The therapeutic potential of psychedelics

Case scenario

Thom, 37, a regular patient of the pharmacy, presents their venlafaxine repeat for dispensing. You know this has been prescribed for PTSD and ask how they have been going with their treatment. They disclose that their symptoms have been difficult to manage over the last few weeks and that they don’t feel like their medication has been working as well. Thom explains that a friend mentioned MDMA could be used for PTSD, and they’re now considering taking it to help them feel better.

Introduction 

The Therapeutic Goods Administration (TGA) has announced the down- scheduling of psilocybin and 3,4-Methylenedioxymethamphetamine (MDMA) from Schedule 9 (Prohibited Substances) to Schedule 8 (Controlled Drugs) under certain conditions, for specific populations. This change is from 1 July 2023, and while there is still some uncertainty related to the change in legislation, pharmacists will likely be involved in supplying these medicines. This article outlines the changes in Australia, gives an overview on the evidence behind the use of these psychedelics, and gives examples of potential interactions to be alert for with these substances.

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The details 

Psilocybin and MDMA can only be prescribed by specialist psychiatrists who have obtained approval from a human research ethics committee (HREC) and have been authorised by the TGA under the Authorised Prescriber Scheme.¹

Importantly, the scheduling changes are applicable only when these medicines are being used for certain indications. Psilocybin can only be prescribed for treatment-resistant depression (TRD), and MDMA only for post-traumatic stress disorder (PTSD).¹ Psychiatrists will only be able to prescribe these substances when other available, clinically appropriate treatment options have been considered or have been unsuccessful.¹

The TGA’s reasons for this down- scheduling includes recognition of the need for new treatment options for TRD and PTSD, with these substances showing promise in clinical trials without significant safety concerns at the doses used in controlled environments.¹

Given that the changes limit prescribing of these substances to patients under the supervision of authorised specialist prescribers only, in controlled medical settings, it was decided that benefits for some patients would outweigh the risks.^1,19

As the Poisons Standard is implemented by states and territories, it is up to each individual state or territory government to decide whether it will adopt the changes in their entirety, or subject them to variations.¹

At time of press it was not known how each state or territory may deviate from or align with this change in legislation. It is possible that supplying, using or possessing psilocybin or MDMA will remain an offence under legislation in individual states and territories.¹

Access to psilocybin and MDMA may also be challenging due to the lack of TGA-approved products on the Australian Register of Therapeutic Goods (ARTG). But there may be the ability to access unapproved products, which requires an Authorised Prescriber to obtain a permit to import overseas products containing psilocybin and MDMA.¹

History of psychedelics as therapy 

Psychedelics have a long history of use, with evidence showing psychotropic plants were used as far back as 5,700 years ago in Mexico, with their introduction to the Western world occurring around 1897.² Both psilocybin and MDMA have previously been used

in a therapeutic capacity, with Sandoz manufacturing a product, Indocybin, for depression in the 1960s,² while MDM was synthesised by Merck around 19123 as an appetite suppressant.⁴

However, the therapeutic use of psychedelics ended in 1967 when they were classified as Schedule I in the UN Convention on Drugs, meaning they had ‘no accepted medical use and the maximum potential for harm and dependence’.²

Over the last few years, there has been a resurgence of interest in the therapeutic potential of these substances, which has culminated in the recent rescheduling of psilocybin and MDMA by the TGA.

Evidence for psilocybin and MDMA 

There is a significant amount of emerging clinical evidence supporting the therapeutic use of psilocybin and MDMA.

Psilocybin

The clinical trials involving psilocybin in TRD show great promise. One study found that all participants with TRD who were given a single dose of psilocybin showed some reduction in depression severity at 1 week, with these results continuing in the majority of patients for 3–5 weeks.⁵ Another larger study supported these findings; when participants with TRD were given a single dose of psilocybin and psychological support, there was a reduction in depression scores lasting over 3 weeks.⁶

Depression is associated with the serotonin (5-HT) system, with reduced serotonergic functioning implicated in an increased risk of suicidal ideation.⁷ However, there is emerging evidence suggesting there is ‘no consistent evidence’ of an association between depression and serotonin, with potential alternative causes for depression related to blood flow and connectivity in the brain.⁸ It has been shown that there is increased cerebral blood flow (CBF) and increased connectivity in the default- mode network (DMN) seen in those with major depressive disorder (MDD).⁹

Psilocybin appears to act on both of these systems. Psilocybin is a prodrug, and the active compound of psilocybin is psilocybin, which has a half-life of around 108 minutes¹⁰ and is a mixed serotonin receptor agonist.¹¹ Psilocybin binds to the 5-HT 2A receptor 12 with high affinity, the 5-HT 1 receptor with low affinity, and it also interacts with the 5-HT 1D and 5-HT 2C receptors.¹³ Psilocybin affects CBF, with decreases in CBF in cortical and subcortical regions of the brain, which can result in reduced depressive symptoms.¹³ Psilocybin has been found to be generally well tolerated in trials,⁵ with some potential adverse effects including headaches, nausea and dizziness.⁶

MDMA 

MDMA has been shown to significantly reduce symptoms of PTSD, as measured by a reduction in Clinician Administered PTSD Scale for DSM-IV (CAPS-IV) score. Features of PTSD include abnormal neurochemical regulations involving acetylcholine, serotonin, oxytocin and cortisol, all of which are related to stress and fear responses.¹⁴

A recent study reported that after two sessions of MDMA and psychotherapy, 54.2% of participants in the active group did not meet the CAPS-IV PTSD diagnostic criteria, compared to only 22.6% of the control group.¹⁵ A systemic review and meta- analysis of 10 studies exploring the use of MDMA for PTSD concluded the findings indicate that MDMA administered alongside psychotherapy for treatment of PTSD holds great promise.¹⁴

MDMA has a half-life of 8–10 hours 16 and is a weak 5-HT1 and 5HT2 receptor agonist (mainly targeting 5-HT2A , 5-HT2B and 5-HT2C).¹⁴ MDMA also promotes the release of dopamine, serotonin and norepinephrine in the brain, while also indirectly contributing to the release of oxytocin and cortisol.¹⁴ In modulating these neurochemicals, MDMA can improve the ability of traumatic memories to be reprocessed and increase engagement with the therapeutic process.¹⁴ Adverse effects of MDMA can include anxiety, headache, jaw tightness, tinnitus, nausea, tremor, tics and dysuria.¹⁴

Interactions

MDMA and psilocybin both work on the 5-HT system and, as such, have them potential to interact with a wide range of medicines, such as antipsychotics and antidepressants.¹⁷

Psilocybin has been administered concurrently with an SSRI and was shown to be relatively safe; however, more research is needed to understand the potential risks.¹⁸ Given that psilocybin acts on the serotonergic system, there is a potential risk of serotonin syndrome if the person is using other medicines acting on the same receptors.¹⁰ MDMA can interact with some classes of medicines. These include anaesthetics, muscle relaxants, amphetamines and stimulants, benzodiazepines, ethanol, opioids and antidepressants.¹⁷ Some antidepressants carry a particularly high risk when used with MDMA, including bupropion, citalopram, sertraline and venlafaxine.¹⁷

If supplying psilocybin or MDMA, pharmacists must ensure they are consulting appropriate references when reviewing the appropriateness of therapy, for potential or actual drug interactions with any concomitant medicines the patient is taking.

Conclusion

Psilocybin and MDMA are novel treatments for TRD and PTSD and are showing great promise when used in a therapeutic environment. As of 1 July 2023, scheduling changes to the Poisons Standard allow prescribing by specialist psychiatrists when specific conditions are met. It is not yet known how this change will affect pharmacists, but it is anticipated that pharmacists will be involved in the supply of these medicines and in the provision of information. Understanding how these medicines work is important when considering potential interactions between psilocybin or MDMA and pharmaceutical medicines.

Key points 

• As of 1 July 2023, psilocybin and MDMA are rescheduled from Schedule 9 to Schedule 8 for therapeutic use in certain indications. They will only be able to be prescribed by approved specialist psychiatrists. 
• There is evidence to support the use of psilocybin and MDMA in a therapeutic capacity for certain conditions. 
• There are various interactions between psilocybin and MDMA and other pharmaceutical medicines. Pharmacists must be alert for potential interactions.

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References

1. Australian Government. Re-scheduling of psilocybin and MDMA in the Poisons Standard: questions and answers. In: Care DoHaA, editor.: Therapeutic Goods Administration; 2023.
2. Rucker JJH, Iliff J, Nutt DJ. Psychiatry & the psychedelic drugs. Past, present & future. Neuropharmacology 2018;142:200–18.
3. Freudenmann RW, Oxler F, Bernschneider-Reif S. The origin of MDMA (ecstasy) revisited: the true story reconstructed from the original documents. Addiction 2006 101(9):1241–5.
4. Hurley RA, Reneman L, Taber KH. Ecstasy in the brain. J Neuropsychiatry Clin Neurosci 2002;14(2):125–9.
5. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology 2018;235(2):399–408.
6. Goodwin GM, Aaronson ST, Alvarez O, et al. Single-dose psilocybin for atreatment-resistant episode of major depression. NEMJ 2022;387(18):1637­48.
7. Duval F, Mokrani M-C, Danila V. Dopamine function and hypothalamic-pituitary-thyroid axis activity in major depressed patients with suicidal behavior. Brain Sci 2022;12(5):621.
8. Moncrieff J, Cooper RE, Stockmann T, et al. The serotonin theory of depression: a systematic umbrella review of the evidence. Mol Psychiatry 2022. Epub 2022 Jun 21.
9. Hamilton JP, Farmer M, Fogelman P, et al. Depressive rumination, the default-mode network, and the dark matter of clinical neuroscience. Biol Psychiatry 2015;78(4):224–30.
10. MacCallum CA, Lo LA, Pistawka CA, et al. Therapeutic use of psilocybin: practical considerations for dosing and administration. Front Psychiatry 2022;13:1040217.
11. Carhart-Harris RL, Erritzoe D, Williams T, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 2012;109(6):2138–43.
12. Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacol 2019;44(7):1328–34.
13. Lowe H, Toyang N, Steele B, Vet al. The therapeutic potential of psilocybin. Molecules 2021;26(10):2948.
14. Tedesco S, Gajaram G, Chida S, et al. The efficacy of MDMA (3,4-methylenedioxymethamphetamine) for post-traumatic stress disorder in humans: a systematic review and meta-analysis. Cureus 2021;13(5):e15070.
15. Mithoefer MC, Feduccia AA, Jerome L, et al. MDMA-assisted psychotherapy for treatment of PTSD: study design and rationale for phase 3 trials based on pooled analysis of six phase 2 randomized controlled trials. Psychopharmacol 2019;236(9):2735–45.
16. Freye E. Pharmacokinetics of MDMA. In: Pharmacology and abuse of cocaine, amphetamines, ecstasy and related designer drugs. 2009. p. 161–72.
17. Cohen IV, Makunts T, Abagyan R, et al. Concomitant drugs associated with increased mortality for MDMA users reported in a drug safety surveillance database. Sci Rep 2021;11(1):5997.
18. Becker AM, Holze F, Grandinetti T, et al. Acute effects of psilocybin after escitalopram or placebo pretreatment in a randomized, double-blind, placebo-controlled, crossover study in healthy subjects. Clin Pharmacol Ther 2022;111(4):886–95.
19. Therapeutic Goods Administration. Understanding the changes to MDMA and psilocybin access. 2023: At: www.tga.gov.au/news/blog/understanding-changes-mdma-and-psilocybin-access

Our author

Amber Domberelli (she/her) BPharmaceutSc, MPharm, MMedRes, GradDipAppPharmPrac, MPS, JP, PhD Candidate is a pharmacist with a background in research, community and hospital pharmacy. She has almost completed her PhD, which explores the practice of microdosing with psychedelics.

Our reviewer

Shani Pickering (she/her) BPharm, MPS, AACPA
Professional practice pharmacist.