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.

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

“I have Bi Polar Type 2 (not officially diagnosed as my GP had already started my treatment on mood stabiliser Olanzapine) I am diagnosed as having Major depression, I’m on a SNRI Venlafaxine, also diagnosed with very mild BPD, and generalised anxiety disorder, I have taken street ketamine before and use once a week, it seems to work on my suicidal thoughts very well, I’d like to investigate how I get it prescribed legally please, thanks hope to hear from you, Kind regards…”

Hi, thanks for getting in contact with us, as a medical team we are looking to specialise further in esketamine if you have any further questions please do not hesitate to contact us. As for the specifics of your enquiry…

In your first sentence, you mentioned that you have been “not officially diagnosed” as “Bi Polar“. The current license (Aug 2020) of Spravato mentions “the medicine should specifically be used in the treatment of Treatment-Resistant Major Depression” and does not mention bi polar until later in the document where it specifies: “Spravato should be used with caution”… “in patients with a history of mania or bipolar disorder“. This does not mean it cannot be used in bi-polar, only the psychiatrist that may prescribe Spravato will need to keep this in mind as other complications may arise.

You then mention you have been officially diagnosed with Major Depressive disorder, but you do not mention whether this is classified as Treatment-Resistant of not. Again, for you to meet the requirements of the license you will have to have been diagnosed with Treatment-Resistant Major Depression (TRMD). But what defines Treatment Resistant? Unfortunately, this term differs dependent on which psychiatrist you use. The most simplistic definition of treatment resistance “is the failure to achieve and sustain euthymia (normal, tranquil mental state) with adequate antidepressant treatment.” ² Whether the “treatment” includes ECT, or different types of medicines is unspecified. Lastly, please be aware that accessing “street ketamine” has its own associated risks we highly recommend that you first try accessing the medicine from a licensed prescriber and subsequently get access to the medicine via a verified supply chain.

To summarise, to be prescribed esketamine you will need to meet the following criteria¹:

• taking an SNRI (which you already meet as you are taking venlafaxine) ✓
• diagnosed by a licensed doctor as suffering from “treatment-resistant Major Depressive Disorder”. (it doesn’t seem you have this yet). ✗
• unresponsive to at least two different treatments with antidepressants in the current moderate-to-severe depressive episode. (this is the definition of treatment-resistant within the license, however, in your enquiry, you do not mention how many previous treatments you have tried)?

“I would like to try the ketamine nasal spray. I’ve tried six different anti depressants over the years and currently taking duloxetine, but nothing helps..only makes me tired and just as depressed. I’ve tried homeopathy and acupuncture also. Hoping to try this medication.”

As per the current license¹, you potentially meet the definition of treatment-resistant major depression (TRMD), however, as above this definition is at the psychiatrist’s discretion. It doesn’t seem you are taking an SNRI currently.

What is the mechanism behing how ketamine works?

As far as the most recent research has discovered it seems ketamine operates on a receptor level as NMDA antagonist and regulate the availability of the neurotransmitter glutamate in the brain. The antidepressant effect appears to be mediated by downstream signal effects of AMPA receptors. A variety of other receptors are targeted and contribute to the acute and ongoing effects of treatment.

What is the clinical ketamine experience like in practice?

Prior to treatment:

– Patients are expected to abstain from all substance use for a period of 48 hours; including alcohol tobacco, cannabis, and illicit substances.

– In certain instances, a urine toxicology screen may be required prior to treatment, including on the day of treatment

– No dietary food or opaque drink intake for at least 4 hours prior to treatment.

– One cup of clear fluids is permitted between 4 and 2 hours prior.

– Strictly NO intake is allowed for the 2 hours leading up to the appointment.

– Hold medication that may raise blood pressure – i.e. stimulants

• Continue on anti-hypertension and diabetic medication, with a dose of adjustment of insulin based on dietary intake adjustment.

Standard course:

Preparation:

– Medical evaluation of readiness for treatment including Informed Consent.

– Blood pressure screening.

– Confirmation that an after-care/support person is available for pick-up from office and accompany you for a further 4 hours after discharge.

– Completion of K10 screening forms

Dosing: Onset 15-45minutes

– Ketamine, initial dose based on 0.5mg/kg lean body mass

– Subjective evaluation of patient capacity to tolerate the dissociative state.

Sedated state: 45-90 minutes:

Generally restful, mostly non-verbal, supported by soothing music and eye shade to minimize light effect(please bring with you)

– Patient will typically experience a heaviness in the physical body, possibly with the changes in sensation, followed by a separation from the usual state of cognitive processing, such that verbal expression may either become limited.

– Patients will remain rousable to an alert and interactive state and will be checked in on by verbal cue to determine if there are any concerns. Physical contact will consist of provider placement of hand on the arm or shoulder of the patient – with contact over clothing; unless there is a concern for a medical emergency.

– Some patients may experience unfamiliarity with this state that is disconcerting perhaps in the heaviness/floating sensation, vertigo like sensation, physical discomfort (nausea), the presentation of distressing imagination.

– During this phase of treatment blood pressure will be checked.

– Patient also consents to allow for video monitor of the experience in order to assure safety and mutually mitigate concern for behaviour that may be aversive, intrusive or experienced as such by the patient in an altered state of awareness. – i.e. a gentle hand placed on the shoulder.

Integration Phase: 90-120 minutes: Opportunity for reflection and discussion

– Patient will be engaged verbally to describe the experience and potentially engage in discussion of thoughts, emotional states and physical sensations.

Disengagement from treatment

At any point in the treatment course, the patient may disengage from the defined and recommended process i.e. sit up and take off the eye shade. However, patients will not be allowed to leave the office on their own until 90 minutes after dosing of ketamine. The patient may request that the defined after-care support assume custody at any point during the treatment, with full release into care to be determined by the physician providing care / administering the dose.

Initial dosing (i.e. 0.5mg/kg ) is designed to place patients in state that is often described as a “one glass of wine effect”. Patients not exhibiting significant effects are given an option to increase the nasal spray treatment dose on the next treatment episodes to 0.75 & 1.0mg/kg.

If you are interested in submitting a question to our team, please contact us.

Reference

1. Spravato UK license accessed on 18th August 2020 via: https://www.medicines.org.uk/emc/product/10977/smpc (last updated 29 Jul 2020)

² DEFINITION AND EPIDEMIOLOGY OF TREATMENT-RESISTANT DEPRESSION, Psychiatric Clinics of North America, Volume 19, Issue 2, 1 June 1996, Pages 179-200. Accessed on 18th August 2020 via https://www.sciencedirect.com/science/article/abs/pii/S0193953X05702835

Depression is a common and debilitating condition that is recognised as a leading cause of disability worldwide. A survey published in 2016 found that 3.3 out of every 100 UK adults had experienced depression in the week before being interviewed.

One of the key symptoms of depression is ‘Anhedonia‘ (the loss of pleasure). An important component of this symptom is an inability to feel excitement and also involves a lack of motivation.

A new study conducted on Marmosets, a type of non-human primate at the Wolfson Brain Imaging Centre and Translational Neuroimaging Laboratory in 2018 has shown that ketamine affect those brain regions thought to be responsible.

On 21st May, a trial which involved 227 patients who were randomly assigned to intranasal esketamine 56mg or 84mg twice-weekly or placebo, plus an antidepressant. Depressive symptoms were measured on the Montgomery–Åsberg Depression Rating Scale (MADRS), with a mean score of 37 out of 60 in both groups at baseline.

At 28 days, the change in MADRS score was significantly greater in the esketamine group than in the placebo group at –21.4 versus –17.0, respectively. Adverse events, such as dizziness, dissociation, vertigo and nausea, were more common in the active treatment group2.

Esketamine is the s-enantiomer of Ketamine. Ketamine is a mixture of two enantiomers (mirror-image molecules). This is the first time that the FDA has approved esketamine for any use. The FDA approved ketamine (Ketalar) in 1970.

Esketamine is contained within the standard pharmaceutical form of ketamine, which has traditionally been used at higher doses as an anaesthetic. The difference between Esketamine and Ketamine is that the latter contains the former. Pharmaceutical forms of ketamine contain two mirror-image molecules of itself called enantiomers (R-Ketamine and esKetamine – see below), the pharmaceutical industry has isolated one mirror image and shown some benefits (rapid onset whilst lower side effect profile) of using that “enantiomer” over the combination mixture¹.

Simply put, ketamine in its “natural” form is seen as “dirtier” than the pure form of esketamine as the original contains two enantiomers, one of which has been suggested by the pharmaceutical manufacturer as causing unwanted side effects.

Esketamine may prove to be a promising treatment for patients diagnosed with major depressive disorder who have not experienced an improvement in symptoms despite treatment with various medications and therapies. The intranasal route of administration for this drug allows for easy administration and a fast onset of action, which sets it apart from many other antidepressant agents that may take several weeks to take effect. This drug is indicated in conjunction with an oral antidepressant for the treatment of treatment-resistant depression (TRD) in adults.

Esketamine is not approved as an anaesthetic agent. The safety and effectiveness of esketamine as an anaesthetic agent have not been established to this date.

Other uses of Esketamine

Esketamine has shown some efficacy for Tinnitus and inner ear conditions. This is because it can work as an NMDA antagonist of receptors in the cochlea. Esketamine has been formulated as an intratympanic biodegradable gel, is manufactured by Auris Medical and can be accessed in the UK via secondary care.

Mechanism of action

Esketamine, the S-enantiomer of racemic ketamine, is a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, an ionotropic glutamate receptor. The exact mechanism by which esketamine acts as an antidepressant is unknown. The primary circulating metabolite of esketamine (noresketamine) shows activity at the same receptor with a weaker affinity.

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

Dosing: adult

Depression, treatment-resistant: Note: Administer in conjunction with an oral antidepressant. Must be administered under the direct supervision of a health care provider with patients monitored for adverse effects for at least 2 hours following administration.

Intranasal:

• Induction: 56 mg twice weekly; may increase dose (after first dose) based on response and tolerability up to 84 mg twice weekly. After 4 weeks, evaluate for evidence of therapeutic benefit to determine need for continued treatment.
• Maintenance: Beginning on week 5, using the previously established dose (56 or 84 mg) decrease the dosing frequency to once weekly. At week 9 and onward, adjust the dosing frequency to the least frequent interval to maintain remission/response; continue once weekly or decrease to every 2 weeks.
• Missed treatment sessions or worsening of symptoms: Consider returning to patient’s previous dosing schedule (eg, every 2 weeks to once weekly or weekly to twice weekly).

Dosing: Renal Impairment: Adult

There are no dosage adjustments provided in the manufacturer labeling (has not been studied).

Dosing: Hepatic Impairment: Adult

• Mild to moderate impairment (Child-Pugh classes A and B): There are no dosage adjustments provided in the manufacturer labeling (has not been studied); patients with moderate impairment may need to be monitored for adverse effects for a longer period of time.
• Severe impairment (Child-Pugh class C): Use is not recommended (has not been studied).

ALERT: US Boxed Warning

• Sedation and dissociation: Patients are at risk for sedation and for dissociative or perceptual changes after administration of esketamine. Because of the risks of sedation and dissociation, patients must be monitored for at least 2 hours at each treatment session, followed by an assessment to determine when the patient is considered clinically stable and ready to leave the health care setting.
• Abuse and misuse: Esketamine has the potential to be abused and misused. Consider the risks and benefits of prescribing esketamine prior to use in patients at higher risk of abuse. Monitor patients for signs and symptoms of abuse and misuse.
• REMS: Because of the risks of serious adverse outcomes resulting from sedation, dissociation, and abuse and misuse, esketamine is only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the SPRAVATO REMS.
• Suicidal thoughts and behaviors: Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for the emergence of suicidal thoughts and behaviors. Esketamine is not approved in pediatric patients.

Pharmacodynamics

1. General effects: Esketamine is considered a central nervous system (CNS) depressant agent. It may cause sedation, dizziness, and lethargy, among other symptoms. This drug has dissociative and antidepressant properties. Acutely, esketamine may impair attention, judgment, thinking, reaction speed, and motor skills. Two placebo-controlled studies were performed to evaluate the effects of ketamine on the ability to drive. The effects of esketamine 84 mg were comparable to placebo at 6 hours and 18 hours post-ingestion.
2. Effects on cardiac electrophysiology: The effect of esketamine (84 mg nasal spray and 0.8 mg/kg esketamine intravenously infused over 40 minutes) on the QTc interval was studied in a randomized, double-blind, placebo-, and positive-controlled (moxifloxacin 400 mg), 4-period, crossover study in 60 healthy volunteers. A marked increase in heart rate (higher than 10 bpm) was measured in subjects receiving intranasal and intravenous esketamine. Summative evidence from both nonclinical and clinical data suggests a lack of clinically relevant QTc prolongation at the normal therapeutic dose of esketamine.
3. Effects on blood pressure: Eskestamine causes increases in systolic and/or diastolic blood pressure at all therapeutic doses. Peak blood pressure elevation after esketamine administration occurs about 40 minutes after administration and lasts approximately 4 hours.
4. Cognitive effects: In a study of healthy volunteers, one dose of this agent caused a decline in cognitive performance 40 minutes after administration. Compared to subjects ingesting a placebo, esketamine-treated subjects required a higher level of effort to complete assigned cognitive tests at 40 minutes after administration. Cognitive performance and mental effort were found to be similar between esketamine and placebo at 2 hours after administration.

Patient-Reported Effects

The acute subjective effects of ketamine dosing can range from sub-perceptual disturbances in cognitive processing and body sensation to full dissociative states in which one feels separate from the body and thoughts dissolve fully. Research evidence suggests that some level of dissociation may be correlated with treatment response for depression.

These experiences are classified as non-ordinary states of consciousness and may represent novel experiences for patients. It is possible that some patient may experience a departure from their usual mind and physical state as challenging or unsettling in the moment. The treatment environment, supportive therapist stance and dosing protocol is designed to optimize the positive nature of the subjective experiences.

References

• Who.int. 2020. Depression. [online] Available at: <https://www.who.int/en/news-room/fact-sheets/detail/depression> [Accessed 3 August 2020].
• Turecki G, Brent DA: Suicide and suicidal behaviour. Lancet. 2016 Mar 19;387(10024):1227-39. doi: 10.1016/S0140-6736(15)00234-2. Epub 2015 Sep 15. [PubMed:26385066]
• Janssen slides, esketamine 
• Lexicomp, esketamine
• Alexander, L, et al. Fractionating blunted reward processing characteristic of anhedonia by over-activating primate subgenual anterior cingulate cortex. Neuron; 4 Dec 2018; DOI: 10.1016/j.neuron.2018.11.021
• https://www.pharmaceutical-journal.com/20206698.article?utm_campaign=2483_PJ_weekly_roundup&utm_medium=email&utm_source=Pharmaceutical%20Journal#fn_1