The Dustbin of Schedule 1: How Schedule 1 control may stifle medical advances

The Back-story
Months ago, the Advisory Council on the Misuse of Drugs (ACMD) were asked by the government to gather the evidence on the harms of methoxetamine (MXE, ‘mexxy’), a new drug related to ketamine (a ketamine ‘analogue’), and recommend to the Home Secretary what should be done about it. The ACMD did this, produced a report, the conclusions of which the government has accepted. As a result, an Amendment Order to the Misuse of Drugs Act 1971 has been drawn up, adding methoxetamine into the Class B and Schedule 1 categories of the Act. In an attempt to prevent legal high manufacturers looking for a new ketamine analogue to sell, the government will also follow the ACMD’s advice to place countless other ketamine analogues into Class B and Schedule 1.

This Amendment Order, making methoxetamine and a range of ketamine analogues Class B Schedule 1 drugs is of real concern to the ISCD. As will be outlined, Schedule 1 regulation, a dustbin category for controlling drugs with no medical use, may prevent medical advances that could help relieve depression and pain. 

More harm than good?

There are a number of problems with this approach, not least that ketamine is by far and away the major drug of this class causing problems, with use massively greater than that of methoxetamine which users tend to dislike. Methoxetamine was made the first ever subject of a Temporary Class Drug Order in March 2012. Since then its use appears to have dwindled and although there have been cases of extreme intoxication requiring hospital assessment and treatment the ACMD did not find evidence to date of lasting harm or deaths directly caused by it. A recent report by the All-Party Parliamentary Group on Drug Policy Reform interestingly suggested that making TCDOs a model for a more permanent form of control rather than proceeding with full bans could work to reduce harms without criminalising users.

Reducing the impacts of ketamine use is a priority because of the known problems of bladder pathology, addiction, depression and cognitive impairment. However the banning of a range of analogues causes concern because it is unlikely to be an effective way to minimise the harms of these ketamine-type drugs but will also inevitably significantly impair research, particularly into finding medicines that work in the brain, a field that is currently in crisis.

For ketamine analogues, in addition to their potential as new anaesthetics (tiletamine, an analogue already in use as an animal anaesthetic, is exempt from the ban) there is growing interest in their potential as treatments of depression. The finding that ketamine can rapidly ease depression is widely considered the most significant advance in the last 50 years for tackling treatment-resistant depression and suicidal thinking. However, ketamine itself has significant side-effects, so the ketamine analogues are being considered as even more useful drugs for this indication.

Moreover the growing use of long-term ketamine for chronic pain syndromes, and the emergence of high-dose approaches raises the concern of bladder damage as a side-effect in these patients so safer alternatives would be welcome. Medicine progresses by finding better alternatives to existing drugs, a point well demonstrated by ketamine itself. Ketamine was discovered by scientists looking for a safer analogue of phencyclidine (PCP, ‘angel dust’), which was tried as an anaesthetic. PCP worked, but was pretty useless because patients emerging from anaesthesia experienced a long delirium. So analogues were systematically tested until ketamine was discovered, which produced the same benefits but fewer problems. 

Now, decades later, the side-effects of ketamine are driving fresh interest in finding better drugs that work in a similar way. Some hopeful signs are appearing already, with successful trials of one new drug with ketamine’s antidepressant effects (one that has a structure that would not be covered by the new ban). Ketamine derivatives based on tenocyclidine have been studied as anti-organophosphate poisoning agents and in the treatment of cancer, and others are potential treatments of sepsis. Also, the psychoactive effects of ketamine provide a useful model of psychosis for research, but one that might be improved by the testing of analogues.

Although putting analogues in Schedule 1 still theoretically allows them to be researched, the current situation regarding Schedule 1 licenses is such that this research will be severely hampered. The holding of Schedule 1 drugs is subject to a specific Home Office license that now costs about £5000 to obtain and then incurs significant time and other costs in relation to inspection . It also takes up to a year to get one. Currently we know of only 4 hospitals in the UK with one; neither Hammersmith Hospital or University College Hospital, two of the leading clinical research centres in the UK hold one. In contrast NHS hospital and university departments that conduct biomedical research which requires controlled drugs in Schedules 2-5 are exempt from the need to purchase a license to hold these. These hurdles induced by Schedule 1 status, though surmountable, effectively stifle research.

Many university pharmacology depts. do not have Schedule 1 licenses so would not be able to work with these compounds. One compound covered by the proposed ban, eticylidine, has been a useful radioligand for studying NMDA receptors and is being considered as a starter molecule for PET tracers. Moreover we know that forensic chemistry experts working in this field of legal highs have found Scheduling of other drug classes, particularly the cathinones and cannabis agonists severely hampers their ability to work in this area due to restrictions of supply and increased costs.

History tells us that pharmaceutical companies are very averse to funding work on compounds that would be subject to controls. This aversion also applies to close analogues of currently controlled drugs since there is no guarantee that these too would not be controlled under analogue legislation, such as that being proposed. 

Conclusion - we cannot continue depositing drugs into the dustbin of Schedule 1
Control, particularly at Schedule 1 level, stifles and may kill research in a field. It is imperative we do our best avoid this outcome with drugs like ketamine that act at the NMDA receptor as these are so promising therapeutically. This is particularly important as there is no reason to think that this legislation will have any impact on ketamine use and harms. Indeed it may paradoxically increase harms if safer analogues are not discovered and so ketamine use – both clinical and illicit - continues.