Journal of Psychopharmacology 20(3) (2006) 325–326
By Ian Ragan CIR Consulting Ltd, London, UK.
For those fortunate to know David Nutt, this article will be instantly recognizable in the way it challenges its readers to think about things differently. In this instance, he asks us to consider the desirability of an alternative to alcohol and possible ways in which one could be developed from a knowledge of the pharmacology of one of our favourite but most dangerous psychoactive substances.
The need for such a substance does not require any further justification – the death toll alone is sufficient reason. So an alcoholic substitute that did all the right things, but was limited in its pharmacological effects even in overdose and did not cause chronic tissue damage would be on my list along with calorie-free chips and chocolate. The current trend to produce wines and beers of ever increasing strength beggars belief. David Nutt’s suggestion to provide a greater choice of low or no alcohol drinks is as sensible as the previous trend is not and therefore is unlikely to occur without legislation. In the current political climate even this seems improbable. In any case, a lot more work will be required to improve the taste of these drinks if they are to serve any purpose other than disguising the fact that one is on the wagon i.e. if they are to be a pleasure to drink rather than a penance. This would apply equally to drinks containing an alcohol alternative if they are to gain acceptance and stand alongside alcoholic drinks as part of the ‘normal’ social environment. A substitute is not just for those whose alcohol consumption is a threat to the health and safety of the consumer and those around them. One can envisage the need for an acceptable alternative in many social and work situations especially if the effects of the alternative can be antagonized rapidly and pharmacologically if needed.
The mechanisms by which alcohol causes its effects are still not completely clear and it is one thing to know which receptors it interacts with and another to know which interactions are responsible for the anxiolytic, sedative, motor, cognitive and addictive properties of the drug. Much of the work on alcohol is directed towards finding agents to counteract one or more of these aspects of its pharmacology as treatments for alcohol abuse and dependence, or to develop other drugs whose actions are not reinforced by alcohol. The complexity of the topic is well illustrated by the review of alcohol effects on mice with mutated GABA-A receptor subunits by Boehm et al., (2004). As this is David Nutt’s preferred receptor target for an alcohol substitute, the article serves to show how difficult this might be. Many GABA-A receptor subunits (α1, α2, β2, β3, γ2 and δ) have been shown in these knock out or transgenic animals to be involved in one or more aspects of ethanol behavioural sensitivity. Furthermore, the GABA-A receptors are by no means the only pharmacological targets of alcohol. Although the dose–response relationship of alcohol’s potentiating effects on certain GABA-A receptors is attractively similar to that of alcohol’s effects in man (Wallner et al., 2003) one cannot ignore other actions. As David Nutt points out, alcohol is an NMDA receptor antagonist (Woodward, 2000) and whether this is responsible for the attractive features of alcohol or the unpleasant ones is not only unclear but also a matter of opinion. Psychotomimesis? Amnesia? Choose your poison as they say. Sedative effects – sometimes a good thing as anyone trying to sleep on a plane will attest – may be mediated by certain isoforms of calcium-stimulated adenylyl cyclase (Mass et al., 2005). Is it out of the question to consider the cocktail bar of the future offering the customer a Nutt Special – a subtype-specific GABA-A agonist of one’s choice, with a dash of NMDA antagonist, an AC8 stimulator and a cherry? The answer is undoubtedly yes for several good reasons.
The idea of GABA-A receptor benzodiazepine site partial agonists (PAs) is attractive theoretically but unproven in practice. There has been insufficient clinical experience with non-selective PAs such as bretazenil to conclude that they are free or relatively free from the undesirable effects of full agonists such as diazepam. Bretazenil was non-sedating in animal tests but was stopped in clinical development by lack of separation between anxiolytic and sedative doses (Atack, 2005). The ability of PAs to avoid the problems of tolerance, dependence and withdrawal are unproven in the clinic. However, they would undoubtedly be safer in that their pharmacological actions would not increase with higher dose and the safety record of even full agonists is excellent in this respect. However, even the so-called non-selective PA’s do not act on all alcohol-sensitive GABA-A receptors, proving that a well-known lager really does reach the parts that other drugs do not. There has been recent interest in the extra-synaptic GABA-A receptors containing the δ subunit as the target for the hypnotic drug, gaboxadol. These receptors are also activated by much lower alcohol concentrations than other GABA-A receptor subtypes, with a threshold in the sub or low mM range (Sundstrom-Poromaa et al., 2002; Wallner et al., 2003). Despite some differences between these papers, they agree that these receptors are activated by alcohol at concentrations lower than those causing motor incoordination but compatible with the pleasurable and stress-relieving effects of a good glass of wine. However, the current generation of non-selective PA’s do not activate δ-containing receptors (Adkins et al., 2001) and it is possible that the latter do not contain a conventional benzodiazepine binding site. Whatever the reason, it remains true that if these receptors are important for the ‘positive’ actions of alcohol we have at present no way into the development of selective agents. It is not clear whether the hypnotic profile of gaboxadol is entirely attributable to action at these receptors and whether gaboxadol or another directly acting agonist would meet the goal of an alcohol alternative.
In view of this, the task for the pharmaceutical industry to develop the right subtype-selective benzodiazepine PA is daunting. Molecules with some degree of selective affinity or selective agonist or inverse agonist efficacy for α1, α2, α3 and α5 containing GABA-A receptors have been developed (Atack, 2005) but this does not mean that it will be trivial to discover compounds selective for other subtypes or with the required level of agonist efficacy even if the target was better defined.
Whether the pharmaceutical industry would be ambitious enough to take up the challenge in David Nutt’s words depends on several things, among which is technical feasibility discussed above. The industry is quite cautious about entering the drug abuse field and even more cautious about getting into lifestyle drugs. An alcohol alternative would find use in both areas regardless of why it was developed in the first place. The pharmaceutical industry is presently committed to the treatment of human disease because there is the greatest need and the benefit/risk balance is more favourable (Ragan, 2005). It is difficult enough to make drugs safe enough even for use in serious medical conditions, but for non-medical use the risk is too high. Regardless of whether society and the regulators are open to the concept of an alcohol alternative, it would only be developed for the treatment of alcohol abuse, a genuine and serious life threatening medical condition. In the minds of many, though, this is a difficult and financially unrewarding target. However, it is always true that drugs developed for one condition frequently find use in others and the treatment of substance abuse, whether alcohol, cocaine or tobacco, is likely to benefit from the development of drugs to enhance executive function and reduce stress and craving (Ragan, 2005). These though are a far cry from the Nutt Special, which will remain in its bottle for a few years yet, a great idea maturing slowly. Cheers!
Corresponding author: Dr C. Ian Ragan, 51 Slaidburn St, London SW10 0JW, UK.
© 2006 British Association for Psychopharmacology
SAGE Publications Ltd, London, Thousand Oaks, CA and New Delhi