EXPERT ANALYSIS At THE ECNP CONGRESS
VIENNA (FRONTLINE MEDICAL NEWS) – What a difference a decade can make in the world of psychiatry.
Take, for example, the case of 3,4-methylenedioxymethamphetamine, better known as MDMA or, when used recreationally, as ecstasy, the love drug.
“Ten years ago at pretty much every scientific meeting where MDMA was being discussed, people were looking to find problems with it. People were dredging around trying to vilify this drug, because there was a hope that it might cause brain damage, which would justify having made its use illicit. Ten years later, we’ve changed direction completely, from fear and hating MDMA to loving it. Now we’re talking about the possibility that MDMA might actually heal the brain, and restoring MDMA to the therapeutic armamentarium,” David Nutt, MD, observed at the annual congress of the European College of Neuropsychopharmacology.
Indeed, the drug’s potential as an adjunct to psychotherapy in patients with posttraumatic stress disorder was the topic of a packed-to-the-gills session in the largest hall at the ECNP Congress, where Dr. Nutt highlighted recent insights into the psychopharmacology of MDMA and other speakers described evidence of the drug’s salutary effects on autobiographical memory and social cognition.
“The biggest problem with MDMA is its name,” quipped Dr. Nutt, professor of neuropsychopharmacology at Imperial College London.
“It used to be called ‘empathy,’ but when it started being used recreationally at raves and in the clubs, the dealers decided to change its name to ‘ecstasy.’ And that created havoc, because there’s nothing that aged editors of newspapers hate more than young people having ecstasy. They hated the term, and so the drug had to go,” according to the psychiatrist.
MDMA’s comeback as a potentially valuable medication in psychiatry can be traced to the first report of the drug’s impressive success when used as an adjunct to psychotherapy in a randomized, placebo-controlled pilot study. Michael C. Mithoefer, MD, a psychiatrist in private practice in South Carolina, and his coinvestigators stunned the psychiatric world by reporting that 10 of 12 patients with chronic PTSD refractory to both medications and psychotherapy showed significant clinical improvement in response to just two sessions of MDMA-assisted psychotherapy supplementing a more conventional course of psychotherapy ( J Psychopharmacology. 2011 Apr;25[4]:439-52 ).
Moreover, the benefits proved durable: In a subsequent paper, the investigators reported the clinical benefit of this two-dose treatment program persisted at a mean 3.8 years of follow-up and no safety concerns had been seen (J Psychopharmacol. 2013 Jan;27[1]:28-39 ).
This study, which eventually drew the attention of military veterans’ groups with political clout, proved hugely influential, especially since PTSD is so common and often is highly treatment resistant.
“We’re now living in a very strange world where trauma has in some ways become the No. 1 problem facing many societies,” Dr. Nutt observed.
He predicted that with the Food and Drug Administration’s recent approval of clinical trials of MDMA in patients with PTSD, the drug will be licensed for that indication “within the next couple years.”
How MDMA works
The pharmacology of MDMA is complex, he continued. The drug is chiefly a serotonin-releasing agent and 5HT reuptake blocker, but it also acts as an agonist on alpha-adrenergic receptors, has muscarinic and histamine-blocking effects, and promotes release of oxytocin.
Animal studies have demonstrated that MDMA facilitates extinction of fear memories through a mechanism involving changes in levels of brain-derived neurotrophic factor. Experience in humans has shown that the drug has diverse pro-social effects: It is activating, enhances mood, promotes more flexible thinking, boosts tactile experiences, and increases empathy, which in turn aids patients in bonding with their therapists.
Dr. Nutt and his coinvestigators performed the first whole-brain study of the effects of MDMA using functional MRI. This double-blind, placebo-controlled, crossover study in healthy volunteers used measurements obtained through arterial spin labeling and analysis of blood oxygen level–dependent resting state functional connectivity. The investigators documented that the marked increase in positive mood and decreased magnitude of negative personal memories produced by MDMA was accompanied by profound reduction of cerebral blood flow in the right amygdala and hippocampus. Cerebral blood flow also was reduced in the right medial temporal lobe, thalamus, and inferior visual cortex. MDMA also resulted in decreased amygdala-cortical connectivity ( Biol Psychiatry. 2015 Oct 15;78[8]:554-62 ; Int J Neuropsychopharmacol. 2014 Apr;17[4]:527-40 ).
The changes in those particular brain systems are consistent with and most likely underlie the drug’s therapeutic effects, he said. Taken together, they could serve to assist a patient in re-engaging with traumatic memories with less interference from emotional centers, thereby helping to gain executive control of the memory of the trauma.
H. Valerie Curran, PhD , a coinvestigator in the brain imaging study, cautioned the rapt audience that while there are abundant favorable anecdotal reports from psychotherapists going back as far as the 1970s, the actual evidence base for MDMA as a therapeutic adjunct to psychotherapy for PTSD is still pretty thin. She noted that in their groundbreaking study , Dr. Mithoefer and his colleagues used an unconventional form of psychotherapy modeled on the LSD therapy developed by Stanislav Grof, MD, PhD. The two MDMA-assisted sessions were each 8 hours long and included shamanistic techniques and specialized breathing to promote diminished oxygen to the brain. Also, the patient sat on a futon listening to music with a male therapist on one side and a female therapist on the other. As a clinical psychologist herself, she assured the audience that this is not standard practice in her field.
Only one other randomized, double-blind, placebo-controlled study of MDMA-assisted psychotherapy has been published to date ( J Psychopharmacol. 2013 Jan;27[1]:40-52 ). With just 12 participants, it was too small to be conclusive. So there is a definite need for additional controlled studies on the interaction between MDMA and evidence-based forms of psychotherapy. Fortunately, additional clinical trials are ongoing, noted Dr. Curran, professor of psychopharmacology at University College London.
She presented highlights of a study she and her coinvestigators carried out to determine how MDMA affects the encoding and recall of emotional autobiographical memories, since the core of most psychotherapy for PTSD entails controlled revisiting of traumatic memories. The nonblinded study included a group of recreational MDMA users who – on two separate occasions, one under the influence of street-quality MDMA of uncertain dose and purity, the other on placebo – were tasked with responding to self-threatening scenarios, exposure to compassionate imagery, and a large series of positive and negative adjectives addressed at themselves or another person ( J Psychopharmacol. 2015 Sep;29[9]:961-70 ).
The investigators found that MDMA enhanced the emotional intensity, vividness, and positivity of the subjects’ best autobiographical memories while modestly reducing the negativity of their worst memories. Structured ratings of compassion markedly increased while on MDMA. Overall, the drug’s effects were similar to those obtained through rigorous cognitive training methods developed in venerable Eastern contemplative practices in pursuit of a compassionate mindset, according to Dr. Curran.
The study results suggest a mechanism by which MDMA might enhance psychotherapy not only by improving the therapeutic alliance but also by reducing self-referential emotional processing without diminishing declarative memory, she added.
Findings of Swiss studies
Matthias E. Liechti, MD, head of the psychopharmacology research unit at the University of Basel, explained that at present Switzerland is the only country in the world where it’s legal to prescribe MDMA. Ditto LSD. Psychiatrists can do so on a case-by-case basis outside of a clinical trial setting in patients with treatment-resistant PTSD or anxiety disorders.
Dr. Liechti and his coinvestigators are interested in examining how MDMA affects social cognition as assessed by outcome measures, including a structured face emotion recognition test, the multifaceted empathy test, and a sexual arousal task.
In a series of studies in which they exposed subjects to MDMA, alcohol, methamphetamine, or LSD, they have established that both MDMA and LSD produce empathogenic effects that are possibly serotonin mediated. On a visual analog scale, subjects on those drugs gave high marks for feeling happy, open, trusting, and extroverted, and having a sense of well-being. MDMA impaired recognition of fearful, angry, and sad faces.
In contrast, methamphetamine, a pure stimulant that activates the norepinephrine/dopamine system, produced no empathogenic effects, but it enhanced recognition of sad or fearful faces. Alcohol slightly increased self-ratings for trust, happiness, and openness.
Methamphetamine increased ratings of sexual arousal in response to explicit sexual stimuli, while MDMA had no effect on sexual arousal.
MDMA and LSD increased oxytocin, prolactin, and cortisol levels consistent with their serotonergic effects. Methylphenidate did not, Dr. Liechti said.
A neuroscientist in the audience raised a possible safety concern regarding MDMA: If the drug has an agonist effect on serotonin receptors, couldn’t it have cardiac side effects similar to those of fenfluramine, a drug now banned because it stimulated the abundant 5HT-2b receptors present in the heart, resulting in increased risk of pulmonary hypertension and other adverse cardiovascular effects?
Dr. Nutt replied that there are multitudes of serotonin receptor subtypes, and it’s not yet known whether MDMA acts upon the 5HT-2b receptor. In any case, it shouldn’t be an issue for the drug’s medicinal use.
“Luckily, the effects of MDMA wear off quickly, and when it’s used with psychotherapy we may be giving only one or two doses in a lifetime, so it shouldn’t be a concern,” he said.
Dr. Nutt reported that the functional MRI brain imaging study was funded by a British television station and a private foundation.
“The reason for that is we’ve found it impossible to get any money from any traditional government funders to study drugs like MDMA unless you write grants to show they’re harmful,” he asserted.
Dr. Curran reported having no financial conflicts of interest regarding her studies. Dr. Liechti’s work is supported by the Swiss National Science Foundation.
