Currently, prescribing pharmacists in the UK cannot prescribe cannabis-based products for medicinal use (CBPMs).
Prescribing of CBPMs for medicinal use in the UK is restricted to only those clinicians listed on the Specialist Register of the General Medical Council¹. The GMC² does not specify what type of speciality is needed (there are over 60 possible fields) however, it makes sense that the chosen speciality should relate to the use of the medicine.
What are CBPMs prescribed for?
There are two licenses for CBPMs in the UK Epidyolex, a purified cannabidiol used to treat Lennox-Gastaut syndrome and Dravet syndrome, rare forms of childhood epilepsy and Sativex which has an approved license for treating muscle stiffness and spasms, known as spasticity, in multiple sclerosis.
In the unlicensed realm, where the majority of cannabis medicine prescribing lies, specialist doctors could prescribe Epidyolex or Sativex for conditions other than mentioned in the SPC. Alternatively, unlicensed CBPMs or “Specials” are often prescribed for:
- Chronic pain
- Sleep disturbance
- Appetite loss
- Increasing appetite and decreasing weight loss associated with HIV/AIDS
- Improving symptoms of Tourette syndrome
- Social anxiety disorders
- Posttraumatic stress disorder
National Academy of Science Report “no or insufficient evidence“:
- Cancer
- Crohn’s disease
- Epilepsy
- Immunological disorders
- Glaucoma
- Irritable bowel syndrome
- Mental health conditions: schizophrenia and posttraumatic stress disorder (PTSD)
- Wasting syndrome (cachexia)
The two lists above have been arranged in descending order of strength of evidence in accordance with The Chief Medical Officer for England’s June 2018 review³.
So, if the Doctor who is looking to prescribe CBMPs and would like to work to Clinical Best Practice, they should specialise in childhood epilepsy or multiple sclerosis (both of which are not classified as speciality areas by the GMC). Broadening this list to conditions with less evidence, a CMBP prescribing doctor should hold a speciality in:
- Clinical oncology
- Gastroenterology
- Palliative medicine
- Paediatrics
- Medical oncology
- Clinical neurophysiology
In fact, as mentioned at the beginning of this article any speciality would suffice. What is odd is that this ability is not available to any other type of prescriber notably nurses, midwives, pharmacists, physiotherapists, podiatrists, paramedics or optometrists.
What needs to happen for pharmacists and other prescribers to be able to prescribe medicinal cannabis?
More evidence needs to be established for the safety profile and clinical efficacy of CBMPs. Once this reaches a threshold, the government can be petitioned to loosen the unlicensed prescribing requirements from not only allowing Specialist Registrants of the General Medical Council but enable all CD prescribing clinicians to prescribe the CBMPs.
Final note.
Not all pharmacists are prescribers, however, the majority of pharmacists are involved in the other major part in medicine supply, dispensing. As such, pharmacists have a legal requirement to check the legal validity of prescriptions presented to them. As of late, it has become more apparent that prescribers do not all have the same permissions to prescribe. We have been charting this via our Prescriber Permissions Chart (see below) which as of late has had two new additions, esketamine and CBMPs.
Finally, a second potential solution to this issue is that a Specialist Register is set up within the GPhC Register which would enable willing pharmacists to undergo the required training to safely prescribe these medicines. Within our Independent Pharmacist Prescriber Group, we are currently working on a strategy to open dialogue with the GPhC see if we can make this happen.
Reference
³Cannabis Scheduling Review Part 1: The therapeutic and medicinal benefits of Cannabis based products – a review of recent evidence Professor Dame Sally Davies Chief Medical Officer for England and Chief Medical Advisor to the UK Government. Published on June 2018, accessed on 27th January 2021 via https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/722010/CMO_Report_Cannabis_Products_Web_Accessible.pdf
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In the latter half of 2020, it has been reported in the popular press¹’²’³, that a number of school-aged children from Camden, London, UK have been taken to hospital having taken imitation “Nerds” sweets containing the psychoactive element of cannabis, THC. The pack (see above) states it contains a total amount of 600 mg of THC which is approximately 50 joints (see below).
These THC edibles look identical to the popular sweets Nerds “Gummy Clusters”, which are bite-sized version of “Nerds Rope” an American product marketed to children.
The bogus packaging warns “keep away from children” – despite having packaging that would appeal to kids.
Who are making Nerd THC sweets?
What’s fascinating from a pharmaceutical point is that it seems whoever has manufactured these sweets has gone through a lot of trouble to make a product which does the same thing as generic cannabis oil. At first, glance it seems a crafty drug dealer has designed the packaging and created an industrial process to create a tricky formulation en masse. However, this is not the case.
A quick search on Youtube shows a young Youtuber showing how people can make their own THC edibles. This makes you think, that this must be some sort of small scale copy cat operation. However, a quick search on DHGate and ebay and Wish shows that anyone can buy the prefabricated packets for less than £0.27 GBP (Figure 4 below).
There is strong meta-analysis evidence of the association between the level of cannabis use at a young age and the risk of psychosis⁵.
In conclusion, it is highly likely that decriminalisation around the world will follow suit as to what is occurring in the US at the moment. Cannabis like any other medicine are tools and can be used for good but can be abused to cause harm which as healthcare professionals we have a duty of care to protect patients against. We need to make sure that these powerful products do not get in the hands of the most vulnerable. One mechanism to stop this type of illicit trade is legislation, if decriminalisation goes ahead, there should be strict rules on age ranges which can access the product and from what location.
References
² The Sun.
⁴Cannabis-induced attenuated psychotic symptoms: implications for prognosis in young people at ultra-high risk for psychosis. Journal of Psychological Medicine, Volume 47, issue 4 (2017), DOI: 10.1017/s0033291716002671
⁵Marconi A, Di Forti M, Lewis CM, Murray RM, Vassos E. Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis. Schizophr Bull. 2016;42(5):1262-1269. doi:10.1093/schbul/sbw003
]]>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
- 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.
- 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.
- 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.
- 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.
| Pharmacokinetics | |
| Absorption | Due to the fact that this drug is administered via nasal spray, absorption is rapid. The mean absolute bioavailability is approximately 48% after esketamine nasal spray administration. The time to achieve peak esketamine plasma concentration is 20 to 40 minutes after the last nasal spray of esketamine. Inter-subject variability of esketamine ranges from 27% to 66% for Cmax (maximum concentration) and 18% to 45% for AUC (area under the curve). The intra-subject variability of esketamine is about 15% for Cmax and 10% for AUC. |
| Volume of distribution | The average steady-state volume of distribution of esketamine administered by the intravenous route is 709 L. |
| Protein binding | The protein binding of esketamine is about 43% to 45%. |
| Metabolism | Esketamine is mainly metabolized to the noresketamine metabolite by cytochrome P450 (CYP) enzymes, CYP2B6 and CYP3A4, and to a lesser extent, CYP2C9 and CYP2C19. Noresketamine is metabolized by cytochrome-dependent metabolic pathways followed by subsequent glucuronidation of metabolites. |
| Route of elimination | Less than 1% of a dose of nasal esketamine is measured as unchanged drug, excreted in the urine. Following intravenous (IV) or oral (PO) administration, esketamine-derived metabolites were mainly recovered in urine (≥ 78% of a radiolabeled dose), and a smaller percentage was measured in the feces (≤ 2% of a radiolabeled dose). |
| Half-life | The mean terminal half-life (t1/2) ranges from 7 to 12 hours. |
| Clearance | The average clearance of esketamine is approximately 89 L/hour following intravenous administration. Elimination of the major esketamine metabolite, noresketamine, from plasma is slower than esketamine. The decrease of noresketamine plasma concentrations occurs in a biphasic fashion, with a more rapid decline for the first 4 hours post-administration, and an average terminal t1/2 of approximately 8 hours. |
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
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:
- 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.
- A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression (SUSTAIN-2): https://www.australianclinicaltrials.gov.au/anzctr/trial/NCT02497287
Current NHS availability in the UK
In late 2019 Spravato was licensed for use in the UK. The current license holder is Janssen-Cilag and the medicine is listed in the British National Formulary as:
“Available in the UK. Price 1 x 28mg nasal spray = £163“
To access esketamine for depression, a prescription written by a psychiatrist is needed. Psychiatrists in the UK work either within the NHS (where you can potentially source the prescription + medicine for free) or from the Private sector (at a cost). Even though the National Institute of Clinical Excellence (NICE)4 has shown esketamine has positive effects it has limited availability on the NHS as it is not generally considered cost effective. The only publicised NHS availability of esketamine is in Scotland where the Scottish Medicines Consortium (SMC) accepted the use of esketamine (Spravato; Janssen) nasal spray for use within NHS Scotland for adults with treatment-resistant major depressive disorder on 8th September 2020.
This does not mean it is not available eslewhere in the UK, only it is unlikely you can access the medicine through an NHS GP, you will need to consult outside of the NHS i.e. via a private prescriber.
Current Private sector availability in the UK
The main source of esketamine for depression in the UK is via private medical clinics5. The license of esketamine in the UK requires patients to meet the following three conditions:
- taking either an SSRI or an SNRI.
- diagnosed by a licensed doctor as suffering from “treatment-resistant Major Depressive Disorder”.
- unresponsive to at least two different treatments with antidepressants in the current moderate-to-severe depressive episode.
If you meet the above crietria and are interested in obtaining treatment we have found the following clinics as possible sources of the treatment.
- Leeds – 07547759264: [email protected]
- Northamptonshire Healthcare – 01604 685590/91: [email protected]
- Warrrington – experttms.co.uk/esketamine-clinic/- 01925 691502: [email protected]
- London – Saveminds.co.uk – +442077220865: [email protected]
- Oxford – Littlemore Mental Health centre: [email protected]: 01865901000
In the event that you need further help in sourcing the medicine of finding if you are eligible, contact our Psychopharmacologist specialist via this link.
How esketamine is administered
Spravato is intended to be self-administered by the patient under the direct supervision of a healthcare professional. A treatment session consists of nasal administration of Spravato and a post-administration observation period. Both administration and post-administration observation of Spravato should be carried out in an appropriate clinical setting.
Alternatives to esketamine
There are some clinicians administering the drug in its original ketamine form as ‘off-label’ treatment, below is a list of what is available in the UK:
- Oxford health – NHS foundation Trust – initial consultations cost £150.
We will be continually updating this blog (last updated 30th July 2020) to chart esketamine’s progress so if you are interested and would like alerts please consider following us on social media or subscribe to this blog for further updates.
Frequently Asked Questions about Esketamine
Our prescribing team at Voyager Medical has received a wide range of questions regarding esketamine availability in the UK. We have now created a dedicated page called Frequently Asked Questions about Esketamine, click the link for more information.
References:
- Ketamine enantiomers in the rapid and sustained antidepressant effects. Published: 2016 Jun. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4910398/
- 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.
- A Long-term Safety Study of Intranasal Esketamine in Treatment-resistant Depression, 2016: https://clinicaltrials.gov/ct2/show/NCT02782104
- Esketamine for treatment-resistant depression (ID1414). https://www.nice.org.uk/guidance/proposed/gid-ta10371
- Ketamine-like drug for depression could get UK licence within the year, published 14th July 2019. https://www.theguardian.com/science/2019/jul/12/ketamine-like-drug-for-depression-could-get-uk-licence-within-the-year