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.

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

It is no secret in the medical sector, that evidence for the efficacy of traditional antidepressants (SSRIs, SNRIs, NASSAs…) is underwhelming. In 2018, the largest-ever meta-analysis concluded that the majority of their effect, if any, can be attributed to placebo¹. That being said, the clinical rationale for taking them is still sound, as prescribing them is thought to offer a harm reduction strategy, enabling the sufferer to seek additional talking therapy to address the underlying causes of the disease. This therapy often takes the form of psychotherapy, however, due to high private costs and the chronically underfunded NHS, it is often difficult for the general public to break out of limbo and fix the root cause of their condition.

Is there an alternative route?

If “Best Practice” care is being followed, something like the NICE CKS guidance on depression should have been carried out. This pathway includes the most up-to-date, proven science on the topic. The starting point will always be a non-drug approach, this includes:

1. Eat a healthy diet – supplementation of Vitamin D3 / Omega, ↓ intake of alcohol.
2. Getting enough sunlight – exercise outside as below can bolster Vitamin D3 as above.
3. Exercising regularly – 3+ times a week get heart rate above resting and maintain.
4. Sleeping well – by increasing exposure to sunlight you can reset your Circadian Rhythm whilst exercise will help you sleep.
5. Not overstimulating – anti rumination, reduce caffeine intake do more mindfulness and meditation.
6. Accessing talking therapy – self-therapy, counselling, cognitive behavioural therapy, increased social contact.

Once these factors have been exhausted, the second stage is to take a medicine, which usually starts with an SSRI such as citalopram or fluoxetine. If this initiation fails (after 6-12 months), there is usually a “switching or augmenting” to different medicines. This can only go so far as there are a limited amount of treatment options. When an inadequate response to at least two antidepressants has been tried this is referred to as Treatment-Resistant Depression (TRD). TRD is a relatively common occurrence in clinical practice, with up to 50% to 60% of the patients not achieving adequate response following antidepressant treatment. In the UK alone, 2.7 million people have treatment-resistant depression which accounts for 10% and 30% of all people with depression².

So what else can be done to treat TRD?

There are treatments that have been used in mainstream medicine for almost half a century that have proven clinical safety profiles and high relative efficacy for the treatment of TRD. One of the most common, esketamine, has been discussed at length on this blog in another article, another option which is the subject of this article is the mushroom-derived molecule, psilocybin.

A short history of Psilocybin as a Medicine.

In the 1960s psilocybin was marketed as a medicine by Sandoz (now Novartis) as a “catalyst” for people with treatment-resistant depression. In a systematic review of clinical trials, Rucker³ showed that approximately 80% of patients who are given psilocybin show clinical improvement.

In 1970, in response to a UN convention in 1971, psilocybin was made a schedule 1 drug in the UK, making it nearly impossible to use in clinical trials. The evidence that placed psilocybin into schedule 1 widely seen in the scientific community as flimsy⁴.

Fast track to today and the government’s opinion is now shifting making it possible for clinicians to study psilocybin in the same way as all potential new medicines. A recent Imperial study published the following inclusion and exclusion criteria for a new study on the medicine:

Inclusion criteria:

• Aged between 18-65
• Currently suffering from moderate to severe depression. Mild depression or historical depression are not being looked at in this study
• Willing to take two doses of psilocybin and a six-week course of Escitalopram

Patients, they would exclude from treatment include:

• You have a diagnosis of Emotionally Unstable (Borderline) personality disorder
• You have a personal or immediate family history of psychosis (drug-induced psychosis, Schizophrenia, Bipolar). Bipolar disorder is not being looked at in this study
• You are currently addicted to alcohol or any illicit drugs
• You have taken a full course of Escitalopram in the past (please note that there is a similar medication called Citalopram which is fine to have taken
• You have epilepsy or any serious heart conditions

This criterion is interesting because it indicates what the prescribing requirements may be when a legal psilocybin medicine is launched. However, as of 1st March 2021, psilocybin is still illegal in the UK, the drug belongs to the Class A substance category alongside heroin and cocaine.

When will psilocybin be legally available in the UK?

Unfortunately, unlike esketamine, psilocybin has yet to become a licensed product in the UK (so that it can be prescribed) as it is still criminalised. Decriminalisation is occurring slowly around the world, notably in the State of Oregon in the US. Within the UK, this has been said to be at least 2-3 years away. If you would like to help in the movement to decriminalise psilocybin here is a simple argument for decriminalization and here is a template you can use to send to your MP expressing your support for the cause. However, if you cannot wait there is always another route. First is the use of a legal alternative, there is a lot of evidence to suggest that ketamine, which has over 50 years of clinical use and a strong safety profile has much the same effects as psilocybin. The second route is to recognise that healthcare legality is based upon regionality, i.e. the fact that psilocybin is illegal in the UK does not mean it is illegal worldwide…

Health Tourism

“Health Tourism” is a term used when someone wants to source medical treatment from a country other than where they reside. The most common destinations for general medical conditions include Canada, Singapore and the UK. Health Tourism usually occurs where the country of origin has a high cost associated with healthcare and the destination has a lower cost.

Similarly for psilocybin treatment, health tourism is burgeoning. Instead of travelling to avoid high costs, patients are migrating to avoid criminal prosecution. Some countries including the Bahamas, Jamaica, Netherlands, Samoa and the aforementioned US State, Oregon, either never classified magic mushrooms as illegal or have been through the decriminalisation process.

So flying to these countries and receiving treatment avoids any prosecution action for the originating country. The main issue with this is that the standards of care in the treatment country may not be as regulated as treatment in the UK. Below is a list of attributes you should check before accessing treatment:

• On-site medical team, in case of any medical emergencies.
• Regulated by the national authority with a recent inspection report.
• Third-party, impartial patient feedback submission system.
• Quality Management System.

If you would like our medical team to review the Medical Tourism destination based on their regulation and safety please get in touch with our team.

References

¹Network meta-analysis of antidepressants, published in The Lancet on September 22, 2018, accessed on 23rd February 2021 via: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)31783-5/fulltext

² Treatment-resistant depression: what are the options. BMJ 2018; 363 doi: https://doi.org/10.1136/bmj.k5354 (Published 18 December 2018) BMJ 2018;363:k5354

³ Rucker JJ, Jelen LA, Flynn S, Frowde KD, Young AH. Psychedelics in the treatment of unipolar mood disorders: a systematic review. J Psychopharmacol 2016;30:1220-9.27856684

⁴Hawkes N. Sixty seconds on . . . psilocybin. BMJ 2016;353:i2775. 10.1136/bmj.i2775 27194646

⁵https://www.independent.co.uk/news/health/magic-mushroom-depression-psilocybin-trials-kcl-mental-health-addiction-a9251451.html