Novel rapidly acting drugs introduction

By J.E- Newcastle University

Ketamine and esketamine Psilocybin and LSD MDMA Buprenorphine

Major Depressive Disorder (MDD) affects over 350 million individuals world-wide. While antidepressants are effective for many people, as many as a third remain unwell, even after several adequate trials of antidepressants [1-3]. There is therefore an unmet need for patients who fail to respond to conventional therapies. It can also take 4-6 weeks of treatment with conventional antidepressants before clinically significant improvements are observed. Exploring treatments that have a different mechanism of action to standard antidepressants and a rapid onset of antidepressant actions (within a few days), could have a great impact on patient care. It is important for rapidly acting antidepressants to have robust and sustained efficacy.

One group of drugs being explored as potential rapidly acting antidepressants are psychoactive agents that can cause hallucinations, perceptual anomalies, and other substantial subjective changes in thoughts, emotions, and consciousness [4]. They include:

These drugs are being examined for other conditions as well. For example, both psilocybin and buprenorphine have been found to be effective in treating obsessive-compulsive disorder (OCD).

Other similar drugs are being used to treat other conditions such as the drug Ecstasy/MDMA used to treat post-traumatic stress disorder (PTSD).

Many of these rapidly acting drugs can lead to hallucinations and can be referred to as “hallucinogens”. Traditionally they have been used in medical and religious practices for centuries. However, their recreational use and public concerns over abuse has overshadowed their therapeutic potential. In the last 2 decades, there has been a renewed scientific and medical interest in the treatment of several mental disorders with hallucinogens and other psychoactive agents. It has been claimed that a single acute exposure to a novel psychoactive agent, may elicit an immediate and lasting improvement in symptoms. Such effects may persist long after the drug is metabolised and gone from the body [5]. “Expectancy” may play a large role in the effects of these drugs. The expectancy effect is seen in medical treatments when the patient expects a given result and therefore unconsciously affects the outcome or reports the expected result. Some expectancy effects are unavoidable as it would be unethical not to inform patients about the range of possible effects of these psychoactive agents.

Most of the hallucinogens and psychoactive drugs being examined as possible rapidly acting treatments for depression or other mental health conditions are “controlled” or “scheduled” drugs due to concerns regarding abuse. Details of the UK categorisation of controlled drugs can be found here. There are two elements to this, summarised below.

Firstly, the Misuse of Drugs Act classifies controlled drugs into 3 categories. These are class A, B, and C depending on the perceived degree of harm attributable to each drug, their relative abuse potential, and the likelihood of causing dependence, though there is a great deal of controversy about how certain drugs are classified [6]. Class A to C define restrictions in the manufacture, supply, and possession of various drugs. All are “controlled” drugs – i.e., there are restrictions in their manufacture, supply, and or possession above and beyond other medications, including ones provided normally by doctors on prescription. Class C includes drugs that can be reasonably easily prescribed by doctors (e.g. benzodiazepines and some sleeping tablets) but for which there are tighter controls than the average medication (e.g. an antidepressant or antibiotic). Class B includes drugs where there is more concern about possible misuse or dependence. This includes ketamine. These drugs can still be reasonably easily prescribed by doctors, but there are more controls than for class C drugs. Class A drugs are the group with the greatest concerns. It includes drugs such as heroin and cocaine. It also includes MDMA and LSD. It is this classification of A to C that is used by the Police and criminal justice system when prosecuting people for possession or supply of drugs.

Secondly, The Misuse of Drugs Regulations describes Schedule 1 to 5 categories that define regulations regarding the supply, storage, prescription, and monitoring of drugs in clinical practice. Schedule 5 are drugs with minimal regulations over and above those related to usual prescription medicines. Schedule 1 and 2 drugs have many more regulations and requirements to be met for them to be able to be prescribed. For example, this includes where and how these drugs are stored in a hospital, with them being kept in specified locked cabinets separate from routine prescription medication. In addition, legally required logs have to be kept of the medications recording all new supplies received by the hospital and every dose prescribed and by whom. Schedule 1 drugs include psilocybin and LSD. A hospital that holds and uses schedule 1 drugs has to be inspected and approved by the Home Office, and only doctors named on the Home Office license are allowed to prescribe the drugs. Most hospitals do not hold a schedule 1 license and it is a time consuming and complex process to acquire this.

The Drug Enforcement Administration in the USA similarly defines schedule drugs I-V (one-five) based on whether they have currently accepted medical use in treatment in the United States, their abuse potential, etc. Schedule I drugs are argued to have the highest potential for abuse and potential to create severe psychological +/or physical dependence. Schedule V drugs represent the least potential for abuse.

Many of the drugs being considered for psychiatric use are UK Category A and Schedule 1 or 2. This raises concerns. It is very important to know the abuse and dependence risks of these drugs that are being developed and the steps required to minimise these risks. It is important to emphasise that the risks may not be as great as previously perceived, and which led to the classification of the drug as e.g. schedule 1. It is also important to recognise that it is much harder to do research on schedule 1 drugs, or to use them in clinical practice.

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Ketamine and Esketamine Psilocybin and LSD MDMA Buprenorphine