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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

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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

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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.

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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).

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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.

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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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