3,4‐methylenedioxymethamphetamine (MDMA)‐assisted psychotherapy: what the pharmacist needs to know

On 1 July 2023, the Therapeutic Goods Administration approved 3,4‐methylenedioxymethamphetamine (MDMA)‐assisted psychotherapy for the treatment of post‐traumatic stress disorder (PTSD). Accordingly, the purpose of this review is to provide an overview of MDMA and what pharmacists should know as this treatment emerges.

The scheduling of 3,4-methylenedioxymethamphetamine (MDMA) was altered in Australia on 1 July 2023 to be included in Schedule 8 of the Poisons Standard (Standard for the Uniform Scheduling of Medicines and Poisons, the SUSMP) when used in psychedelic-assisted psychotherapy (PAP) in post-traumatic stress disorder (PTSD). 1 As patients in the community begin to receive this treatment, pharmacists need to be aware of their potential role in the delivery of MDMA-assisted psychotherapy.Accordingly, the aim of this review is to give an overview, for pharmacists and clinicians, of the mechanism of action of MDMA and describe the key pharmacological principals to address potential drugdrug interactions (DDIs) in a clinical setting with both psychiatric and non-psychiatric medicines.

SOURCES OF INFORMATION
EMBASE, MEDLINE, and CINAHL databases were searched to provide an overview narrative synthesis of literature on MDMA, relevant to pharmacists.

KEY FINDINGS A Brief Overview of MDMA-Assisted Psychotherapy
Psychedelics are classified based on their pharmacology and chemical structures: MDMA is an amphetaminetype substance classed as an empathogen or entactogen due to its ability to produce a state of altered consciousness characterised by a number of effects, including empathy and compassion to oneself and others. 2However, MDMA is not considered a classical psychedelic, which primarily act as agonists at the serotonin (5-hydroxytryptophan, 5-HT) 2A receptor.
PAP evolved in the 1950s to 1970s and began with the discovery of lysergic acid diethylamide (LSD), which is beyond the scope of this review.Modern PAP typically involves three stages: preparatory sessions, medication sessions, and integration sessions. 3During the preparatory sessions, the therapist(s) explores the patient's symptoms, life history, and intentions, as well as educating the patient on what they should expect during the psychedelic session. 2,3The therapist(s) will also work to develop a rapport and therapeutic alliance with the patient as this is associated with positive outcomes.During the medication session, the patient is typically accompanied by a male and female therapist and the medicine is administered in a comfortable room that is decorated to avoid the feeling of being in a medical office or laboratory.Patients are able to listen to music or cover their eyes with sleeping masks, while the therapists typically take a supportive stance.The therapists may guide the patient while maintaining a safe environment that allows them to explore unexpected perceptions that surface during the session. 4Different therapeutic models for PAP have been proposed; however, trials of MDMA in PTSD conducted to date have predominately used a supportive approach.Following the medication session(s), integration sessions are conducted so the patient can reflect on, interpret, and consolidate the psychedelic experience, and process and transform the insights and experiences gained from the session(s) into long-term change. 4,5number of randomised control trials have now assessed the efficacy MDMA in the treatment of PTSD.[6][7][8][9][10] Typically, the inclusion and exclusion criteria for these trials requires participants to withdraw from psychotropic medicines prior to therapy, resulting in limited information on the DDIs in clinical settings.

Prescribing and Dispensing MDMA
On 1 July 2023, MDMA was rescheduled in Australia to Schedule 8 when used to treat PTSD and otherwise remains a prohibited substance in Schedule 9 of the Poisons Standard.MDMA can only be prescribed by a psychiatrist who is a Fellow of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) and must be an Authorised Prescriber (AP) under the Authorised Prescriber Scheme, which requires approval from both a human research ethics committee and the Therapeutic Goods Administration (TGA). 11It is important for pharmacists to be aware that MDMA can only be dispensed directly to an AP of MDMA, and this authorisation must be held prior to the pharmacy obtaining and supplying MDMA.MDMA cannot be supplied to a patient.
Australian guidelines for the acquisition and dispensing of MDMA vary by state and territory.Pharmacists should consult their respective health department for "Once all authorisations are obtained, unapproved products containing MDMA may be available to be imported.To import therapeutic goods that contain a Schedule 8 product the Authorised Prescriber, or person acting on their behalf, will require to apply to the Office of Drug Control for a licence and permit to import.""Treatment with MDMA in NSW must take place in a private health facility which is licensed in the mental health class under the Private Health Facilities Act 2007."Queensland 13 "A Queensland wholesaler can supply to a sponsor of a clinical trial, a psychiatrist who is an Authorised Prescriber or a pharmacist who can demonstrate they have a supply arrangement with a psychiatrist who is an Authorised Prescriber." "A Queensland pharmacist can possess [MDMA] if they can demonstrate that they have a supply arrangement with a psychiatrist who is an Authorised Prescriber to supply the goods directly to the psychiatrist for the purpose of subsequent administration to a patient.""The TGA has indicated that the intention is for these medicines to be administered in a clinic or hospital setting, so it is unlikely that authority will extend to possession by a patient outside a healthcare setting.""It is expected that most products supplied will be those that have been imported under an Office of Drug Control licence and permit."". ..pharmacists wishing to extemporaneously compound medicines containing MDMA in Queensland will require a Good Manufacturing Practice (GMP) licence from the TGA that expressly authorises the manufacture of goods containing MDMA to avoid prosecution under Commonwealth law."Victoria 14 "Pharmacists are required to comply with Schedule 9 requirements when handling MDMA, including compounding of MDMA." "If pharmacists import or wholesale MDMA, they must comply with wholesale and importation requirements, in addition to complying with Commonwealth legislative requirements."MDMA = 3,4-methylenedioxymethamphetamine; NSW = New South Wales; TGA = Therapeutic Goods Administration.more information. 12-14A summary of state guidelines for pharmacists in New South Wales, Queensland, and Victoria are given in Table 1.

Clinical Use in PTSD and Adverse Events
PTSD is a serious and difficult-to-treat disorder with a 12-month prevalence of 5.7% in Australia. 15Treatment guidelines are complex and depend on a number of factors; however, treatment typically involves psychotherapy, with or without pharmacotherapy. 16The majority of patients assessed for PAP will have been treated with serotonergic antidepressants at some point in time, and many will still be on them when preparing for treatment, requiring medication withdrawal prior to the commencement of MDMA-based treatment.
A growing body of evidence for the use of MDMA in PTSD has been emerging for over a decade.Clinical trials assessing the efficacy of MDMA-assisted psychotherapy typically assess, as the primary endpoint, the difference in the Clinician Administered PTSD Scale (CAPS) from baseline.A meta-analysis of six unique controlled trials showed that treatment with MDMA-assisted psychotherapy (two or three multihour sessions) reduced CAPS scores by a clinically significant amount (risk ratio [RR] 3.65, 95% confidence interval [CI] 2.39-5.57)and increased the number of participants deemed to no longer meet the criteria for PTSD (RR 2.10, 95% CI 1.37-3.21)when compared to the control arm. 17The highest and most commonly used dose in the studies was 125 mg MDMA with an optional supplemental dose of 62.5 mg. 17In an aggregate of phase 2 studies of moderate or high-dose MDMA, the most common adverse events were anxiety (72%), jaw clenching (64%), reduced appetite (49%), dizziness (40%), and nausea (40%). 17hile these studies yield promising results, one of the greatest criticisms is the lack of adequate blinding to treatment allocation as participants can mostly guess whether they received MDMA or placebo.For example, in a recent phase 3 trial, 75% of participants in the placebo group were certain or thought they received placebo and 94.2% of participants in the MDMA group were certain or thought they received MDMA. 18armacology MDMA is a ring-substituted amphetamine (stimulant) with a chiral centre creating two enantiomers ((S )-MDMA and (R)-MDMA); however, clinically and recreationally, MDMA is taken as a racemic mixture. 19DMA is a potent releaser of presynaptic 5-HT, dopamine (DA), and noradrenaline (NA) via the reversal and inhibition of the membrane transporters (e.g.serotonin transporter [SERT]) (Figure 1) and has been shown to increase oxytocin levels. 20Additionally, MDMA is a mild inhibitor of monoamine oxidase (MAO) and is more selective for MAO-A, which is responsible for the metabolism of 5-HT, than MAO-B. 21Synergistic with the reversal of membrane transporters, MDMA interferes with vesicular monoamine transporter 2 (VMAT2), causing elevated concentrations of monoamines in the cytosol, which permits rapid efflux into the synapse. 22MAT2 is responsible for the packaging of neurotransmitters, such as 5-HT, DA, and NA, into synaptic vesicles for release. 23Additionally, MDMA may have affinity as an agonist at a number of 5-HT (1A, 2A, 2B, and 2C), DA (1 and 2), adrenergic (a 2A , a 1 , and b), acetylcholine (ACh) muscarinic (1 and 2), histamine (1), and ACh nicotinic receptors. 24The pharmacokinetic parameters of MDMA are given in Table 2.
The combination of these actions results in profound increases in synaptic monoamine concentrations, particularly 5-HT.This results in an altered state of consciousness characterised by euphoria, empathy, increased interpersonal trust, compassion for oneself and others, as well as transient increases in heart rate, blood pressure, and body temperature. 25When used as a treatment for PTSD (MDMA-assisted psychotherapy), anxiety and other negative emotions are more common.
MDMA is metabolised via two main metabolic pathways: (1) O-demethylation by cytochrome P450 (CYP) 2D6 (CYP2D6) and other isoenzymes (CYP1A2, CYP3A4, and CYP2B6) to 3,4-dihydroxymethamphetamine (HHMA); and (2) N-dealkylation to 3,4-methylenedioxyamphetamine (MDA), a minor metabolite of MDMA. 26,27MDA can be O-demethylated to form 3,4-dihydroxamphetamine (HHA) and catechol-O-methyltransferase (COMT) is involved in HHMA and HHA O-methylation; however, these metabolites can also form sulphate or glucuronide conjugates.The metabolism of HHMA to HMMA via COMT may be a safety consideration as HMMA may be more potent than MDMA in releasing antidiuretic hormone (ADH).Therefore, variability in COMT expression may influence the potential for the syndrome of inappropriate ADH secretion; however, this is unlikely to have any clinical effect in MDMA-assisted psychotherapy given the short duration of treatment.Accordingly, drugs that affect these enzymes, namely CYP2D6 substrates and inhibitors, can affect MDMA metabolism, which can have clinically significant impacts.Additionally, MDMA is a strong inhibitor of CYP2D6 (autoinhibition) and can convert a rapid or extensive CPY2D6 metaboliser into a poor metaboliser within 2 h. 28Note that this means subsequent doses of MDMA during the period of enzyme inhibition (CYP2D6 activity recovered to 90% of baseline activity by 10 days in a sample of 12 women taking 1.5 mg/kg MDMA and were CYP2D6 extensive metabolisers) can increase the plasma concentration of MDMA greater than what would be expected due to accumulation. 26,29,30This autoinhibition may partly explain the non-linear kinetics of MDMA, which has been observed in dose ranges typically used during MDMA-assisted psychotherapy.Therefore, increases in MDMA plasma concentrations may not follow the same proportionality as increases in MDMA doses. 31

DrugÀDrug Interactions and Safety
There are many factors to consider when interpreting potential drug interactions with MDMA.For example, considerations about the impact that a single MDMA dose will have on the pharmacokinetics/pharmacodynamics of another drug, cardiovascular risk factors, or whether there is a true risk for serotonin toxicity when combined with another serotonergic drug.

A Quick Note on Serotonin Toxicity
When considering drugs that may induce serotonin toxicity, it is pivotal to understand the pathophysiology.Serotonin toxicity is primarily mediated through 5-HT 2A receptors; 32 therefore, serotonergic drugs that do not Only investigated in dog plasma.increase 5-HT transmission or do not act on this receptor as an agonist (e.g.mirtazapine is primarily an antagonist at 5-HT 2A receptors, triptans have very minimal 5-HT 2A receptor activity, and buspirone is a 5-HT 1A receptor partial agonist) are unlikely to be causative agents in serotonin toxicity as serotonin toxicity requires 5-HT concentrations to increase by 10-50 times the baseline level.Symptoms of severe toxicity include hyperthermia, confusion, delirium, sustained clonus, and rhabdomyolysis.Interestingly, while classical psychedelics' primary mechanism of action is via agonism at 5-HT 2A receptors, there is very weak evidence linking them to serotonin toxicity, which may be explained by biased agonism (i.e. the drug triggers different signalling pathways compared to other 5-HT 2A agonists while acting on the same receptor). 32Therefore, when combining psychedelics, such as psilocybin or dimethyltryptamine, with serotonergic drugs (e.g.selective serotonin reuptake inhibitors [SSRIs] and MAO inhibitors [MAOIs]), while these interactions may dampen (SSRIs) or amplify (MAOIs) the psychedelic effects, serotonin toxicity is unlikely due to different activation pathways utilised by psychedelics and 5-HT. 33lective Serotonin/Noradrenaline Reuptake Inhibitors and Tricyclic Antidepressants Clinical trials assessing the efficacy of MDMA in PTSD have generally excluded patients taking antidepressants; therefore, much of the toxicity data comes from non-clinical populations pre-dosed with an SSRI or from recreational use.Based on the pharmacology of MDMA, we know that the risk of serotonin toxicity when combining SSRIs and MDMA is minimal.In fact, SSRIs diminish the effects of MDMA, which can be explained by MDMA's mechanism of action.Since MDMA utilises SERT for uptake into the presynaptic terminal (where it inhibits VMAT2) and the reversal of membrane transporters, blocking SERT with an SSRI inhibits MDMA's action.These effects have been demonstrated in a number of clinical trials using the SSRIs paroxetine, 34 citalopram, 35 and fluoxetine, 36 and the serotonin noradrenaline reuptake inhibitor (SNRI) duloxetine. 37The results demonstrated a reduction in physiological measures, such as blood pressure, heart rate, and pupil dilation.Two studies assessed MDMA pharmacokinetics, whereby pre-treatment with paroxetine (20 mg for 3 days orally prior to 100 mg of oral MDMA administration) and duloxetine (120 mg orally at 16 and 4 h prior to 125 mg of oral MDMA) increased MDMA maximum serum concentration (C max ) by 16% in both studies, as well as the area under the curve (AUC) 0-21 and AUC 0-6 , respectively, which were mediated by the CPY2D6 inhibitory effects by paroxetine and duloxetine. 34,37These data highlight the effect that CYP2D6 inhibitors can have on the pharmacokinetics of MDMA and may have clinically significant cardiovascular consequences; however, this is less likely with SSRI/SNRI drugs as they inhibit the increase in physiological measures associated with increased cardiovascular risk (i.e.blood pressure and heart rate).Additionally, SSRI/SNRI drugs dampen the subjective effects of MDMA, [34][35][36][37] which may limit its therapeutic utility in PTSD, but more research is required. 38Like SSRI/SNRI drugs, tricyclic antidepressants (TCAs) are unlikely to result in serotonin toxicity due to competition at the SERT binding site, and are more likely to diminish the effects of MDMA. 39However, TCAs carry additional risks, such as QT interval prolongation.Note that some over-the-counter (OTC) medicines may also act as serotonin reuptake inhibitors (Table 3).

Monoamine Oxidase Inhibitors
Unlike SSRIs and SNRIs, MAOIs, such as the reversible MAO-A inhibitor moclobemide (5-HT and NA are substrates of MAO-A), carry the risk of serotonin toxicity and hypertensive crisis when combined with MDMA, which can be fatal. 40,41Serotonin toxicity can be explained by the increased release of 5-HT by MDMA and decreased metabolism by the MAOI.Accordingly, this combination should always be avoided, and it is important to recognise that other drugs, such as isoniazid, can act as MAOIs (Table 3).

Amphetamines
Amphetamines are considered as neurotransmitter releasers (5-HT, DA, and NA), but when compared to MDMA, other amphetamines, such as dexamfetamine, show a lower affinity for SERT. 42Nevertheless, amphetamines have the ability to release 5-HT in a similar mechanism to MDMA and can increase 5-HT, DA, and NA transmission; therefore, caution should be exercised if combining these drugs due to the risk of cardiovascular events and serotonin toxicity.

Noradrenaline/Dopamine Reuptake Inhibitors
Other drugs, such as reboxetine and bupropion, 43 increase MDMA plasma concentrations by 20% and 15%, respectively, while also reducing the 'high' from MDMA.Unsurprisingly, methylphenidate did not alter MDMA plasma concentrations but did increase heart rate and concentrations of adrenaline compared to MDMA alone; however, no changes in blood pressure, temperature, or pupil dilation were observed. 44

Lysergic Acid Diethylamide
Anecdotal and observational data suggest that co-administration of MDMA (dose undefined) with psilocybin or LSD may buffer against challenging experiences and enhance positive experiences. 45However, clinical results are conflicting and highlight the potential pharmacokinetic interactions.Results showed that MDMA prolongs the effects of LSD, which is explained by higher plasma concentrations and longer elimination half-life of LSD, likely due to CYP2D6 inhibition by MDA. 46ffeine, Alcohol, and Over-the-Counter Medicines Commonly used licit substances are sometimes not thought about in the context of DDIs, but they have the potential for significant interactions.Animal studies have demonstrated that caffeine potentiates the acute toxicity of MDMA (increased body temperature and tachycardia). 47While it is unknown to what extent this translates to humans, a cautious approach to MDMA administration may be to avoid caffeine intake on the day of dosing or to limit intake in regular consumers.Alcohol should also be avoided as it has been shown to alter the pharmacokinetics of MDMA by increasing MDMA plasma concentrations. 26atients often forget to disclose OTC medicines; therefore, directly asking about OTC, supplements, and alternative and complimentary medicines is important to determine whether there may be any interactions with MDMA.OTC medications and alternative medicines, such as chlorpheniramine, dextromethorphan, and St John's Wort, can also act as serotonin reuptake inhibitors; 48 therefore, they may also dampen the effects of MDMA, which may be clinically significant and should be avoided until further research is conducted.
As 5-HT is synthesised from dietary tryptophan with the intermediate 5-hydroxytryptophan (5-HTP), supplementation with tryptophan or 5-HTP can theoretically lead to increases in 5-HT.However, it should be noted that oral tryptophan and 5-HTP can be converted to 5-HT in the periphery and 5-HT does not cross the blood-brain barrier.Therefore, whether these supplements can lead to clinically significant increases in central 5-HT concentrations is not clear and based off limited evidence. 49

Multiple MDMA Administrations in a Session
Clinical trials assessing the efficacy of MDMA in PTSD have often used an initial dose of MDMA with or without a supplemental dose. 18A number of clinical trials have demonstrated that repeated administrations of MDMA in the same session result in higher than expected MDMA plasma concentrations.One study examined the effect of 50 mg of MDMA followed by 100 mg 2 h later.The results showed that the AUC was 16.2% greater than that expected by simple dose accumulation and the C max was 12.8% greater. 50HMMA and HMA concentrations were significantly lower, which may be attributed to CYP2D6 autoinhibition.

Cardiovascular Risk
In relation to cardiovascular risks, it is noteworthy that in a clinical population of patients with PTSD with no marked QTc prolongation at baseline, no adverse events that could indicate QT prolongation were reported (MDMA arm n = 46); however, electrocardiograms were not conducted while under the influence of MDMA. 18hile MDMA has been associated with cases of QT prolongation and Torsades de pointes, cases typically involve concomitant drugs and it is unclear whether this is due to the sympathomimetic action or mediated by CYP2D6 inhibition increasing plasma levels of other QT interval prolonging drugs. 51s a stimulant, elevations in blood pressure, heart rate, and temperature are common with MDMA.A study of 166 healthy participants demonstrated that blood pressure >160 mmHg, heart rate >100 bpm, and body temperature >38°C occurred in 33%, 29%, and 19% of participants, respectively, all of which were greater in the 125-mg dose compared to the 75-mg dose.Consideration should, therefore, be given to patients receiving MDMA with significant cardiovascular risks and uncontrolled hypertension. 52Carvedilol has been shown to reduce these cardiostimulant and thermogenic effects, without affecting the subjective effects of MDMA or plasma exposure to MDMA in a small placebo-controlled randomised crossover study (n = 16). 53

Other Considerations
There are also a number of prodrugs that require activation via metabolism by CYP2D6.Examples of these include codeine (metabolised into morphine and morphine-6-glucuronide), tramadol (metabolised to Odesmethyltramadol), and tamoxifen (metabolised to endoxifen).Inhibition of CYP2D6 may decrease the analgesic effect of codeine and tramadol, and the serotonin and noradrenaline reuptake inhibitory action of tramadol should also be taken into account in the context of MDMA administration.Guidelines for tamoxifen advise against the combination of strong CYP2D6 inhibitors (e.g.MDMA), but given the infrequency of MDMA administration in MDMA-assisted psychotherapy, each patient should be assessed on an individual basis for the potential risk and benefit, as these recommendations were centred around daily administration of CYP2D6 inhibitors (e.g.paroxetine and fluoxetine). 54Additionally, co-administration of paroxetine and tamoxifen failed to significantly increase the risk of subsequent breast cancer rates in a cohort of 16 887 women, which underlines the potential lack of clinical significance that an interaction with infrequent MDMA use and tamoxifen may have.

The Role of the Pharmacist and Clinical Guidance
Pharmacists in clinical settings are positioned to make medication risk assessments as they have the appropriate knowledge and tools to determine DDIs and their significance, the risk of serotonin toxicity, and potential cardiovascular risks.When considering interactions with MDMA, it is important to consider the metabolism of the potential interacting drug(s) and the metabolism of MDMA, as well as drug-disease interactions, particularly cardiovascular disease and possible cardiovascular risks.Additionally, reviewing medication lists and dispensing history for drugs that may dampen the effects of MDMA is crucial as this may consequently hinder clinically meaningful MDMA-assisted psychotherapy sessions.Drugs metabolised by CYP2D6 and prodrugs activated by CYP2D6 should be flagged, and the effect of MDMA's CYP2D6 inhibitory action should be considered in the context of its infrequent administration (Table 3).The effect of CYP2D6 inhibitors should also be considered as this can increase MDMA plasma levels.Serotonergic agents should be considered as potential causative agents for serotonin toxicity; however, understanding the dampening effect of 5-HT reuptake inhibitors versus the additive and potentiating effects of direct 5-HT agonists, releasers, or MAOIs must be understood before making clinical decisions.Finally, consideration should be given to non-prescription substances (e.g.caffeine, alcohol, and OTC medications).Typically, drugs will be cleared from the body after five half-lives, which can assist in determining appropriate wash-out periods.

CONCLUSION
MDMA-assisted psychotherapy is now approved in Australia for the treatment of PTSD and is being used in real-world clinical settings.Doses of MDMA result in profound increases in 5-HT transmission, which make it a useful tool in psychotherapy; however, there are a number of DDIs that must be considered when administering MDMA.As MDMA is metabolised by, and is a strong inhibitor of, CYP2D6, other drugs (substrates and inhibitors) of this enzyme must be administered with caution.Drugs that inhibit the reuptake of 5-HT (i.e.SSRIs and SNRIs) are unlikely to cause serotonin toxicity, but they can blunt the effects of MDMA and may diminish MDMA's clinical value.Care should be taken to collect the patient's full medical history, including prescription, OTC and alternative/complimentary medicines, and drug-disease interactions, to inform whether MDMA can be administered safely.

Table 1
State-specific guidance on the importation and dispensing of MDMA

Table 2
MDMA pharmacokinetic parameters max = maximum serum concentration; MDMA = 3,4methylenedioxymethamphetamine; T max = time to reach C max ; V d = volume of distribution.aBased on a 100 mg dose; this is similar to values reported for 50-125 mg doses.bBased on a 100 mg dose.c

Table 3
Examples of drugs to consider as potential drug interactions with MDMA a Used in ayahuasca as a MAOI to potentiate the effects of dimethyltryptamine.