MDMA-assisted therapy has shown significant promise in the treatment of various psychiatric disorders, including post-traumatic stress disorder (PTSD), depression, and anxiety. This article provides an overview of the best practices in MDMA-assisted therapy, synthesized from recent scientific research.

Introduction

MDMA, commonly known as ecstasy, when used in a controlled therapeutic setting, has been shown to enhance the effectiveness of psychotherapy for certain mental health conditions.

Best Practices in MDMA-Assisted Therapy

1. Therapeutic Setting: MDMA is administered in a controlled clinical setting, often accompanied by psychotherapy sessions. This combination is critical for achieving the desired therapeutic outcomes (Yazar‐Klosinski & Mithoefer, 2017).
2. Dosage and Administration: Clinical trials have experimented with different dosages to find the optimal amount for therapeutic use. Typically, MDMA is administered in a single dose during therapy sessions (Oehen, Traber, Widmer, & Schnyder, 2013).
3. Safety and Tolerability: Research indicates that MDMA can be safely administered in a clinical setting, with no significant drug-related serious adverse events (Feduccia & Mithoefer, 2018).
4. Efficacy: Studies have shown that MDMA-assisted psychotherapy can lead to clinically significant improvements in PTSD symptoms and potentially other disorders (Smith, Sicignano, Hernández, & White, 2021).
5. Extended Benefits: MDMA catalyzes shifts toward openness and introspection that can result in lasting benefits without the need for ongoing administration (Danforth, Struble, Yazar-Klosinski, & Grob, 2016).
6. Patient Diversity: Recent trials indicate the efficacy of MDMA therapy across a diverse range of patients, including those with severe PTSD and other comorbidities (Mitchell et al., 2021).
7. Mechanism of Action: MDMA enhances the release of neurotransmitters and hormones that modulate emotional memory circuits, aiding in the reprocessing of traumatic memories and facilitating fear extinction (Feduccia & Mithoefer, 2018).

Conclusion

MDMA-assisted therapy represents a breakthrough in the treatment of certain psychiatric disorders, offering a unique combination of pharmacological and psychotherapeutic interventions. The controlled use of MDMA in therapeutic settings has shown significant efficacy and safety, making it a promising option for patients who are resistant to traditional treatments.

The information presented in this article is based on current scientific research and is subject to change as new studies emerge. Always consult with a healthcare professional for medical advice and treatment.

There are some exceptions to this rule, such as in the case of telemedicine, where a healthcare provider may prescribe controlled substances via a video call if certain conditions are met. However, the use of psychedelics for medical purposes is still highly regulated and not widely accepted.

One recent example of poor online prescribing practice is a story of a patient who was prescribed 75 doses of Ketamine in 5 minutes online which was then delivered to his house for under $300. Whilst providing access to low-cost medicine for patients is an ethical virtue of practice one should keep in mind that there is an online prescribing best practice which should be followed. This includes online prescribing risk analysis and subsequent mitigation which should be performed after each medicine is added to an online prescribing formulary.

However, if proper safeguards are in place there are a wide range of opportunities in the medical space, including:

• Psilocybin availability in the UK

If you would like more information concerning these opportunities you can contact one of our expert consultants here.

Many studies have found that people who use psychedelics are more likely to have pro-environmental behavior and ecology beliefs when compared to other people. A recent study by the University of Oregon found that people who took psychedelics were more likely to recycle, donate money to environmental organisations, buy products with less plastic packaging, or use public transportation. The results were not just because of the drugs themselves but also because of the spiritual experiences they create.

Over the last two decades, there has been a gradual political shift, towards a resurgence of psychedelic research, culminating in the first experimental study involving LSD administration in 40 years. First and foremost, many of these new research programs focus on clinical applications of psychedelic substances in the treatment of anxiety and mood disorders. Although oftentimes limited to small sample sizes, preliminary results of these studies indicate that administration of psychedelics can considerably benefit psychotherapeutic interventions, revealing a marked reduction of anxiety in patients who suffer from various life-threatening conditions.

One common experience encountered by many during the neuroplastic state induced by psychedelics is a profound feeling of connectedness or unity—a presumed consequence of a loss of self-awareness or ego-dissolution. This manifests in a sense of connectedness with all living beings, certain plants and animals, or nature as a whole.

References

1.  Manifesting Minds: A Review of Psychedelics in Science, Medicine, Sex, and Spirituality. Doblin, Rick; Brad Burge (2014) North Atlantic Books. ISBN 1583947272.
2. ↑ Lifetime experience with (classic) psychedelics predicts pro-environmental behavior through an increase in nature relatedness. Matthias Forstmann and Christina Sagioglou Journal of Psychopharmacology 2017. DOI: 10.1177/0269881117714049
3. ↑ From Egoism to Ecoism: Psychedelics Increase Nature Relatedness in a State-Mediated and Context-Dependent Manner. Hannes Kettner, Sam Gandy, Eline C. H. M. Haijen and Robin L. Carhart-Harris Centre for Psychedelic Research, Department of Brain Sciences, Faculty of Medicine, Imperial College London. International Journal of Environmental Research and Public Health. Published: December 2019 DOI: 10.3390/ijerph16245147

Two academic disciplines that look at how non-biological variables affect the response to therapy are placebo response theory and set and setting theory. Both believe that aspects like expectations, planning, and beliefs are essential for comprehending the extra-pharmacological processes that determine how the body responds to medications.

But the two theories also have important distinctions of their own. Set & setting only considers how people react to psychoactive medications; placebo theory applies to all forms of treatment. Set and setting theory is intended for both experts and drug users, whereas placebo theory is targeted at medical professionals. Set and setting theory is mostly prescriptive, teaching therapists and users how to regulate and maximise the effects of medications, whereas placebo theory is primarily descriptive, explaining how placebo operates.

Although the precise interactions between these two perspectives still need to be clarified, when taken together, the advantages of their combined consideration become clear: While placebo theory suggests that psychedelics, as suggestibility-improving, meaning-magnifying substances, may serve to boost placebo response, set and setting theory gives a paradigm for the reintegration and optimisation of placebo response in clinical practice.

AMT
ALPHA-METHYLTRYPTAMINE
A designer drug that produces hallucinogenic effects paired with euphoria. Side effects can include vomiting and nausea.

Aya·hua·sca
BANISTERIOPSIS CAAPI
A powerfully psychedelic, traditionally used as a spiritual medicine in the indigenous Amazon. It contains a mixture of MAOI and DMT that allow the DMT to be orally active in the human body. Ayahuasca produces extremely intense visions and insights, combined with a form of purging. These effects are used as medicinal properties amongst the shamans of the Amazon.

Co·caine
BENZOYLMETHYLECGONINE
One of the most popular stimulants worldwide. It derived from the Erythroxylum coca plant and can produce stimulating and euphoric effects. Cocaine can also be highly addictive.

DMT
N,N-DIMETHYLTRYPTAMINE
A very strong psychedelic which is short-acting when being smoked, producing intense visions. Since it is produced in many plants, animals and the human body, it is not orally active. However, in combination with an MAOI, it is also part of the indigenous medicine Ayahuasca.

DXM
DEXTROMETHORPHAN HYDROBROMIDE
Used as a cough suppressant, DXM is a available over-the-counter. When taken in very high dosages, it produces strong dissociative effects, similar to Ketamine.

GBL
GAMMA BUTYRLACTONE
A precursor to GHB that produces very similar effects that come and go more rapidly. GBL is also acidic and has to be watered down if consumed as a drug. The effects and the side effects are more extreme than with GHB which makes it even more difficult to handle.

GHB
GAMMA-HYDROXYBUTYRATE
A GABA-based neurotransmitter that is part of the human central nervous system. It is used as a medication for instance to treat narcolepsy. Used as a drug, it produces short acting alcohol like intoxications that makes GHB popular as a party drug. Due to its sexual stimulating effects it is also very popular amongst MSM (Men who have sex with men) populations. GHB is very hard to dose and especially in combination with alcohol, it can lead to a long lasting coma-like state (‘G-sleep’) or even death. When used over long periods of time, it can also cause forms of psychological and physiological addiction.

Ha·wai·ian ba·by wood·rose
ARGYREIA NERVOSA
The seeds contain the psychedelic substance LSA.

Pir·ac·e·tam
2-OXO-1-PYRROLIDINEACETAMIDE
The first and still very popular ‚nootropic‘ or smart drug that is said to induce cognitive enhancement.

Mo·da·fi·nil
BENZHYDRYLSULPHINYLACETAMIDE
Originally a medication to treat narcolepsy, Modafinil is also used as a cognitive enhancement drug that is said to increase focus and wakefulness.

Mel·a·to·nin
N-[2-(5-METHOXY-1H-INDOL-3-YL)ETHYL]ACETAMIDE
Melatonin is a hormone produced by the pineal gland and involved in the regulation of sleep. It is used as a sleep aid and to help reset the body’s clock and help reduce jet-lag.

Morn·ing glo·ry
IPOMOEA VIOLACEA
A psychedelic plant that contains LSA, a naturally occurring relative of LSD. It has a long history of traditional use as a medicine amongst indigenous tribes in Mexico.

Ke·ta·mine
2-(2-CHLOROPHENYL)-2-(METHYLAMINO)-CYCLOHEXANONE
Ketamine is a dissociative drug that has a history in veterinary and human anaesthetics. In low dosages it produces ‘fluffy’ sensations which can transform into dissociation of the consciousness in higher dosages (‘K-Hole’). Ketamine is widely used as a party drug.

Kra·tom
MITRAGYNA SPECIOSA
It has a long history of use in Thailand and South East Asia. The leaves are chewed as an opiate substitute and stimulant, primarily among the working class.

Laugh·ing gas
NITROUS OXIDE
Nitrous Oxide is an anaesthetic that is also used in dentistry. It is also used as a whipped cream propellant which makes it highly available. Its effects are short lasting and dissociative, similar to DXM or Ketamine.

LSD
2-(2-CHLOROPHENYL)-2-(METHYLAMINO)-CYCLOHEXANONE
LSD is the best known and most researched psychedelic in the western sciences. Discovered in 1943 by Swiss biochemist Albert Hofmann, the substance produces pseudo-hallucinations, synesthesia and in higher dosages phenomena like ‘ego-death’ and mystical experiences.

MDMA
3,4-METHYLENEDIOXYMETHAMPHETAMINE; XTC
MDMA is one of the most popular synthetic drugs, especially in Western countries. It is either sold in crystalline form (‘Molly’, MDMA) or as the main ingredient in XTC (‘Ecstasy’) pills. It produces strong empathogenic, euphoric, and stimulant feelings. The emotional openness which it produces makes it popular in the electronic dance music scene but also interesting as a tool psychotherapy.

Mush·rooms
PSILOCYBE MUSHROOMS
Many species contain the psychedelic chemicals psilocybin or psilocin. They have a long history of use in Mexico and are currently one of the most popular and commonly available natural psychedelics. Their effects are very similar to LSD, including pseudo-hallucinations and profound insights or realizations.

Nut·meg
MYRISTICA FRAGRANS
Produces deliriant effects when used in large quantities. It has a history of use from the Arabian Peninsula to South East Asia.

Sal·via di·vi·no·rum

Its leaves contain the extremely potent Salvinorin A. It has a long history of use as spiritual medicine amongst the Macatecs in Mexico. Since the mid 1990s it became widely available and popular despite the fact that its hallucinogenic effects are considered unpleasant by many people.

Syr·i·an rue
PEGANUM HARMALA
Its seeds contain harmine and other harmala alkaloids that act as a MAO-A inhibitor which potentiates and prolongs the effects of other drugs, especially psychedelics. It is one of the plants that is speculated to be the ancient Soma (India) or Haoma (Persia).

Mental health disorders are on the rise, whilst the development of novel psychiatric medications has been dwindling for the past decade⁶. Developments in drug treatments for psychiatric problems as well as neurological conditions such as Alzheimer’s and Parkinson’s disease has shrunk by at least 70% in the past decade. This stall in innovation has sparked intense debate about historical diagnostics categories such as the DSM-V and explanations for mental disorders, leading to a new invigoration of research into psychedelics.

Psychedelic medicines, pre-1970’s were used by the scientific community with great effect until the mid 70’s “War on Drugs” by Richard Nixon. In recent years, because of the lack of novel molecular entities for new drugs have been making their way back into mainstream medicine. Recently, a law change in Canada has let a select cohort of healthcare professionals to legally obtain psychedelics for personal use so that they can “better understand” what they will be prescribing¹. This event is just one of many in this new paradigm shift which has led to the development of psychedelic-assisted psychotherapy (PAP): professionally supervised use of ketamine, MDMA, psilocybin, LSD and ibogaine as part of elaborated psychotherapy programs.

Clinical results so far have shown safety and efficacy, even for “treatment-resistant” conditions, and thus deserve increasing attention from medical, psychological and psychiatric professionals. But more than novel treatments, the PAP model also has important consequences for the diagnostics and explanation axis of the psychiatric crisis, challenging the discrete nosological entities and advancing novel explanations for mental disorders and their treatment, in a model considerate of social and cultural factors, including adversities, trauma, and the therapeutic potential of some non-ordinary states of consciousness².

For psilocybin, ketamine, mescaline and LSD it has been found that the psychedelic experience have yielded magnetoencephalographic (MEG) signals values exceeding those of normal waking consciousness. Indicating psychedelic drugs induce ‘heightened state of consciousness‘. The scans found the most notable effects in parts of the brain that are known to be important for perceptions, rather than other roles such as language and movement.

Medicinal Chemistry

All psychedelics are chemically unique and but can be catergorised into four main main types:

Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides and many tend to act via serotonin 2A receptor agonism which plays a key role in regulation of cortical function.

Neuropsychopharmacological effects

Whilst the pharmaceutical industry markets that psychedelics can cure everything from obesity to hair loss, in reality there is little evidence that they can treat any other conditions apart from mental health issues. The is a lot of subjective data (see https://erowid.org/experiences/) suggesting that each psychedelic has an individual nuanced effect. A analysis of 2947 publicly available trip reports concluded:

MDMA experience reports featured an emotionally intensifying profile accompanied by many cognitive process words and dynamic-personal language. In contrast, Ayahuasca and DMT experience reports involved relatively little emotional language, few cognitive process words, increased analytical thinking-associated language, and the most semantic similarity with psychedelic and mystical experience descriptions[8]. LSD, psilocybin mushroom, and ketamine reports showed only small differences on the emotion-, analytical thinking-, psychedelic, and mystical experience-related language outcomes. Further research has concluded: “Both doses of LSD and the high dose of psilocybin produced qualitatively and quantitatively very similar subjective effects, indicating that alterations of mind that are induced by LSD and psilocybin do not differ beyond the effect duration”[7].

Relative to standard antidepressants, the reports featured more negative emotional and cognitive process-related words, fewer positive emotional and analytical thinking-related words, and were generally not similar to mystical and psychedelic language [8].

Brain Activity effect

Psychedelic drugs significantly increased the fractal dimension of functional connectivity networks, and that LSD significantly increased the fractal dimension of BOLD signals, with psilocybin showing a non-significant trend in the same direction. [4]

Psychedelic Tolerance

Tolerance builds with all psychedelics (inlucing cross-tolerance) with repeated usage, lasting for a few days.

Psychedelic Dose Equivalency

The 20 mg dose of psilocybin is likely equivalent to the 100 µg dose of LSD base.

References

[1] https://www.cbc.ca/news/canada/london/some-doctors-therapists-get-health-canada-permission-to-use-magic-mushrooms-1.5834485

[2] Schenberg EE. Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. Front Pharmacol. 2018;9:733. Published 2018 Jul 5. doi:10.3389/fphar.2018.00733

[3]Hibicke, Meghan & Landry, Alexus & Kramer, Hannah & Talman, Zoe & Nichols, Charles. (2020). Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression. ACS Chemical Neuroscience. XXXX. 10.1021/acschemneuro.9b00493.

[4] Mational Institute of Drug Abuse: https://d14rmgtrwzf5a.cloudfront.net/sites/default/files/hallucinogensrrs4.pdf

[5] Serotonergic psychedelics LSD & psilocybin increase the fractal dimension of cortical brain activity in spatial and temporal domainshttps://www.sciencedirect.com/science/article/pii/S105381192030535

{6] https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(20)30491-0/fulltext

[7] Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. https://www.nature.com/articles/s41386-022-01297-2

[8] Analysis of recreational psychedelic substance use experiences classified by substance. https://link.springer.com/article/10.1007/s00213-022-06062-3

If you would like to watch a short video of how esketamine may work have a look at the video below:

Current availability in Australia

Esketamine was launched in Australia on the 9th of March 2021. Below is a timeline published by the Therapeutic Goods Association of Australia.

Ketamine vs Esketamine in Australia

Obtaining esketamine for psychiatric conditions in Australia is difficult as there are few prescribers and those that do charge a large amount of money for access. Off-label prescribing of ketamine for major depression is a possible alternative however this is uncommon, given regulatory hurdles (esketamine is still classed as a Schedule 8 poison) and uncertainty around efficacy and safety.

The reason for caution is primarily the taboo surrounding “psychedelics” which has been spurred by the Royal Australian and New Zealand College of Psychiatrists (RANZCP) calling on medical practitioners to proceed with caution when treating patients with ketamine.

However, this RANZCP announcement was not out of the blue, it followed a small unsuccessful clinical trail² of Intranasal Esketamine for Treatment-resistant Depression which was completed in 2016, and was ended prematurely because of unexpected side effects suffered by patients. It was found at the dose given, 100mg – over 10 sprays, more than twice the dose of any previous trial – their blood pressure shot up, they became uncoordinated and they suffered “unpleasant” psychotic-like effects. This is in light of other successful international trials seem to indicate not that the drug is ineffective, however, that the dosage range should be below this top threshold of between 50mg-100mg.

Who will be most likely to be prescribed esketamine?

The main inclusion criteria that would allow patients to obtain esketamine in Australia include:

• At least a single-episode major depressive disorder (MDD) that lasted for a minimum of two years.
• must have a MADRS total score of >=22
• nonresponse to 2+ oral antidepressant treatments

Who will be LEAST likely to be prescribed esketamine?

Again, according to the original clinical trial patients who were excluded from use include:

• previously not responded to ketamine in the past.
• MDD with psychotic features, bipolar or related disorders, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
• homicidal ideation
• history of moderate or severe substance or alcohol abuse
• neurodegenerative disorder such as Alzheimer’s disease, vascular dementia, Parkinson’s disease)

Alternatives to esketamine

One alternative to esketamine is the original form of the medicine, ketamine. There are some clinicians administering the original drug form as an ‘off-label’ treatment. At these clinics Ketamine, is administered in a variety of ways: via an intravenous ketamine infusion (IV), an intramuscular injection (IM), a subcutaneous injection (SC), intranasally (NAS), sublingually(SL) and orally. Routes vary in the onset of action, bioavailability and clearing time through the system for each individual. While there is generally a predictable response based on past administration, it is possible that patients may experience variable physiological and subjective experiences with the same dose.

There are a variety of dosing protocols in practice. Much research and attention has been focused on the provision of 0.5mg/kg of ketamine by IV infusion over 45 minutes, in a repeated series consisting of 2/week for 3-4 weeks. Other described protocols include the provision of a single infusion, twice weekly, weekly or longer interval dosing as determined by patient need and response.

Another alternative is to investigate the use of other agents (often termed psychedelics) including psilocybin (magic mushrooms) or NDMA. The science surrounding these substance has progressed a long way in recent years, so much so that there is a petition to the organisation which regulates medicines in Australia the TGA to decriminalise their use.

Conclusion

In conclusion, it is now highly likely that in the near future that there will be dedicated esketamine clinics set up in Australia. If you are desperate to access the medicine now, possibly try accessing the medicine “off-label” (potentially very expensive as above). Institute, or wait till the end of the year…

Reference:

1. Ketamine-related drug could be ‘watershed’ in treating depression, 2019,https://www.theguardian.com/society/2019/mar/08/new-ketamine-related-drug-could-be-watershed-in-treating-depression.
2. A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression (SUSTAIN-2):  https://www.australianclinicaltrials.gov.au/anzctr/trial/NCT02497287