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Cerebral tuning

Extracted from cannabis, cannabidiol acts against anxiety and other mental disorders

FRANZ EUGEN KÖHLERCannabis sativa in an 1887 sketch by Franz Eugen Köhler: in use some 6,000 years agoFRANZ EUGEN KÖHLER

In an exceptionally large laboratory on the second floor of a mansion built in the neoclassical style and painted in ocher, from whose windows one can appreciate the garden brimming with trees at the Medical School of  the University of São Paulo (USP) in Ribeirão Preto, new studies are building up the potential medical uses of cannabidiol, one of the most abundant substances of a plant that sets off passions, sweet delusions or sad memories, furious criticisms and, over the last few years, growing scientific interest: marijuana. As demonstrated by way of experiments with animals carried out by professor Francisco Guimarães’ team, cannabidiol deters anxiety in a manner equivalent to synthetic medicines that have been in use for decades and, according to the preliminary results of one of the ongoing studies, it could also reduce depression. As other studies had indicated, cannabidiol can also work against leukemia, epilepsy and neurodegenerative illnesses such as Alzheimer’s disease.

In another USP laboratory at Ribeirão Preto, on the fourth floor of the Hospital das Clínicas, behind the mansion, which was previously the headquarters of a coffee plantation,  Antonio Zuardi has found evidence that this compound can also work as an anti-psychotic and placate the most serious symptoms of schizophrenia, such as delusions and the difficulty of recognizing the patient’s own body. This month Zuardi should be starting tests on patients with humor bipolar disorder, previously called manic-depressive psychosis, since cannabidiol can act against the intense acceleration of thought and other psychotic symptoms that accompany this type of metal disorder.

In parallel, research carried out mainly  in the United States, Britain and Australia show that cannabidiol can protect the central nervous system, widening the lifespan of neurons, as well as helping to deter inflammations and to control blood pressure. There are indications that cannabidiol can even block the growth of brain tumors, opening up the prospect that this chemical compound – which has nothing to do with the typical effects of marijuana – could be used on its own or in combination with the most studied of the famous plant’s constituents, delta-9-tetrahydrocannabinol or, for short, THC.

Equally versatile, but with some side effects that can be minimized by cannabidiol, THC already forms the basis of two medicines, one in the United States and the other in the United Kingdom, both indicated for use against nausea and vomiting in chemotherapy treatment against cancer. The French, observing one of the phenomena resulting from the consumption of Cannabis sativa – intense hunger, created a category of medicines that block the molecules of the surface to which the THC binds itself, thus helping people to lose weight, according to tests already carried out. The company GW Pharmaceuticals, with its head office in England, combined cannabidiol and THC in equal proportions in a medicine approved in Canada in 2005 against pains resulting from multiple sclerosis.

The scientific papers that relate to the effects of cannabidiol and THC, serving as the basis for new medicines, inevitably can be traced back to pioneering research that began to be carried out some thirty years ago by a team at the Federal University of Sao Paulo (UNIFESP) led by professor Elisaldo Carlini, of which Zuardi was a member. The discoveries have been increasing the knowledge about the plant also called the devil’s herb because of its narcotic power: in the end, one is dealing with the illicit drug most consumed in the world. According to the Brazilian Information Center on Psychotropic Drugs (Cebrid), 6.9% of the Brazilian population has already used cannabis at least once in their lives – a result below that of the United States (34.2%), the United Kingdom (25.0%) or Chile (19.7%). Its social impact, nevertheless, may not be as intense as has been imagined. According to the Cebrid, the number of dependents will reach 1% of the country’s population, the equivalent of around 450,000 people. Of the 55,000 hospitalizations caused by drugs, registered during 2005, only 1.3% was associated with cannabis and 90% were due to alcohol.

Fibers in the Portuguese man-of-war 
Originating from Asia, with elongated and jagged leaves, the Cannabis sativa can reach a height of 3 meters. Its stock provides a highly resistant natural fiber, hemp used in the sails of the Portuguese ships that arrived in the city of Salvador in 1500. Some decades later hemp seeds arrived, hidden in the cloth dolls ties to the ends of the loincloths of negro slaves, according to the book Cannabis sativa L. e substâncias canabinóides em medicina [Cannabis sativa L. and cannabinoid substances in medicine], published by the Cebrid.

At the beginning of the last century, hemp stopped being used whenever its synthetic equivalents began to be produced. Later an association was created between the habit of smoking the leaves and flowers of this plant with the lowest classes of the population and with madness. Today these relationships are seen with restrictions by researchers such as Franjo Grotnhermen, from the nova Institute for Ecology and Information, of Germany, who demonstrated how inconsistent they are in an article published in the May 15th edition, this year, of the medical magazine, Lancet.
The plant’s negative image, which has turned it into an icon of rebellion, began to be unmasked some 40 years ago with the identification of the chemical structure of its components and the discovery of how they could function in the organism.

Research into the plant’s effects began to gain legitimacy mainly with the discovery of the surface molecules of the nerve cells, the so called CB1 and CB2 receptors, to which the THC links itself. Then a torturous question was raised: would the nervous system have a natural mechanism to deal with the THC? This doubt was only uncovered when Raphael Mechoulam, from the Hebrew University of Jerusalem, In Israel, isolated a molecule very similar to the main active ingredient of cannabis, which was given the name anandamide – in Sanskrit, “ananda” signifies well-blessed. This would be only the first of the endogenous cannabinoids, chemical messengers produced when the nerve cells are stimulated and consumed within a few seconds.

Against insects
As well as THC, cannabis contains another 65 substances called cannabinoids, which can exercise some effect upon the neurons – the majority of them have been only slightly studied. Some of them have effects opposing each other, such as cannabidiol itself, which inhibits the action of THC. Both present a very similar chemical structure and are formed in the small glandules that mainly cover the leaves and the female flowers of Cannabis. When these fragile glands break apart, a highly powerful narcotic resin is liberated known as hashish, which for the plant should function as a defense against insects.

Responsible for the most well known effects of cannabis, such as sedation and euphoria, the THC has had wide medical applications: it has shown itself capable of dulling pains, nausea and inflammatory processes, as well as stimulating the appetite. Such wide versatility explains why this plant had begun to be cultivated and used with medical endpoints in China around 6,000 years ago. Its therapeutic use reached a climax at the end of the 19th century when it was easy to obtain quality extracts, until it diminished drastically during the first decades of the last century, “to a large extent due to the difficulty in obtaining consistent results of plant samples with different potentials”, wrote Dr. Zuardi in an article published in the Brazilian Psychiatry Magazine.

Against pains
Studies carried out in Brazil, the United States and England indicate that  THC can help to mollify health problems such as Aids, arthritis pain, multiple sclerosis and insomnia. “There’s no longer any ethical justification for doctors not to prescribe THC”, comments Carlini, a pioneer in Brazil in the study into the effects of cannabis. One of the latest pieces of research, carried out by a team at Imperial College London and published in May in Anesthesiology, indicates that the cannabis extract – a mixture of cannabinoids, predominantly THC – helps to alleviate the pain that comes about after surgery, with minimal side effects when in low doses; higher doses cause nausea and tachycardia.

Isolated THC presents other undesirable effects such as a languid smile and uncontrolled laughing, which can last two or three hours, according to the description of an 1888 edition of Formulário e guia médico [Formulae and medical guide], by Pedro Luiz Napoleão Chernoviz, that professor Carlini takes down from his bookcase and reads with care – here there are also uses that today are hardly mentioned, such as the treatment of chronic bronchitis and different types of breathing difficulty or dyspnea. He himself, in a revision article published in 2004 in Toxicon, mentioned other risks: THC can also reduce the capacity to discriminate time intervals and distances, vigilance, memory and the ability to carry out mental tasks and to generate disconnected thoughts, anxiety, panic reactions, delusions or hallucinations. Up until now cannabidiol has only presented one side effect, sedation, in very high doses.

It is for these reasons that that cannabidiol could be adopted in the first instance to reduce the undesirable effects of THC – a possibility that strengthens the work that has been developed since 1998 by GW Pharmaceuticals with Sativex, a medicine that combines the two compounds in equal proportions. The alliance between the two brother substances could go beyond multiple sclerosis, the illness for which Sativex has already been approved for medical use by the Canadian government. In the United States, the Food and Drug Administration (FDA) has qualified it as a new drug under investigation (IND), permitting the initiation of tests in search of alternatives to reduce the pain for people with cancer.

In order to show the mechanisms through which the combination of cannabidiol and THC can act and avoid the undesirable side effects of using THC on its own, in an article published in 2005 in the magazine Medical Hypotheses, Ethan Russo, a researcher with GW and the universities of Washington and Montana, both in the United States, based himself on the rich crop of papers produced between 1970 and 1985 at the UNIFESP laboratory headed by Carlini and still today mentioned in exploratory studies into Cannabis sativa. Carlini and his then doctorate student Jomar Medeiros Cunha, today a full professor at the Federal University of Uberlândia, in Minas Gerais State, had demonstrated that cannabidiol reduced the convulsions of epilepsy patients by half. It was also Carlini who showed that in animals cannabidiol sometimes amplified and at other times blocked the effect of THC. It was only in 1990 that professor Guimarães, from USP in Ribeirão Preto, resolved this mystery by demonstrating that the conflicting results observed in animal models of anxiety with cannabidiol could be explained by the dose: low doses produced ansiolytic effects, whilst high doses did not.

When he was working at the Carlini’s laboratory, between 1976 and 1980, for his doctorate degree, supervised by professor Isaac Karniol, Zuardi did something daring: he tested the two compounds on eight healthy volunteers, who knew about cannabis from word of mouth. Each week they received a placebo, cannabidiol, THC, a mixture of cannabidiol with THC or diazepam, a very well known anxiolytic drug, which served as an active control. The THC, on its own, produced anxiety and psychotic symptoms such as intensive thought alterations, which diminished considerably when the study volunteer would also receive cannabidiol. “It was the first indication of the possible ansiolytic and antipsychotic effects of cannabidiol”, explains Zuardi.

Some two years ago his student José Alexandre Crippa coordinated an experiment that demonstrated by way of images of the nervous system that cannabidiol activates the regions of the encephalon associated with anxiety, in which the blood flow was increased. Also helping to deepen and to explain the studies carried out 25 years earlier, Leonardo Resstel, Fabrício Moreira and Sâmia Joca, from the professor Guimarães laboratory, in a study accepted for publication in Behavioral Brain Research, showed that cannabidiol can function as well as diazepam in reducing conditioned fear in rats.

The studies with schizophrenia are less mature. In 1995 Zuardi treated a 19-year-old woman who suffered from serious side effects when using haloperidol and other medicines indicated for schizophrenia. In this case the cannabidiol functioned well. But in another case, with three participants resistant to conventional treatment, the cannabidiol brought only modest gains, indicating that the people resistant to other medicines also did not present a good response to this component of Cannabis sativa.

Even at that there are good prospects. A revision article published at the beginning of the year in the Brazilian Journal and Biological Research proposed that cannabidiol can bring benefits to schizophrenic patients who have not shown resistance to other medicines. With one advantage: without causing muscle rigidity and the tremors that can come about with the anti-psychotics normally used. “Haloperidol activates two regions of the nervous system, the limbus areas and the base nuclei, leading to the maintenance of abnormal posture”, observed professor Guimarães, “whilst cannabidiol activates only the limbus areas”. The initial results of a test with dozens of people coordinated by Markus Leweke, from the University of Köln, in Germany, indicates that cannabidiol can act as well as amisulpride, another anti-psychotic widely used.

“Valuable opportunity”
If some doors open others however, close. At the end of April the FDA put out a declaration that prohibited any use of the medicine from cannabis, reinforcing the division between the federal government and the eleven American states that have already approved the use of the drug to alleviate pain. The communication generated protests with the argument that there had not been evidence of safety and efficiency in the medicinal use of cannabis, although the American Medical Association  itself had recommended in 1999 that the use of the plant against nausea, loss of appetite and anxiety should be studied more intensely, in the face of the positive results that had been obtained. “Scientifically, related professor Guimarães, “there’s no way of justifying these restrictions”.

However, he is wagering: from this research will come other medicines. In a study published during 2005 in Drugs of the Future, Leonora Long, Daniel Malone and David Taylor, from the Australian Monash University, sustained the idea that the exploration of cannabis constituents such as cannabidiol represent “a valuable clinical opportunity”. Certainly the opportunities of the utilization of the research done in Brazil will be clearer if there was not a vacuum so large between the universities and industry.

For the scientists a new cycle of use of the derivatives of cannabis as a medicine is beginning. “A more consistent use than in the past”, underlines Zuardi. “The structures of the chemical compounds are now known, the action mechanisms in the nervous system are being elucidated and the effectiveness and safety of the treatment is being scientifically proven.”

The harmful effects of Cannabis
Evidently the potential medical indications of Cannabis sativa do not justify its recreational use, marked by a series of harmful effects upon the organism. Red eyes, dry mouth and accelerated heart beat are only the first signs. The habit of smoking cannabis can bring about in men a decrease in testosterone, the hormone that provides muscle mass, makes the voice deeper and actions the production of spermatozoids; in women, the hormonal alterations can even inhibit ovulation. The smoke, by being irritating, can effect the lungs and bring about respiratory problems – the most common being bronchitis. Parallel to the sensation of calm, relaxing and the desire to laugh, continual use can bring on tremors, sweating, anguish and the loss of fear and mental control -” it’s a bad trip, as the users call it. The temporary loss of the capacity of space perception, of short term memory and of abstract thinking can prejudice the performance of activities that demand attention and concentration, such as studying or driving. Continual use can even set off or aggravate psychic illnesses. More information: Cebrid.

The Project
Participation of glutamate and nitric oxide in the physiopathogeny of psychiatric disorders (02/13197-2); Modality: Thematic Project; Coordinator: Francisco Silveira Guimarães – USP; Investment: R$ 501,016.74 (FAPESP)