients with PTSD (Sullivan et al 2013), and that genes encoding 5-HT2C receptors exerting a higher
expression in patients with anxiety disorders (Inada et al., 2003), while expression of 5-HT1A receptors
was found to be reduced (Lanzenberger et al., 2007).
2.3 The neurophysiology of PTSD: A
summary. Chronic stress is shown to cause
structural and functional changes in brain
regions such as the hippocampus, the amygdala
and the mPFC. Increased amygdala activity in
response to fearful stimuli is normally regulated
by the mPFC and the hippocampus, but
decreased function of these brain regions in
PTSD attenuates the inhibition of amygdala
activity, and can eventually lead to a decreased
ability of modulation of the fear response (see
figure 1.). Decreased volume in the
hippocampus is possible as a result of
glucocorticoid driven down-regulation of 5-
HT1A receptors, a receptor system which exerts
anxiolytic actions. These findings indicate that
the hippocampus, the mPFC, the amygdala, and
the 5-HT1A and 5-HT2C receptor subtypes, are
important targets for treating PTSD
3 Brain mechanisms of MDMA
3.1 Pharmacology and subjective effects. MDMA is a ring-substitute amphetamine
structurally similar to methamphetamine and mescaline. All have the monoamine phenethylamine as
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the chemical backbone, with the substituent on this aromatic ring determining the specific
pharmacological actions of the drug (see figure 2). (de la et al., 2004).
After oral ingestion of a single active dose of MDMA (1.3 – 1.8 mg/kg) there is a 30 to 60
minute delay until the onset of the effects. The mean duration of the subjective effects is around 3.5
hours. Acute subjective effects of a single dose of MDMA in healthy humans have been studied
experimentally, and most subjects enrolled in these studies reported a state of profound well-being,
happiness, an increased responsiveness to emotions, a heightened openness and sense of closeness to
other people, increased extroversion and increased sociability. Adverse effects include difficulty
concentrating, accelerated thinking, and impaired decision making, but no evidence is found of
confused or delusional thinking or paranoid ideations. Unlike psychedelic drugs, MDMA does not
produce hallucinations, dissociative symptoms or depersonalization. (Cami et al 2000; Harris et al
2002; Kolbrich et al 2008; Liechti et al 2001; Tancer and Johanson 2001, Vollenweider et al.,
1998;Vollenweider et al., 2002).
3.2 Neuropharmacology. MDMA interacts with postsynaptic and presynaptic membrane-
bound transport proteins that regulate the release and reuptake of neurotransmitters, interacts with
enzymes that regulate the metabolism of serotonin and stimulates the serotonin receptors directly
(Dumont et al., 2009; Nash et al., 1988). Increase in extracellular levels of serotonin (5-HT), dopamine
(DA) and norepinephrine (NE) is facilitated by MDMA stimulating both the release and inhibition of
re-uptake of these three neurotransmitters. Although MDMA acts on the transport proteins of all
these neurotransmitters, it displays the highest affinity for the 5-HT transporter (SERT) and at least a
ten times lower affinity for both the NE transporter (NET) and the DA transporter (DAT) (Verrico et
al., 2007; Iversen 2006).
Acute 5-HT release after exposure to MDMA has been demonstrated in vitro for the first time
in 1982 by Nichols et al, from synaptosomes prepared from whole rat brain and in 1986 by Johnson et
al. in hippocampal brain slices (Johnson et al., 1986;Nichols et al., 1982). Several animal studies
followed showing acute and rapid release of 5-HT after MDMA (Green et al., 2003) (see figure 3).
When SERT activity is blocked by fluoxetine and imipramine as pre-treatment (both highly specific
blockers of SERT), the ability of MDMA to cause an elevation in 5-HT release is significantly
impaired, indicating a critical role for SERT in MDMA-induced 5-HT release (Mechan et al.,
2002;Gudelsky and Nash, 1996;Upreti and Eddington, 2008).
The serotonergic neurons in the raphe nuclei of the brain stem project to almost every region
in the brain, but there are some brain areas that show a relative higher density of serotonergic axons
and serotonergic receptor sites. These brain regions are the prefrontal cortex, the hippocampus, the
basal ganglia, the thalamus, the substantia nigra and the amygdala (Beyer and Cremers, 2008), and
they play in particular an important role in MDMA’s mechanisms. A dose related increase in
extracellular 5-HT concentrations has been reported in the striatum, the mPFC and the hippocampus
following peripheral administration of MDMA (Green et al., 2003;Gudelsky and Nash, 1996).
Figure 2: The molecular structure of Amphetamine, Mescaline and 3,4-Methylenedioxymethamphetamine
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Fig. 4 (Adapted from White et al., 1996): A dose-
dependent increase in levels of 5HT and DA in dialysate
samples 60-80 minutes after infusion of MDMA directly
into the nucleus accumbens of awake rats (n= 6-14).
*Significant increase (p < 0.01) from basal levels.
Fig. 3 (Adapted from Gartside et al., 1997): Time-course of
the effects of MDMA on 5-HT levels in the PFC (open
symbols) and dorsal hippocampus (closed symbols) of rats,
after administration of either 1 mg/kg (squares, n=5), or 3
mg/kg MDMA (circles, n=5)
Besides elevations of 5-HT release, a dose-dependent increase in extracellular DA levels after
MDMA in regions which are rich in DA-containing axon terminals is shown both in vitro as in vivo.
This increase is especially noticeable in the striatum, the caudate nucleus and the nucleus accumbens
(Gudelsky and Yamamoto, 2007; White et al 1996) (See figure 4). Specific DA re-uptake blockers
reduce the rise in DA after MDMA in some (Nash and Brodkin, 1991), but not all studies (Mechan et al
2002), and there are strong indications for serotonergic mechanisms being involved in elevated DA
release after MDMA (Green et al., 2003;Gudelsky and Yamamoto, 2007). Infusion of 5-HT2A/2C receptor
agonists like 2,5-dimethoxy-4-iodoamphetamine (DOI) or 5-methoxy-N,N-dimethyltryptamine (5-
MeODMT) directly into the nucleus accumbens or the striatum causes an increase in extracellular
levels of DA, while this effect is significantly attenuated when 5-HT2A/2C receptor antagonists (e.g.
ritanserin) are co-administered (Green et al., 2003;Gudelsky et al., 1994) (Yamamoto et al., 1995).
MDMA also works as an agonist on the 5-HT1A and the 5-HT2 receptors (Green et al., 2003).
The affinity of MDMA is however estimated to be over a 1000-fold higher for the 5-HT1A receptor than
for 5-HT2 receptors (Giannaccini et al., 2007). MDMA is found to act on both postsynaptic as
presynaptic 5-HT1A receptors (Giannaccini et al., 2007; Aguirre et al., 1998; Aguirre et al., 1995).
However, while it seems that while MDMA overall behaves as a 5-HT1A agonist, it is speculated to
partially act as a non-competitive 5-HT1A antagonist in limbic areas rich in 5-HT1A receptors such as
the hippocampus and the amygdala (Giannaccini et al., 2007). Furthermore, the outcome of MDMA’s
agonist effects on neuronal activity is thought to depend upon whether presynaptic 5-HT1A auto
receptors in the raphe nuclei are preferentially stimulated or postsynaptic 5-HT1A sites in other cortical
regions (Muller et al., 2007).
BOX 2. Apart from MDMA’s actions on these membrane-bound transporter proteins and
receptor-systems, elevations in synaptic neurotransmitter levels is also mediated by the
inhibition of both A and B subtypes of the degrading enzyme monoamine oxidase (MAO) by
MDMA. The enzyme is critical in reducing the metabolism of 5-HT and DA. By blocking the
activity of this enzyme MDMA further contributes to the increased levels of these
neurotransmitters in the synaptic cleft. (Green et al., 2003;Leonardi and Azmitia, 1994).
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3.3 Neuroimaging studies to the acute effects of MDMA in humans. Few neuroimaging studies
have been undertaken so far to the acute effects of MDMA in humans. Vollenweider et al (1998)
examined the effects of MDMA on region cerebral blood flow (rCBF) of MDMA-naïve humans
(Vollenweider et al., 1998) using Positron Emission Tomography (PET). The study found that a single
oral dose of MDMA increased rCBF in the ventral mPFC and other regions, the ventral anterior
cingulate, the inferior temporal lobe, the medial occipital lobe, and the entire cerebellum, while
MDMA decreased rCBF in the posterior cingulate, insula, and thalamus and the amygdala and other
regions. Formisano et al (2009) used fMRI to test the acute effects of MDMA on memory functions,
and found that MDMA suppresses brain processes that are normally involved in prospective memory
performance, including the thalamus, putamen, precuneus, the inferior/superior parietal lobule and
the inferior parietal lobule (Formisano et al., 2009). De Wit et al (2009) showed that MDMA attenuated
left amygdala activation to angry, but not fearful, faces. Furthermore, the study showed that MDMA
enhanced right ventral striatum activation to happy faces. The authors argued that their findings
suggest that MDMA alters processing of (emotionally salient) social information by reducing
responses to threat (angry faces) and by enhancing responses to reward (happy faces).
More recently Carhart-Harris et al (2013, in press) performed two fMRI studies with MDMA
in healthy volunteers as a part of the Beckley-Imperial scientific research program. In the first study
the effect of MDMA on recollecting emotionally-potent personal memories was investigated. This
study was specifically designed in order to inform how the drug may be useful in psychotherapy.
Twenty healthy participants recollected their worst (most painful) and their favourite (most positive)
memories after oral administration of 100mg of MDMA or placebo in a double-blind, repeated-
measures design. Compared to placebo, under MDMA the participants experienced their favourite
memories as more vivid, emotionally intense and positive after MDMA than placebo, while their
worst memories were rated as less negative and more positive (See figure 5). MDMA enhanced
positive emotions by increasing activity in the left fusiform gyrus and the temporal cortices responses
to them, while MDMA reduced negative emotions to painful memories by reducing temporal cortical
responses to them (See figure 6). The intensification of positive emotions, and reduction of negative
emotions, reflects that MDMA induces a bias towards processing of positive emotions. This is
consistent previous MDMA studies.
In a second fMRI study, Carhart-Harris et al1 showed that during resting state, MDMA
reduced brain activity in the amygdala, the hippocampus the posterior cingulate cortex and other
brain regions. Importantly, the study showed a correlation between the magnitude of these decreases
and the subjective effects of the drug, indicating that reducing activity in these brain regions is a key
mechanism to the effects of MDMA (see figure 6). The results of these neuroimaging studies have
important implications to our understanding of how MDMA works in the human brain and be used
therapeutically.
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Figure 5. (Adapted from Carhart-Harris et al 2013).
Subjective ratings of autobiographical memories:
Displayed are the mean ratings (+ standard errors)
for each item after placebo (grey) and MDMA
(pink). P values are shown for significant and trend-
significant results. Paired t-tests, p < 0.05 (two-
tailed).
Figure 6. (Adapted from Carhart-Harris et al 2013).
Subjective ratings of MDMA correlate with the
magnitude of change in the amygdala (upper graph)
and hippocampus (lower graph). P values are shown
for significant and trend-significant results. Paired t-
tests, p < 0.05 (two-tailed).
4 Therapeutic mechanisms of MDMA
The first clinical trial to the effects of MDMA in patients with chronic treatment-resistant
PTSD demonstrated two months after the last (second or third) administration of MDMA, that 83.3%
of the patients who received MDMA versus 25% after placebo showed remission of PTSD symptoms.
A 100% remission rate in the second phase (open-label cross-over) of the study was demonstrated.
What is furthermore important to mention is that one of four patients who were on disability at
baseline, and three who were fit for limited employment at baseline, had all been able to return to
work full-time after MDMA. (Mithoefer et al 2001). A long term follow up of this clinical trial, with an
average of 3.5 years after study exit of the patients, showed that 11% (2 out of 19) showed a return of
their PTSD symptoms, while the other 89% showed persistent remission. More clinical trials towards
the effectively of MDMA in the treatment for PTSD are currently underway in the USA, in Canada,
Australia, Israel and Switzerland.
In the light of the literature reviewed in previous chapters on the actions of MDMA on the
brain and on the neurophysiology of PTSD, we are now able to provide a first theoretical framework,
explaining the therapeutic effects of MDMA for patients with PTSD as observed in the recent clinical
trial (Mithoefer et al 2011). In this chapter MDMA’s therapeutic effects are first defined by comparing
MDMA’s actions on the brain with the neurophysiology of PTSD. After that we will discuss how the
subjective effects of MDMA can be harnessed therapeutically, and how these effects could explain the
observed long term effects in the treatment of PTSD with MDMA.
4.1 MDMA’s effects on the 5-HT1A receptor system. MDMA has the highest affinity for
SERT, which explains the pronounced extracellular increase in 5-HT levels caused by MDMA. But
besides interacting with transporter proteins, MDMA also acts as an agonist on 5-HT1A receptors. The
serotonergic system, and in particular the 5-HT1A receptor system is shown to play a critical role in
14
regulating anxiety, and most pharmacological agents that are currently used in treatment are believed
to function by enhancing the neurotransmission of 5-HT and by up regulating 5-HT1A receptor.
Positron emission tomography (PET) in humans indicate altered expression of the 5-HT1A receptor in
patients with major depressive disorder, social anxiety disorder, panic disorder, and PTSD
(Lanzenberger et al 2007, Nash et al 2008, Sullivan et al 2005, Sullivan et al 2013, Gross et al 2002,
Schneier et al 2008, Hirvonen et al 2008, Parsey et al 2010, Shrestha et al 2012). And the major reasons
why the SSRI’s sertaline and paroxetine are currently used as first-line treatment for PTSD are
because they exert acute anxiolytic effects and promote hippocampal neurogenesis on the long-term.
This is thought to be achieved via re-uptake inhibition of 5-HT and presynaptic agonist effects on 5-
HT1A receptors (Bremner and Vermetten, 2004).
It is stated that an optimal treatment for PTSD should up-regulate 5-HT1A receptors, increase
hippocampal and prefrontal functioning to allow more efficient inhibition of amygdala activity, and
by this decrease HPA-axis activity, to eventually attenuate the fear response (van Praag, 2004). The
powerful effects of MDMA on the serotonergic system, its strong agonist actions on the 5-HT1A
receptor system make the substance an interesting pharmacological agent to be studied in the context
of PTSD. Regarding MDMA’s high affinity for the 5-HT1A receptor system (Giannaccini et al., 2007),
an understanding of the function of this receptor can inform us significantly on MDMA’s potential as
a treatment for PTSD.
Multiple studies have shown that the activation of 5-HT1A receptors increase 5-HT and DA
release in both the PFC and the hippocampus (de et al., 2002;Rollema et al., 2000). These brain areas
are important pharmacological targets for treating PTSD, because the functioning of these areas is
associated with control of amygdala-mediated anxiety and fear-responses (van Praag, 2004). 5-HT1A
receptors in the hippocampus and the amygdala are found to play an key role in the regulation of
anxiety (Li et al., 2006). Various animal studies point out that activation of 5-HT1A (by 8-OH-DPAT)
impairs fear conditioning (Stiedl et al., 2000). Direct injections of flesinoxan, a selective 5-HT1A
receptor agonist, in the hippocampus and the amygdala decreased the expression of conditioned
freezing in rats (Li et al., 2006), indicating that these effects are mediated by the activation of 5-HT1A
receptors in these areas. Misane et al (1998) examined the effects of 5-HT1A agonists on passive
avoidance. When 5-HT1A agonists were injected prior to the training procedure, a dose-dependent
reduction of passive avoidance retention was demonstrated (Misane and Ogren, 2003). The 5-HT1A
receptor antagonists WAY 100635 and pindolol on the other hand blocked the passive avoidance
deficit caused by 8-OH-DPAT ((Misane et al., 1998;Misane and Ogren, 2000).
Other anxiolytic effects of 5-HT1A agonists have been demonstrated in animal studies that
employ ‘Learned Helplessness’. Learned Helplessness is one of the most employed animal models of
depression. It is demonstrated in several studies that the administration of 5-HT1A agonists both prior
and posterior to the exposure to the stressor, prevents or attenuates learned helplessness (Joca et al.,
2003). The authors argued that their results support the hypothesis that facilitation of postsynaptic 5-
HT1A-mediated neurotransmission in the dorsal hippocampus supports adaptation to severe stress.
Furthermore, it is demonstrated that mice lacking 5HT1A receptors in the hippocampus or forebrain
show increased anxiety-like behavior (Gross et al., 2000), and 5HT1A receptor knock-out mice are used
and accepted widely as an experimental animal model for anxiety (Ramboz et al 1998) and PTSD (Lui
et al 2013).
The 5-HT receptor system also plays a major role in regulation of neurogenesis (i.e. the
proliferation of new neuronal cells). Both acute and chronic administration of selective 5-HT1A and 5-
HT2C receptor agonists produce consistent increases in the number of newly formed neurons in the
dentate gyrus and the olfactory bulb in rats (Banasr et al., 2004). The 5-HT1A receptor in particular is
found to be an important factor involved in learning, memory and synaptic plasticity in the
hippocampus. 5-HT1A knockout animals show significant deficits in hippocampal-dependent learning
and memory (Sarnyai et al., 2000), while up-regulation of 5-HT1A receptors reverses or protects
15
hippocampal neurons from further damage in response to chronic stress (Xu et al., 2007). 5-HT1A
receptor activation is considered as a critical step in the activation of cell proliferation and survival
(Radley and Jacobs, 2003), while 5-HT1A antagonism is found to decrease cell proliferation (Radley
and Jacobs, 2002). Interestingly, in our context, there are some studies that show that a single high
dose of MDMA (30mg/kg) in rats, significantly increased 5-HT1A receptor density in the frontal cortex
and hypothalamus by approximately 25-30%, which was blocked when pretreated with a 5-HT1A
receptor antagonist (Aguirre et al., 1998; Aguitte et al., 1995). Persistent up-regulation of 5-HT1A
receptors is in particular considered an important clinical target in the treatment of PTSD, since this
may attenuate the strong and involuntary fear-responses that are typical for PTSD.
4.2 MDMA’s effect on brain circuitry involved in anxiety regulation. As discussed in
chapter two, various brain systems are involved in either facilitating the stress response or providing
necessary feedback control. In particular the hippocampus, the amygdala, and the prefrontal cortex
are considered to play critical roles in regulating fear responses and arousal. These three structures
are richly interconnected (Yehuda, 2001;Yehuda and LeDoux, 2007a), and the hippocampus and the
mPFC are thought to play a prominent inhibitory function over amygdala and HPA-axis activity.
Reduced functioning of the mPFC and the hippocampus, hyperactivity in the amygdala and
prolonged HPA response to psychological stressors are typical for patients with PTSD (McEwen,
2007;Pavlides et al., 2002). Therefore, it are these brain regions that are considered important
therapeutic targets in the treatment of PTSD (van Praag, 2004).
The hippocampus, the medial prefrontal cortex and the amygdala show a relative high
density of serotonergic axons and serotonergic receptor sites (Beyer and Cremers, 2008), and a dose
related increase in extracellular 5-HT concentrations has been reported in these regions following
administration of MDMA (Green et al., 2003;Gudelsky and Nash, 1996). Importantly, neuroimaging
studies in humans have shown acute decreases in amygdala activity after MDMA (Vollenweider et al.,
1998; Carhart-Harris et al.,2013). Considering the critical role of the amygdala generating a stress- or
fear response, deactivation of the amygdala can explain the acute reduced anxiety that patients with
PTSD (Mithoefer et al 2011) and healthy volunteers (Vollenweider et al 1998) experienced after
MDMA.
Psycho-therapeutic exercises wherein patients with PTSD are instructed to verbalize and
emotionally engage in remembering the trauma have shown to be most efficacious in preventing
chronic PTSD, compared to therapeutic interventions wherein patients were not stimulated to
confront their traumatic memories (Bryant et al., 2008;Feske, 2008). This type of exposure based
treatment is thought to work by fear extinction mechanisms (Rothbaum et al., 2006), and by the
integration of corrective information embedded in the reliving experience (Foa and Kozak, 1986). It is
however important that upon exposure to traumatic memories in a therapeutic context, the patient
does not become too overwhelmed by his or her emotions, while it is also critical to prevent
emotional numbing and an emotional disengagement to the process (Ogden and Pain, 2005). For this
reason, elevated anxiety and avoidant/defensive coping styles in patients with PTSD can prevent the
therapeutic procedure to be effectively implemented. From this perspective, MDMA is thought to
enhance exposure-based psychotherapy by attenuating the fear response and decreasing the
defensiveness, so the patient feels he or she can confront the traumatic memories without losing
control (Mithoefer et al 2011,2013).
4.3 MDMA’s effect on therapeutic alliance. In addition to elevated anxiety, most PTSD
patients find it hard to be fully open and to form a trusting relationship with the therapist, especially
when they have been betrayed by someone they trusted in the past (Doblin, 2002). Independent of the
type of psychotherapy, a good therapeutic alliance is found to be a critical factor for the intervention
to yield successful results (Roth and Fonagy, 2005). The therapeutic alliance can be defined as the
16
patient's engagement with a therapist's work, while both the therapist and the patient have the trust
and confidence in positive outcomes of the implemented intervention (Bordin et al 1979).
MDMA’s subjective effects are characterized by a heightened openness and sense of closeness
to other people, increased extroversion and increased sociability, and has for this reason been argued
by some researchers and therapist to embody a new class of drugs: “empathogens” or “entactogens”
(Passie, 2012). The mechanisms underlying these prosocial effects of MDMA effects are not well
understood, but could potentially be explained by increases in levels of the hormone oxytocin after
MDMA (Wolff et al., 2006; Bedi, 2009; Dumont et al., 2009). In a therapeutic context, MDMA allows the
patient and the therapist to establish a deeper trust-relationship, thereby furthering the therapeutic
alliance and improving clinical outcomes (Mithoefer et al 2011).
4.4 Potential mechanisms explaining MDMA’s long term therapeutic effects. What makes
the clinical trial performed by Mithoefer et al (2011) especially of interest is that on a multi-year
follow-up study, the remission of PTSD symptoms was sustained in almost all of the patients
(Mithoefer et al 2013). Since the drug was administered only two or three times to the patients, this
indicates that more than purely neuropharmacological factors are involved. For this reason,
understanding the mechanisms behind the long term remission will allow us to significantly improve
treatments for PTSD and mental disorders in general. In this final paragraph an empirically informed
hypothesis will be outlined that could explain the long term effects of MDMA-assisted
psychotherapy. In doing do, it will also introduce the final chapter of this document, where
suggestions will be given for future research.
There is clear evidence that not every adult copes with trauma in the same way, and it is now
understood that different styles of coping have different clinical outcomes (Olff et al., 1995). Two
different coping strategies are recognized as a response to different types of stress, distinguishable as
active (or proactive) coping against passive (or reactive) coping. Active coping strategies (i.e.
confrontation, cognitive reappraisal) are usually evoked if the stressor or threat is controllable or
escapable, whereas passive coping strategies (i.e. immobility, disengagement, avoidance) are evoked
if the stressor is uncontrollable or inescapable (Koolhaas et al., 2007;Koolhaas, 2008;).
Active coping styles are associated with a good adaptation to stress, while passive coping
strategies such as avoidance, lead to prolonged stress-responses and often have maladaptive health
consequences (Joseph and Linley, 2006;Joseph et al., 2005;Silver et al., 2002). In the case for PTSD,
passive coping strategies might be adaptive on the short term because it protects the individual from
being too emotionally overwhelmed. But when passive coping prevents cognitive appraisal of
stressors, it can maintain anxiety and stress on the long term (Olff et al., 1995). From this point of
view, PTSD has been describes as a condition in which the process of recovery from the trauma is
chronically impeded by a maladaptive coping strategy up to a point in which it becomes pathological
(Yehuda, 2001).
The importance of perceived controllability over the stressor for health is proven to be true in
both animals as in humans, and it is stated that a therapeutic tool that reduces the proactive effects of
trauma most effectively is psychological training in the controlling and predicting of stressors
(Overmier and Murison, 2005). One of the main characteristic of MDMA is that it induces a
positively-toned cognitive emotional state with an attenuated fear response. This is postulated to
facilitate the processing of traumatic material without the feeling of becoming too overwhelmed by
them, and to allow a better encoding of positive emotional experiences (Mithoefer et al 2011, 2013).
What seems however most important, is that by undergoing this experience, patients learn about the
controllability of their emotion, and to adapt more adaptive (active) coping styles (Overmier and
Murison, 2005). Undergoing verbal and emotional exposure to the trauma while experiencing the
subjective effects of MDMA enables explicit memories and thought material to emerge, and implicit
17
learning to take place. This experience can then function as a point of reference that can be
implemented and integrated in following MDMA-free therapeutic sessions and –ultimately- day to
day life (Doblin, 2002). An overview of the subjective effects of MDMA and how they can be
therapeutically useful is displayed in table 1.
5 Safety of MDMA
Along MDMA’s vast rise in popularity as a recreational drug in the 80s, first reports of MDMA-
related medical complications emerged (Baumann et al., 2007). Since then, several acute adverse
effects after MDMA were reported, including cardiac arrhythmias, hypertension, hyperthermia,
serotonin syndrome, hyponatremia, liver problems, seizures, coma, and in rare cases even death
(Schifano, 2004). By now, animal studies have described short-term and long term adverse effects
after high or chronic doses of MDMA and some retrospective studies in human populations of
MDMA users link cognitive deficits to recreational use (Gouzoulis-Mayfrank and Daumann, 2006).
The suggestion to use MDMA in the treatment of PTSD brings therefore the need to assess the safety
of MDMA for therapeutic utilization. In this section both animal studies and human studies are
reviewed to establish an overview on MDMA’s adverse health effects and how this can inform
research to and clinical practice with MDMA-assisted psychotherapy.
5.1 Animal studies. The first experiment describing toxic effects of MDMA was performed in
1952 on flies. ‘Flies lie in supine position, then death’ was the short comment later found in the
personal laboratory book (Freudenmann et al., 2006a). The next study that followed on MDMA’s
neurotoxic effects was performed in 1986 by Schmidt et al, which demonstrated decreased 5-HT levels
and depletion of 5-HT uptake sites in rats’ neostriatum one week after injection of a single high dose
of MDMA (10 mg/kg) (Schmidt et al., 1986). Many studies followed, demonstrating various long-term
alterations in brain chemistry caused by either a single or repeated high doses of MDMA. These
alteration include decreased levels of intracellular and extracellular 5-HT and its major metabolite 5-
Table 1. (Adapted from Mithoefer et al 2011) The subjective effects of MDMA that are theorized to
underlie its therapeutic effects.
18
Fig. 7 (Baumann et al., 2007) : Left: Acute effects of MDMA on core body temperature in rats.
Male rats received three intra peripheral injections of 1.5 or 7.5 mg/kg MDMA or saline, one
dose every 2 hour . Right: Long term effects of MDMA on tissue levels of 5-HT in rats frontal
cortex (CTX), striatum (STR) and olfactory tubercle (OT). Asterisk denotes significance
compared to saline-injected control.
HIAAA, a long term decline in the activity of tryptophan hydroxylase, a reduced density of SERT in
the cell membranes, and a reduced density of serotonergic axons (Gouzoulis-Mayfrank and
Daumann, 2006). Importantly, studies indicate that neurotoxic effects of MDMA seem to occur
preferably on the serotonergic nerve system and not on the dopaminergic system (Green et al., 2007).
The time of persistency of these alterations is shown variable among brain regions and different
animal species, and importantly, in most studies with rats full recovery was shown after 1 year
(Gouzoulis-Mayfrank and Daumann, 2006).
The exact mechanisms by which MDMA induces these effects are not fully understood yet.
Carrier-dependent transport of MDMA’s metabolic products, oxidative stress, hyperthermia,
apoptosis, and increased extracellular concentrations of DA and 5-HT are all postulated as underlying
mechanisms (Green et al., 2003;Sanchez et al., 2004). Much attention has however directed recently on
the deregulatory effect of MDMA on body temperature. MDMA administered in high doses results in
impaired thermoregulation when rats are exposed to high ambient temperature (Colado et al.,
1995;Mechan et al., 2002;Nash, Jr. et al., 1988).
Hyperthermia is considered to be caused by 5-HT2A activation, while in contrast 5-HT1A
activation results in hypothermia (Blessing et al., 2006;Rusyniak et al., 2008). Due the higher affinity of
MDMA for 5-HT1A receptors, it is suggested that only high doses of MDMA will result in
hyperthermia. Evidence for this hypothesis is brought by a study of Giannaccini and colleges in an
experiment where a 7.5 mg/kg dose of MDMA in rats caused pure hypothermia, while a 15 mg/kg
dose of MDMA caused predominantly hyperthermia (Giannaccini et al., 2007). The results in figure 6
support the idea of dose-dependent hyperthermia furthermore, and in addition indicate a
serotonergic mechanism for this effect. Three MDMA injections of 1.5 mg/kg did not cause a
significant rise in body temperature, but when 7.5 mg/kg was administered with the same procedure,
significant hyperthermia is seen 2 hours after the first injection (Baumann et al., 2007).
Although many studies demonstrated neurotoxic effects of MDMA, this is only demonstrated
by administering high or moderate doses repeatedly. O’Shea et al (1998) demonstrated 5-HT depletion
7 days after a single high dose (10 mg/kg) and after multiple moderate doses ( twice daily 4 mg/kg),
but not after a single moderate dose or multiple doses on a large timescale (O'Shea et al., 1998).
Another study also failed to show long term effects (2 weeks after injections) when three injections of
19
1.5 mg/kg MDMA were administered to male rats once per 2 hours (See fig. 5, right graph) (Baumann
et al., 2007). Furthermore, several studies demonstrated a positive relationship between the size of
hyperthermic response and 5-HT depletion and the ambient temperature. MDMA administered to
rats housed in high ambient temperature conditions produced an acute hyperthermic response that
was significant larger than that seen in rats housed at normal room temperatures given the same
treatment (Green et al., 2004).
5.2 Human studies. Mas et al. (1999) did not observe a temperature increase following
MDMA administration of 125 mg (1.8 mg/kg in a person weighing 70 kg) to healthy human
volunteers (Mas et al., 1999), while another human study detected only a modest temperature rise
when 1.5 mg/kg MDMA was administered (Liechti and Vollenweider, 2000). More importantly, when
MDMA was administered to patients with PTSD by Mithoefer et al (2011), no adverse drug-related
neurocognitive effects were observed.
Studies on ecstasy user populations found changes in several parameters indicative of a
potential neurotoxic effect of MDMA, although controversy exists over the interpretation of these
results (Cole and Sumnall, 2003). Reduced cortical SERT availability is demonstrated in several
studies using PET or Single Photon Emission Computed Tomography (SPECT) and inversely
correlating with frequency of MDMA use (McCann et al., 2005). Also mean cortical 5-HT2A receptor
binding ratios was found significantly lower in current MDMA users compared to abstinent users
and control subjects. This indicates a down-regulation of 5-HT2A receptors in MDMA users, possibly
due to MDMA-induced 5-HT release (Green et al., 2003).
Decreased global brain volume and reduced grey matter have been associated with long
periods of MDMA use (Cowan et al., 2003;Green et al., 2003) and PET-scan studies in 93 ecstasy users
found lower metabolic activity in the basal ganglia and amygdala compared to control (Buchert et al.,
2001). Several studies on large populations of ecstasy users have shown reduced concentrations of 5-
HIAA in the cerebrospinal fluid (CSF), the major metabolite of 5-HT (Gouzoulis-Mayfrank and
Daumann, 2006;Green et al., 2003). Bolla et al. (1998) demonstrated that the mean concentration of 5-
HIAA in the CSF of MDMA users was lower than the control group, and that the CSF 5-HIAA levels
decreased with increasing MDMA dose (Bolla et al., 1998).
Whether there exists a causal relationship between the impairments found by these
prospective studies and MDMA use is a topic of ongoing debate. Many studies have been criticized
on methodological limitations (Green et al., 2003;Parrott, 2007). For example, epidemiological studies
are demonstrating that the overwhelming majority of the ecstasy user populations are polydrug
users. Other drugs have neurotoxic properties that are considered larger than MDMA. Also, multiple
studies demonstrate there is a wide variation of constituents in Ecstasy tablets, including substances
that can be far more neurotoxic than MDMA. (Cole, 2002). These findings add to the questionability
of studies on ecstasy tablet users,
More important to the context of therapeutic use of MDMA are studies were cognitive
parameters are measured after single use of MDMA in human subjects naïve to MDMA and other
drugs. Jager and de Win (2007) studied the long term effects of a single low dose of MDMA on
cognitive brain function in healthy MDMA-naïve young adults using fMRI. No evidence for
sustained long term effects of initial ecstasy use was found on brain activity in brain systems engaged
in working memory, attention or associative memory (Jager et al., 2007). In a following study the same
research group found no evidence for significant long term effects of MDMA on working memory
and attention. Importantly, significant reduced associative memory function was only found in
polydrug ecstasy users, and was related to the effects of amphetamine use and not ecstasy use (Jager
et al., 2008).
20
5.3 How safe is MDMA in the treatment for PTSD. It is important to emphasize that many
psychiatric drugs can produce adverse effects that are similar to those produced by high doses of
MDMA. Excessive serotonergic modulation by psychiatric drugs heightens the risk of developing the
‘serotonin syndrome’ (Dvir and Smallwood, 2008). Chronic administration of SSRIs like paroxetine
and sertraline is shown to lead to a marked reduction of SERT density in the hippocampus, and high-
dose administration of SSRIs even produces swollen, fragmented, and abnormal 5-HT terminals
(Benmansour et al., 1999). In any kind of medical procedure, the potential risks and benefits of the
treatment for the individual are critically analyzed, sometimes leading to a trade-off in order to
improve the quality of life for the patient.
Animal studies demonstrate that MDMA can cause long term persistent alteration in SERT
densitity and brain structure when administered in high and chronic doses. However, MDMA’s
adverse effects on the brain are demonstrated to be highly dependent on dosage and ambient
temperature, both pronouncing the adverse effects, while these effects were not found in lower doses
and in controlled ambient temperature (Battaglia et al., 1988;Baumann et al., 2007;Gouzoulis-Mayfrank
and Daumann, 2006). Most animal studies are designed to examine the mechanisms of MDMA
neurotoxicity, and therefore use doses of 10 mg/kg or higher, sometimes repeatedly for several days
and for several times a day. However, some of these studies argue that these repeated doses mirror
the recreational use of MDMA, where MDMA is often used more than once on one night, begging the
critical question whether animal data can be translated directly to humans. The translation of data
from animal studies to humans cannot be made without taking into consideration the anatomical,
physiological, and biochemical differences among the species (Gouzoulis-Mayfrank and Daumann,
2006; Green et al., 2003). Different animals require different doses of the drug to mirror similar effects
in humans. These differences are influenced by body mass, differences in pharmacokinetics and the
metabolic pathway. According to a technique of interspecies scaling (Mordenti, 1985) smaller animals
require higher doses of drug to mirror a similar effect in humans (Green et al., 2003). A single dose of
5 mg/kg of MDMA administered to a 1 kg monkey is argued to stand equal to a dose of 1.4 mg/kg in
a human (Ricaurte et al., 2002). And doses of 10 to 15 mg/kg which produces persistent damage in the
brain of Dark Agouti rats is therefore argued to be equivalent to a human dose of 140 to 190 mg in a
70-kg human (Green et al., 2003).
However, this approach is put into question by some researchers. Differences in metabolism,
active metabolites, and other different pharmacokinetic actions from MDMA between the species are
found to be major determining influences on drug neurotoxicity. As a result of these metabolic
pathway differences humans have been found to be much less liable to neurotoxicity than other
species, particularly rats, on which much of the work on neurotoxicity was done. MDMA-induced
neurotoxicity is dependent on non-linear kinetics in the main metabolic pathway, the regulation of
metabolic pathways by enzymes that are highly polymorphic in humans, and the formation of
neurotoxic metabolites (Easton and Marsden, 2006). These factors are not present consistently across
animal species and thus limit allometric scaling across animal models significantly (de la et al., 2004).
It is argued that in this light there is no scientific rationale for using allometric scaling to adjust doses
of MDMA between rats and humans because the pharmacologically relevant doses are similar in both
species (e.g., 1-2 mg/kg) (Baumann et al., 2007). This is supported by the finding that rats will self-
administer MDMA at doses ranging from 0.25 – 1.0 mg/kg (Schenk et al., 2003), which indicates that
these doses possess reinforcing properties and thus mirror human dosages. Furthermore male rats of
the Dark Agouti strain are found to be extremely sensitive to MDMA-induced neurotoxicity (Cole
and Sumnall, 2003).
In summary, we can safely conclude that currently there is no evidence at hand that suggests
that therapeutic use of MDMA brings significant risks for health and well-being for the patient. In
MDMA-assisted psycho-therapy a dose of 1.5-1.7 mg/kg will be administered on a few occasions, and
animal studies wherein equal doses are administered, together with studies in MDMA-naïve humans
21
which, failed to demonstrate adverse effects of MDMA. Furthermore, MDMA’s potential adverse
effects are shown dependent on dosing and ambient temperature, and in a clinical setting these
parameters can be strictly monitored. More importantly, the first clinical trials with MDMA in
patients with PTSD have shown no adverse effects of MDMA (Mithoefer et al 2011).
6. Conclusions and recommendations for future research
6.1 Document summary. This document discussed the use of MDMA in the treatment for
PTSD. PTSD is a severely disabling anxiety disorder that can develop after exposure to a traumatic
event. The disorder is characterized by a chronic and involuntary re-experiencing of the traumatic
event in the form intrusive memories, nightmares, panic, anxiety, high co-morbidity and somatic
symptoms. Currently speaking there are few effective treatments, with most evidence being provided
for exposure based psychotherapies for severe PTSD. In general, 25% to 50% of patients who develop
PTSD fail to respond to conventional treatments and suffer chronically from their symptoms. The
neurophysiology underlying PTSD includes dysregulations in brain systems involved in the
regulation of the stress response and alterations in serotonergic neurotransmission. In patients with
PTSD, two brain regions that are important for regulating amygdala activity, the mPFC and the
hippocampus, show reduced volume and function, while the amygdala and the HPA-axis are
typically hyperactive. Studies suggest that an under responsive 5-HT1A receptor system could
underlie the reduced ability to regulate anxiety in patients with PTSD.
Recent clinical studies on the effectiveness and safety of using MDMA in the treatment of
patients with treatment-resistant PTSD, showed long-term remission in 89% of the enrolled patients.
MDMA works by releasing and inhibiting the re-uptake of in particular -HT, but also DA and NE.
Serotonin release is in particular pronounced in the hippocampus, the prefrontal cortex, and the
amygdala – which are important clinical targets in the treatment of PTSD. In addition, the drug has a
high affinity for the 5-HT1A receptors, a receptor that is thought to be critically involved in producing
anxiolytic effects, memory consolidation and neurogenesis.
The unique profile of subjective effects of MDMA may be harnessed therapeutically by
enabling the patient to experience verbal and emotional exposure to the traumatic event without
them being overwhelmed by the distressful emotions that accompanies this process (See table 1). The
implicit learning experience and the explicit material that emerges during the MDMA-assisted
psychotherapy session are thought to assist the patient in adopting more adaptive coping styles.
These can be integrated in following MDMA free therapy sessions. By attenuating the fear response
and increasing the tendency to be more open to other persons, MDMA can further the therapeutic
alliance. Normally, this can be very difficult for patient with PTSD, and therefore significantly
prevent successful clinical outcomes.
The results of these studies are promising, but the important questions that are left
unanswered illustrate the pressing need for future scientific research to be performed on the
therapeutic potential of MDMA. First, the neurobiological and psychological mechanisms underlying
the therapeutic effects of MDMA are not well understood, while this could provide significant
advances for psychiatry. Second, there is no consensus on the factors that are involved in causing
treatment-resistance, but an understanding of these factors is likely critical to be able to development
better treatments. Third, the lasting beneficial effects observed after only a few sessions with MDMA
are not understood.
22
6.2 Future research. The Beckley-Imperial scientific research program is currently initiating a
new study that enables us to gain insight in these critical questions. This study involves the first
clinical trial in the UK that looks at the effectiveness, safety and mechanisms of MDMA-assisted
psychotherapy in patients with treatment-resistant PTSD. It differs from previous studies in several
important elements. First of all, it will enroll a larger number of subjects by the collaboration with a
multitude of psychiatric institutes. Secondly, in contrast to previous studies, that included mainly
victims of sexual assault, this study will include patients that have been exposed to a larger variety of
traumatic events (i.e. warfare, violence, natural or manmade accidents, etc.). This will increase the
statistic validity of the study and also enables the identification of those patient populations that are
in particular responsive for the treatment and those that or not.
Thirdly and most importantly, this study incorporates advanced neuroimaging techniques.
This has never been done before, and will provide the academic and clinical community with
invaluable information on the mechanisms involved in treatment response and long-term remission.
Patients undergo brain scanning and in-depth psychological assessments before and on two occasions
after the MDMA-assisted psychotherapy (i.e. assessing short-term and long-term effects of MDMA-
assisted psychotherapy), providing crucial information on the brain systems and corresponding
psychological constructs involved in the psychopathology and remission of PTSD.
Of particular interest is the neural circuitry involved in anxiety regulation and emotional
memory consolidation: the mPFC, the hippocampus, and the amygdala. The scientific team at
Imperial College London is equipped with the most modern and sophisticated methodological
approaches. By modeling brain networks and their modulation by MDMA-assisted-psychotherapy
the research team will supplement the already pioneering nature of this research project. This can
enable the identification of new biomarkers that predict treatment response, and by that assist in the
progression towards a more individualized approach to psychiatric treatment.
Finally, gaining a better understanding of long term remission after MDMA-assisted
psychotherapy will aid to better understand what constitutes mental health and effective treatment
strategies in general. The strategies embodied in MDMA-assisted psychotherapy for PTSD and its
empirical underpinnings can inform the development of new treatments for depression, autism, and
other conditions. This is a critical point, considering the huge global burden mental illness currently
has on society, and which is expected to increase significantly over the coming years. The value and
the opportunity for scientists, funding agencies and educational and political institutions to support
this research can therefore not easily be overestimated.
23
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