When you find out that biologists are studying cannabinoids, you may think that science is ‘going to pot,’ but if they can understand what these mysterious molecules do to the brain, their research may lead to many biological and pharmacological breakthroughs……
It all goes back to 1968 and the ‘Summer of Love’ when cannabis was first widely used in the West as a recreational drug, but it is only now that scientists are beginning to understand the effects of the active components in cannabis, and in the process solve the mystery of how brain cells communicate using endocannabinoids – natural compounds in the brain which affect behaviour in the same way as tetrahydrocannabinol (THC) the major psychoactive component in cannabis.
Cannabis is mentioned in the Bible and has been used for many centuries by doctors in China, but it was only about 40 years ago that scientists began to understand its precise mode of action in the brain. Roger Pertwee, now Professor of Neuropharmacology at the Institute of Medical Sciences in Aberdeen, was one of the scientists who helped to discover the active ingredients in Cannabis sativa in the late 1960s. And today a few metres away from his office, the scientific quest continues, as Professor Tibor Harkany, one of SULSA’s recently appointed international researchers, explores a new dimension of cannabis research, seeking major breakthroughs in our scientific understanding of how nerve cells communicate in the brain and “the specific roles the endocannabinoid system plays in shaping the relevant molecular processes.”
One of the most interesting things about cannabis is that the brain has specific receptors for THC. And these receptors are the same ones that sense endocannabinoids, the compounds found in every mammal’s brain. Endocannabinoids do not help us ‘get high’ but instead are critically important in modulating the functions of complex neuronal networks, thus affecting processes such as memory, mood, pain and appetite.
Research in the area of endocannabinoid research has progressed through a number of stages, but it wasn’t till the early 1990s that researchers cloned the first cannabinoid receptor in the brain and identified the endogenous molecules that bind to the receptors. In 2001, researchers then started to work out how endocannabinoids behave in the brain by establishing how they limit different forms of communication between nerve cells.
In the course of this research, researchers rewrote the textbook for synaptic signalling. The scientific axiom, first established in the late 1940s, was that signals only went in one direction within a synapse, the junction where information is transferred from one neuron to another. The presynaptic terminal had one specific role – to effectively release a neurotransmitter which in turn solely engaged its cognate receptor at the recipient (postsynaptic) cell in order to induce a physiological response. In 1991, scientists made the first observations that suggested that the model of unidirectional communication may be wrong. Partly thanks to research into endocannabinoids, says Harkany, scientists learned that if you stimulate the postsynaptic cell appropriately then it can respond to this by releasing compounds that will travel the synapse in a reverse (retrograde) fashion. These compounds, called retrograde messengers, will find their respective receptors on the presynaptic terminal, thus creating a feedback loop between the two synapses – two-way traffic.
To investigate the different effects of retrograde messenger molecules on their respective receptors, Harkany and his colleagues asked a series of questions, with particular reference to the coordination of activity in neuronal networks underpinning cognition, movements and emotions. And for Harkany the big question was whether molecules responsible for establishing two-way communication in the adult brain are only present when the synapses are mature and functional, or instead actively contribute to defining a synapse’s identity during its course of development. According to Harkany, it’s also like asking: “What comes first, the chicken or the egg?” Do these molecules affect the development of a synapse or does a functional synapse recruit its own specific feedback loop?
Harkany is also therefore interested in the different effects of endocannabinoids on the brains of adults and adolescents, and on the developing brain of the foetus. If there are specific effects, are they limited to one phase of development? Consequently, if endocannabinoids are needed for communication between different brain cells, how is that process disrupted by taking extra molecules on board via exposure to cannabis?
Psychologists have already established that there may be psychological problems associated with cannabis, and also that babies exposed to cannabis in the womb may develop various problems, but Harkany’s challenge was to find the biological evidence and understand what was happening “when the staggering complexity of our brains evolves.”
What is emerging from Harkany’s research is that during foetal development and during puberty, when the brain is busy making neural connections to help the adaptation of brain cells to the increasing amount of stimuli each individual receives, cannabis disrupts the natural functions or spatial and temporal integrity of the signals which pass at synapses. “Quite simply, the cells get confused,” says Harkany. When psychoactive phytocannabinoids flood the brain, he explains, they interfere with the normal ‘on/off’ functions of endocannabinoids which can lead to cells increasingly shutting down, and this has a knock-on effect on the rest of the brain as well as on long-term refinement of neuronal communication.
One immediate outcome of Harkany’s recent research was to attract worldwide media attention when his team announced that taking cannabis while pregnant may affect the brain development of the unborn child. Adolescents may also experience significant problems when they use cannabis during the most critical postnatal phase of brain development, according to Harkany. When asked about the ethical aspects of these conclusions, Harkany says that we do not know everything yet about the effects of cannabis, but the evidence strongly suggests that the brain may be damaged, so his advice to pregnant women as well as teenagers is simply: “Stay away from cannabis.”
Harkany’s experimental data confirms the harmful effects of overloading the brain with phytocannabinoids, but he says that many people “have trouble accepting the biological importance of endocannabinoid signalling” because they confuse it with the social and ethical issues rather than focus on the scientific concepts involved. Harkany explains: “The fact that cannabis is a recreational drug and has become part of our culture provides a clear rationale for this type of research. However, knowing that it may affect our offspring makes these scientific findings socially sensitive.”
According to Harkany, several studies that followed people from birth till their twenties have established the detrimental effects of cannabis on brain development, and his work – processing experimental data from various sources – confirms many of these conclusions, “and now we are beginning to understand the process at the molecular level,” he adds.
THC is the most likely candidate for these disruptive effects, but some work still has to be done to eliminate others, says Harkany. Cannabis is a notoriously ‘dirty’ drug in the sense that it contains several dozen compounds which may have different effects in the human body and can interact with each other. People who use cannabis inevitably do other things – ingesting a chemical ‘cocktail’ – and this ‘polydrug’ use may also make it difficult to study how cannabis affects human beings, since it’s hard to isolate every ingredient.
As well as the effects on early brain development, Harkany’s work on endocannabinoids also has implications for ageing – the ‘mirror of what happens in the womb. “If we can work out how the synapse is built, then perhaps we could prevent its breakdown by being able to pinpoint the most sensitive processes that can lead to cognitive impairment in later life,” Harkany says. Harkany has also done groundbreaking research into the parallels between Alzheimer’s and epilepsy, studying “the common molecular process underlying perturbed communication between different cells.”
Ultimately, says Harkany, if we can understand the ‘rules’ of the endocannabinoid system, and the full impact of THC and other compounds, we will advance our understanding of the brain as a whole, leading to better diagnosis and more ‘personalised’ treatment of various diseases.
If anyone in the 1960s ever suspected that studying cannabis would open the door to a wide range of medical therapies for learning disorders and ageing, and “a fundamental understanding of synaptic plasticity,” you would have thought they had been smoking too much marijuana. But Harkany is proving that cannabinoids may hold the key to a number of biological mysteries far beyond the wildest dreams of any pot-smoking hippy.