19 August 2012

Human testing of illicit drugs - the highs and lows

Should governments make it easier to perform human research to discover medical uses of illicit drugs such as cannabisecstasy(MDMA) and LSD?

August 6 2012
Professor David Nutt of Imperial College London argued recently that the UK, like many other jurisdictions, makes human research on illicit drugs nearly impossible to perform.

Nutt made the point that risks need to be balanced against the potential benefits for new knowledge about how consciousness works and potential medical treatments. There is some truth in this. Research on potential medicinal uses for illicit drugs has remained largely unfunded by UK, US, Australian and other governments despite solid evidence that there are some medical benefits to taking drugs such as cannabis.

There are severe but not insurmountable restrictions on access to such drugs in many countries. But research on any drug in humans is necessarily limited by important ethical considerations aside from any political and security issues.

Knowing the limits

As pointed out by Professor Nutt, research on the potential medical benefits of MDMA and hallucinogenic drugs such as LSD and psylocibin in the 1960s suggested potential therapeutic benefits for some psychiatric disorders.

The illegal status of these drugs limited further progress, and it continues to do so. But it must also be recognised that the regulatory framework for drug testing in humans has changed dramatically in the post-thalidomide era (after the 1960s), when the drug was found to be linked to thousands of mothers giving birth to disabled babies.

It is no longer ethical to test any drugs in humans without a great deal of very expensive safety testing in a variety of specific biological test systems and animals within a strict regulatory framework. Such testing helps to protect against catastrophic errors as seen in the case of thalidomide.

Any planned experiments in humans must also undergo a very careful risk-benefit analysis and be accepted by strictly regulated human ethics committees before a human trial can begin, regardless of any other restrictions. Someone – the public or government research funding agencies – will support some clinical trials of novel medications when the significance or medical need is high.

By and large, pharmaceutical companies undertake this very expensive work only when there is a clear likelihood of profit.

Unless the safety and risk-benefit criteria are met there is little incentive to perform human research, particularly in the face of negative political pressures associated with illegal status.


On the risk-benefit side, drugs which have been used widely for millennia, such as cannabis, are considered safe enough to test. There is solid scientific evidence to pursue this and government commissioned expert reports in the UK, USA and Australia have consistently recommended such research be undertaken.

At the basic, cutting-edge of science there has been an explosion of research on cannabis since the discovery in the early 1990s of the target molecules in the body that cannabis works on and the endogenous messengers, endocannabinoids, which cannabis mimics.
Most of this work has been performed in animal models, isolated tissues and nerve cells and is not restricted much by legal status. From this work there has been a steady growth in knowledge of the systems in the brain that cannabis works on, providing a solid scientific basis for potential medical uses of the drug.

These include stimulation of appetite, relief of spasticity in multiple sclerosis and management of chronic pain. There are hints that cannabis-related drugs may also be useful for other disorders such as Tourette’s syndrome.

But funding for research in humans has lagged behind this basic understanding. Rather than governments, clinical trials in humans have recently been championed and financially supported almost exclusively by companies. GW Pharmaceuticals based in the UK have developed a cannabis extract that can be administered under the tongue, initially to treat spasticity in multiple sclerosis and more recently for management of untreatable chronic pain produced by nerve injury. The drug is now registered for use in several countries.

The growth in knowledge of the molecular mechanisms of action of cannabis has produced other risks. So far about 20 experimental drugs that act in a similar manner to the main psychoactive drug in the plant have been invented, as well as drugs with the opposite actions that block cannabis and the body’s own cannabis-like messenger molecules.

Endocannabinoid-blocking drugs have been developed by several pharmaceutical companies as appetite suppressants and there are other possible uses.

One unintended consequence of such drug development research has been the clandestine synthesis of synthetic cannabis mimics that have until very recently not been classified and are marketed as legal herbs or “spice” that produce a “legal” high similar to cannabis.

Being chemically different from the active drugs in cannabis, these synthetic mimics cannot be detected by routine drug tests. Clandestine manufacturers of these drugs attempt only to avoid the illegal status of the parent psychoactive drug and have no concern whatsoever for the health or well-being of their clients.

Effectively, individuals taking any of these drugs are human guinea pigs testing the toxicity of potentially poisonous drugs. These cannabis mimics might not be as bad as thalidomide but recent case reports of sudden heart attacks in teenagers following use of “spice” or “K2” highlight the severity of risks.


If the case for cannabis research in humans is fraught with complexities, the situation is more problematic for other potentially dangerous drugs, such as MDMA.

The risk of life-threatening adverse events from MDMA is extremely low but other adverse effects, including the high incidence of induction post-MDMA depression – the “Tuesday blues” – could preclude therapeutic use in vulnerable psychiatric populations.

But we might be able to produce better therapeutics from the wealth of basic research on MDMA. Recent research points to MDMA’s enhancement of a natural “empathic” neuro-hormone, oxytocin, in the brain, which has been tested in the context of facilitating therapy for patients suffering post-traumatic stress disorders.

Treatment with this hormone itself may prove to be a safer, more effective therapeutic aid for such anxiety disorders than MDMA itself and is a field of intense human research in Australia and elsewhere. Again, the clandestine market has generated many MDMA lookalikes that are sold as ecstasy, some of which, including PMA, are highly toxic.

A political pill

Testing of illicit drugs on humans is clouded by political concerns. Many illicit psychoactive drugs have potential medical uses but also cause serious problems with misuse. It is a reasonable fear that attributing medical uses to illicit drugs normalises them in the eyes of potential users, along the lines of: “it’s used as a medicine so it must be OK”.

Of course, this is as silly as the misconception that drugs such as psilocybin and cannabis are natural so they must be harmless.

Morphine is a glaring example of a legal drug from a plant with immense medical benefits in serious pain management but also serious risks, including addiction and overdose death with misuse.

Valid medical uses of cannabis or any other drug should not override concerns about misuse.

Friction and addiction; the use of illicit drugs in Australian research

Criminalisation of many drugs of abuse has done little to deter their use. Recent estimates tell us nearly one in 20 individuals aged between 15 and 64 are experimenting with illicit drug use worldwide.

But contrary to the recent statements by Professor David Nutt in the UK, legislation regarding the use of illicit drugs for research purposes has had little impact on the ability of Australian neuroscientists to conduct research – and that research is yielding significant results.

Researching with illicit drugs in Australia

Understandably, the use of illicit drugs for research purposes in Australia is tightly regulated. Yes, licences need to be obtained, and drugs need to be purchased from pharmaceutical companies and stored under lock and key.

The maximum quantities that can be kept on site for authorised research groups and/or organisations are small ranging from milligrams to a few grams depending on the drug under investigation.

Their use is stringently regulated by responsible parties approved under the Drugs, Poisons and Controlled Substances regulations. This includes monitoring of the quantities distributed, which is often maintained through log books requiring more than one signature each time a drug is accessed.

But in reality these procedures are no more involved than for individuals who wish to work with, say, viral vectors and genetically modified tissues.

Obtaining illicit drugs for research purposes is not the central issue. The real challenge lies in understanding the impact of those drugs on the brain, and how this subsequently drives addictive behaviours in some users.

It is estimated only 20% of individuals who engage in drug-taking will meet the criteria for dependence. So the question remains: what is different in the brain of these individuals that makes them compelled to go back for more?

The neuroscience of addiction

There is growing evidence that repeated drug use leads to neuroadaptive changes in the brain, which alter how information is processed and consequently the way the brain functions.

It is believed these adaptations drive the “switch” as an individual transitions from casual drug use to addiction. Furthermore, in individuals who display addictive behaviours these drug-induced alterations in the brain do not necessarily resolve following withdrawal from drug-taking. Indeed, those changes are sufficient to result in relapse even after extended periods of abstinence.

Consequently, behaviours associated with drug-taking are not “unlearned” once an individual stops taking a drug. New evidence suggests that for abstinence to be successfully maintained, the brain needs to be “reprogrammed” so that it learns to make new memories that are not associated with drug-taking.

So does the addicted brain behave the same way, whatever the drug? No, it doesn’t.

The need for illicit drugs

Why do researchers need access to illicit drugs instead of simply alcohol or tobacco to understand the role of these neuroadaptive processes?

As drugs of abuse have differing “pharmacological profiles” – different chemical compositions, uses, effects, rates of metabolism and sites of action in the brain – there’s a strong need to profile each drug individually.

A researcher will find one set of drug-induced alterations in the brain after studying the effects of alcohol consumption, which may differ markedly to those caused by cannabis or morphine, for example.

Adaptive processes can occur at many levels in the brain, including those regulating gene expressionneurotransmissionand synaptic plasticity.
These changes are influenced by not only the use of the drug itself but also environmental factors. They are complex and multifactorial.

While there is no one gene that predisposes an individual to becoming “addicted”, genes and the way they are expressed can increase a person’s vulnerability to addictive behaviours.

Epigenetic mechanisms

Australian researchers are increasingly focused on understanding the role of epigenetic mechanisms in mediating addictive behaviours. This process involves the integration of environmental influences to regulate either the switching “on” or “off” of gene expression, without changes to the genetic code itself.

Regulation of gene expression results in a functional end product (usually proteins) and is akin to pieces of a jigsaw coming together to form a picture.

How does the switching on and off of gene expression play a role in addiction? Our understanding of this process is relatively new. It’s believed that exposure to a drug has the potential to result in stable epigenetic modifications that alter gene expression and lead to neuroadaptive changes.

As the process incorporates environmental influences the resultant outcome will differ across individuals. Understanding the impact of epigenetic processes in addiction is complicated by the fact that the type of change can be heavily influenced by the drug’s unique pharmacological profile, whether it’s taken once or multiple times, and the period of time over which it is taken.

Furthermore, different epigenetic-mediated processes may occur during periods of withdrawal. These changes can also be specific to different regions of the brain and to different genes themselves.

Even if we have access to illicit drugs for research purposes, processes underlying addiction appear so complex we are forced to ask: will we ever be able to successfully treat addicts?

The rise of “optogenetics”

A dramatic leap forward in our ability to achieve this goal has arisen via the recent introduction of optogenetics. Hailed by Nature as the method of the year in 2010, optogenetics incorporates theories from optics, genetics and bioengineering to enable dissection of the microstructural pathways (i.e. at the level of neurotransmitters, receptors or synapses themselves) mediating addictive behaviours.
 That process involves genetic modification of a target population of cells in the brain of animal models that can be activated (or inhibited) by light of particular wave lengths.
The process is rapid, precise and eliminates many of the issues associated with other techniques, such as experiments where discrete pathways are permanently lesioned to determine their function, or the use of transgenic “knockin” or “knockout” animal models.
In these models, the altered expression of a particular gene may result in secondary compensation of other systems during development. While conditional knockins/outs provide some improvement on this, they cannot be independently regulated.

Imaginably, through the use of optogenetics, a researcher would be able to mimic the activation of the circuitry responses believed to play a role in mediating addictive behaviours. Once achieved this has the potential to highlight target sites for intervention therapies.

Australian neuroscientists are at the forefront of research into the processes mediating addiction following illicit drug use. As long as these drugs remain available to us for research, we will continue to strive towards fully understanding the mechanisms contributing to this devastating disorder.

Our work tells us so clearly that addiction is an illness above all else, with those affected worthy of compassion and care in preference to damnation within the criminal justice system.