Freya Masters is a recent graduate from the University of St Andrews where she studied biochemistry. She tell us why we’re in the middle of a very exciting period for psychedelics research.
‘Think of the brain as a hill covered in snow, and thoughts as sleds gliding down that hill…think of psychedelics as temporarily flattening the snow…suddenly the sled can go in other directions, exploring new landscapes and, literally, creating new pathways’
This snow metaphor, devised by Mendel Kaelen, a postdoc at Imperial College London, describes the experience of a trip using psychedelics.
The word psychedelic derives from Ancient Greek words which translate to ‘mind-manifesting’.
It is thought that the experience of a trip is due to a powerful increase in brain ‘plasticity’, a biological process which causes alterations in neural circuitry, thus ensuring corrections in the brain’s structure and function.
Whilst the first lab-based experiment with the famous hallucinogenic lysergic acid diethylamide (LSD) was conducted in 1943 by Dr Albert Kurland, psychedelic substances have been used for thousands of years in culture.
Such substances are derived from mushrooms, tropical plants or cacti. Indeed, shamans dwelling in forests used N,N-Dimethyltryptamine (DMT) to access the spirit world and little mushrooms doused in honey were eaten by the Aztecs, who called the mushrooms teonanacatl (‘flesh of the gods’).
The ‘classic’ psychedelics, such as LSD or DMT, act as agonists at the 5-HT2A receptor, in doing so functioning to stimulate specific physiological responses, such as typical hallucinogenic effects.
The 5-HT2A receptor binds serotonin (or 5-hydroxytryptamine), the crucial hormone responsible for feelings of well-being and aiding bodily processes such as sleeping or digestion.
5-HT2A receptors are located in a brain region called the ‘default mode network’, which is active when we recall memories or daydream.
Therefore, this region is also most affected by psychedelics as they bind to and activate its 5-HT2A receptors.
The effects of classic psychedelics set in within 20-90 minutes of administration – for example, an increased heart rate or a distorted sense of time.
Second class psychedelics or ‘entactogens’, such as 3,4-Methylenedioxymethamphetamine (a bit of a mouthful so we’ll call it the more commonly known MDMA) act as serotonin-releasing agents, resulting in feelings of empathy and wellness during a ‘trip’.
One classic psychedelic is psilocybin, the psychoactive compound found in ‘magic’ mushrooms which was extracted in its pure form from the mushroom Psilocybe Mexicana by the swiss chemist Dr Albert Hofmann in 1959.
The use of entheogenic (a psychoactive substance for spiritual development) mushrooms by westerners was encouraged in the early sixties by the Mazatec curandera (‘medicine woman’) María Sabina, who used them when practicing veladas, sacred ceremonies.
Psilocybin is produced by over 200 species of fungi (or mushrooms) belonging to the genus Psilocybe, which are found in both tropical and subtropical regions of Mexico, South America and the United States.
Once in the body, psilocybin is converted to psilocin, by the removal of a phosphate group.
Psilocin is structurally similar to serotonin and is a modulator of serotonin receptors, conferring typical mind-altering effects of euphoria, a distorted sense of time or altered perception typically for two to six hours.
As the sixties progressed, taking psychedelics such as psilocybin for ‘trips’ was considered as illicit, with warnings of usage risks including birth defects and damage to chromosomes.
However, in more recent times, the field of psychedelic-assisted psychotherapy has exploded, with the past ten years seeing an exponential increase in research into the application of psychedelic substances for the treatment of depression, anorexia and Post-Traumatic Stress Disorder (PTSD) to name only a few conditions, or for the cessation of alcoholism and smoking.
Also in the past decade, the UK has seen the demand for antidepressants more than double.
During lockdown, a 20% increase in the number of antidepressant/anxiety prescriptions was observed in the US.
In that sense, the coronavirus pandemic can also be viewed as a global mental health crisis.
A new breakthrough in mental healthcare is required.
Psychedelic therapy could be this much-needed, fresh line of treatment over the more conventional drug therapies.
Indeed, in 2019, the Food and Drug Administration (FDA) stated that psilocybin-assisted therapy is a ‘breakthrough therapy’.
With the opening of centres for studying the therapeutic potential of psychedelics, such as the University of California (Berkeley) and John Hopkins university in Baltimore, major shifts have occurred in the field.
Here in the UK, Imperial College London opened the world’s first centre committed to researching the clinical potential of psychedelic compounds: The Centre for Psychedelic Research (founded in April 2019). Several ‘landmark’ studies have been conducted into the exciting therapeutic possibilities of psilocybin at Imperial.
One such study, which focused on twenty patients with the treatment-resistant form of depression, elucidated that psilocybin may play a role in resetting the neural circuitry involved in depression.
Whilst the sample size was small, the benefits of psilocybin were perceived to last up to five weeks after treatment, with one such benefit to be an observed reduction in blood flow to the amygdala.
This is the region of the brain involved in processing emotions including fear or stress.
Additionally, the selective serotonin reuptake inhibitor (SSRI) escitalopram was tested against psilocybin; this study is among the most thorough conducted for a psychedelic medicine.
SSRIs, which normally function to create novel connections in the brain, increase neuroplasticity to moderate the stress response, however their mode of action is not curative.
Whilst the results of the study indicated that psilocybin achieved a reduction in depression to the same extent as escitalopram, with strong suggestions that psilocybin even surpassed the SSRI in terms of performance, conclusions were ambiguous, with larger-scale trails for longer periods of time required.
This was due to the study’s focus on the depression metric to assess outcomes, a measure recognised by the FDA. Essentially, different measurements of well-being may have conferred other results.
Another exciting study by Imperial has involved patients who have suffered from anorexia nervosa for over three years.
It is thought that psilocybin may function at a pharmacological level in targeting the imbalance of serotonin in the brain characteristic of anorexia nervosa and by prompting developmental changes, for example in encouraging feelings of self-worth.
Through eight study visits, variable psilocybin doses were administered, and progress checked through a combination of psychological measurements, magnetic resonance imaging (MRIs) and electroencephalogram (EEG) recordings.
The follow-up period of the study is currently ongoing.
Imperial have also been the first to elucidate the effects of LSD, one of the most potent classical psychedelics and a highly controversial drug in society, in the brain through modern brain imaging.
LSD was initially synthesised from lysergic acid (derived from the fungus Claviceps purpurea among other species) by Albert Hofmann in 1938.
It is known that LSD shares common chemical structures with psilocybin and DMT and is thought to bind to serotonin and dopamine receptors such as 5-HT2C and 5-HT1A.
Initial studies for the therapeutic application of LSD were conducted in the 1950s.
However, after the criminalisation of LSD in the USA in 1996, the therapeutic potential of this psychedelic remained unknown.
More recently, the most promising therapeutic application of LSD has been for the treatment of alcoholism as well as for reducing anxiety in those patients who are living with a life-threatening disease.
It is important to note that the studies outlined in this article took place under conditions which were highly controlled, with drug therapy administered in combination with crucial psychotherapy support in regulated environments.
The placebo effect (in which a patient believes in the fake drug’s – the placebo’s – treatment benefits and starts to feel better) also presents a challenge to the interpretation of results.
Additionally, experimentations with powerful psychedelics such as MDMA (an amphetamine derivative), present a risk of an enduring psychotic reaction or substance abuse.
Despite these limitations, the potential of psychedelics for the treatment of conditions such as PTSD or depression is immense and will only continue to grow, as research in this exciting field develops.
The general hope is that, within the next few years, psilocybin therapy in particular will be licensed and marketed in North America and Europe.
One day, through extensive scientific research, psychedelic-therapy may be used in place of normal drug therapies, to enable thoughts, like sleds, to explore afresh and forge novel, healing connections in the minds of those who need it most.
Clerkenwell Health is launching a free UK psychedelic therapist training programme
In this article, communications associate at Clerkenwell Health, Arda Ozcubukcu, discusses how the company is working to ensure psychedelic-assisted therapy is easily adopted by mainstream healthcare systems in the UK.
In recent weeks, much has been made of psychedelic drugs’ potential to redefine mental health treatment. As the sector becomes more visible, major players have started to re-evaluate their traditional roles within the psychedelic research ecosystem.
We’ve seen non-profit organisations like Multidisciplinary Association for Psychedelic Studies (MAPS) start to conduct clinical studies, an extremely uncommon phenomenon due to the vast amounts of funding required, as well as patient groups such as the Psychedelic Participant Advocacy Network (PsyPAN) influence the design of research processes.
Traditionally, a clinical research organisation’s (CRO) sole role is to action the research it has been commissioned to conduct. However, in a sector full of unknowns and firsts, where the necessary infrastructure is being established in real-time, a CRO has significantly more potential. Clerkenwell Health is on a mission to realise this potential, by redefining what a CRO can offer, and becoming a hub for innovation.
As an emerging sector, psychedelic drug development faces a number of bottlenecks, and at Clerkenwell Health we don’t wait for others to solve problems, we tackle them head on.
The UK is fast becoming a central hub for psychedelic research thanks to the conducive regulatory environment brought about by post-Brexit sovereignty, which is attracting business and boosting innovation. Increasing numbers of psychedelic companies are moving their clinical operations to the UK, thus increasing the demand for psychedelic specialty therapists.
A major issue within the psychedelic research ecosystem is the lack of therapists able to deliver psychedelic-assisted therapy, which is an essential component to maximise the therapeutic benefits of psychedelics.
With drugs now progressing to the later stages of development, clinical trials will require the delivery of psychedelic-assisted therapy at a much larger scale, increasing the demand for therapists even further. If sustainable ways of meeting this demand are not developed now, there will be serious capacity problems when these drugs hit the market.
Due to a lack of evidence showing which therapy model works with psychedelics most effectively, there are currently no standardised training opportunities provided by an independent body such as British Association for Counselling and Psychotherapy (BACP).
Limited therapy training opportunities exist, and those that do fail to fully consider the realities of the health system or the therapists who want to specialise in psychedelic therapy. Although some training programmes are offered by drug developers, it does not equip therapists to work across different compounds or disorders, whilst training run independent of developers can be expensive and time-consuming, making training accessible only to those who can afford the time and financial commitment. The situation, if it continues, will fail to create a workforce ready to deliver suitable psychedelic-assisted therapy at the scale required.
At Clerkenwell, our concern is that expensive programmes qualify therapists irrespective of their capabilities. That’s why we have designed a training programme that is free, disease- and compound-agnostic and minimises the time to commit for those interested to participate.
Our programme uses Acceptance and Commitment Therapy (ACT), a model that already has a solid evidence base and is practiced within the health system. This ensures the therapy aspect of psychedelic-assisted therapy is easily adopted by mainstream healthcare systems through medical and regulatory buy-in, which is vital for widespread patient access to these treatments.
ACT seems to work effectively with psychedelics and using them together can maximise the therapeutic outcomes of both the therapy and the drug. Therapists can also keep their skills fresh by practicing ACT without psychedelics and are therefore more readily available to deliver psychedelic-assisted therapy post-marketing approval.
Scaling up psychedelic-assisted therapy is not an easy task, but one that is necessary for its successful adoption in the psychedelic research ecosystem. It’s time for the excitement of developing new psychedelic drugs to mature into developing delivery infrastructure, starting with the workforce.
As a CRO, Clerkenwell Health can help facilitate this process by paving the way for standardised certified training and acting as the cement that supports the psychedelic research ecosystem for different actors to build on. By investing in, innovating, and operating a centre of excellence for psychedelic-assisted therapy right in the heart of Europe’s most vibrant psychedelic research ecosystem, we can become the go-to partner for drug developers, regulators, and researchers who want to fundamentally change the face of mental health care.
Bicycle Day: where are we 80 years since the first LSD trip?
On Bicycle Day 2022, we explore LSD’s journey from its first bicycle ride to MK Ultra to the treatment of addiction.
In 1943, Swiss chemist Albert Hofmann took the first LSD trip – what is it looking like for the compound today?
Switzerland, 19 April, 1943. Chemist Albert Hofmann takes 250micrograms of LSD, proceeding to ride his bike as its effects kick in. So, Bicycle Day is born – a celebration of the first LSD trip.
Hofmann initially synthesised LSD from ergot in 1938 to use as an active pharmaceutical ingredient. Leaving the compound to one side, Hofmann decided to revisit it again in 1943. He felt a slight effect after accidentally absorbing a small amount of LSD through his fingertip three days before 19 April which led to the purposeful first trip. Hofmann later went on to describe the compound as “sacred”.
Since 1943, LSD has built up a rich history. Fuelling the countercultural revolution of the 1960s and animating the minds of great writers, poets, musicians and artists, LSD was previously researched for a number of different uses.
One of the leading researchers was Stanislav Grof, who investigated the compound for its therapeutic use for different mental conditions and addiction. This research showed promising results, and as pointed out in a recent paper, reported limited adverse side effects.
However, the compound also had its dark side. It was used as part of the CIA’s secret MK Ultra programme (1953 – 1973). The programme looked at techniques such as hypnosis and used psychoactive substances for mind control and psychological torture tactics to harness against the Soviet Bloc during the Cold War.
In one experiment, “Operation Midnight Climax”, the CIA employed female sex workers to draw in men, when LSD would be used and the mens’ behaviour observed. Purportedly, renowned writer and psychedelic advocate, Ken Kesey, Acid Test pioneer, was also a volunteer in the MK Ultra programme.
Whilst Grateful Dead kept on truckin’ at their psychedelic concerts, and more young people began experimenting with psychedelic drugs, Nixon declared the worldwide “war on drugs” in 1971. Nixon labelled drug abuse as “America’s public enemy number one” leading to the scheduling of psychedelics in the highest category of the UN Convention on Psychotropic Substances.
Since its scheduling, the last 50 years has seen a scientific censorship unknown in history. Scientists and researchers have been unable to investigate the compound, along with other psychedelics, for their potential therapeutic uses – despite previous research indicating they hold promise.
However, a handful of organisations and researchers have been able to overcome the regulatory and financial hurdles limiting access to compounds such as LSD, and now the world is beginning to see the blossoming of a new psychedelic era.
This time, it is gearing towards the medical application of LSD. Although the cultural impact of psychedelics is easily seen, the spotlight is being put on the revolutionary potential of LSD and other psychedelics in helping the millions across the world living with poor mental health and addiction. From macrodosing to microdosing, LSD without the trip and assisted-psychotherapy, a new wave of scientific investigation is forming.
Discover some of the recent scientific research developments with LSD from Psychedelic Health:
Study to explore effects of LSD microdosing
LSD findings could help understand how the brain generates behaviour
LSD trial for the treatment of adult ADHD initiated
New study to prevent unfounded LSD therapy patents
Novel findings presented on LSD and psilocybin
Is psilocybin safe to administer under medical supervision?
Drug Science has carried out a systematic review of adverse events reported in clinical trials.
Results from a systematic review have led to the conclusion that psilocybin is safe to administer in clinical settings, and that there is a need to revise the classification of psilocybin as a Schedule 1 substance.
Psilocybin is currently classed as a Schedule 1 under the United Nations Convention on Psychotropic Substances (1971). Any substance classified as a Schedule 1 substance fits the criteria of being highly addictive, having no therapeutic and having a lack of safety for use under medical supervision.
However, psilocybin is currently being administered in clinical settings for research exploring the compound’s efficacy as a therapy for mental health disorders and different addictions, such as nicotine dependence.
The systemic review from Drug Science investigated whether clinical trials of psilocybin support the third category of its Schedule I designation, that “there is a lack of accepted safety for use of the drug or other substance under medical supervision”.
The researchers analysed reports in the PubMed database for “adverse events, drug tolerability, and drug safety” stating that “while nearly all the publications reported behavioural and biological effects of the drug, these findings were not included in this review unless it was clearly stated to be an adverse event or safety risk.”
The results demonstrated that 25 of the 52 publications in the analysis did not contain any reference to adverse events, drug safety, or drug tolerability with 27 publications documenting administration of psilocybin on over 800 occasions to 550 individuals.
The authors state that these 27 publications reported no serious or significant adverse events and positive drug tolerability, suggesting that “psilocybin is safe to administer under proper medical supervision”.
Of the adverse events that were reported, the authors state they were generally considered to be “transient and mild, the most common being headaches”, bar a handful of events that were considered to be more severe. However, the conclusions were that “psilocybin was not responsible for these events”.
The authors state: “The reviewed clinical trials demonstrated rigorous medical and psychological screening processes prior to participant enrollment. All studies excluded participants of vulnerable populations (e.g. history of psychosis), in order to avoid serious adverse events.
“This practice is utilised for medications across all levels of scheduling, in the event that a drug may be safe and effective for certain populations, while having increased rates of adverse effects for others (e.g. one would not administer a beta-blocker to a hypotensive patient).
“The participant selection criteria for many of the reviewed trials required prior experience with psychedelics, further screening out individuals who may be prone to psychedelic-related adverse events.”
They go on to say: “Considerable evidence suggests that psilocybin is generally well-tolerated when administered in a controlled setting. Federally and socially accepted selective serotonin reuptake inhibitors also pose a considerable level of risk, and the acceptable level of risk associated with psilocybin should not serve as a barrier to those whom it could provide positively life-altering outcomes.”
The authors also emphasise the role of set and setting as an important factor in the safe administration of psilocybin.
- Top UK and European academics join Clerkenwell Health advisory board
- Psychedelics for addiction research gets $2.7m grant
- Beckley Psytech strengthens leadership team as it progresses clinical pipeline
- Patient approved to receive psilocybin therapy for MDD
- World’s first study on ketamine for behavioural addiction now complete
- New partnership to harness digital tools to enhance psychedelic care
- World’s first study on ketamine for behavioural addiction now complete
- New partnership to harness digital tools to enhance psychedelic care
- DEA grants approval for the manufacture of psychedelic compounds
- Numinus receives Health Canada SAP approval for psilocybin therapy
- Clerkenwell Health is launching a free UK psychedelic therapist training programme
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