Cannabinoid Drugs and Medical Cannabis

On 2 May, the Regional Council of Tuscany approved by majority vote a law that will make it easier for residents to use cannabinoid drugs as opioid adjuvants in pain therapy and palliative treatment of chronic debilitating conditions (AIDS, anorexia, cachexia, etc.) . To this end, hospitals and local health authorities will ensure the import of cannabinoid drugs, which will be administered under the supervision and at the expense of the regional health system.

Meanwhile, across the Atlantic, the DEA (Drug Enforcement Administration) is cracking down on dispensaries of the so-called Medical Cannabis, the therapeutic use of marijuana and cannabis plant preparations. In the U.S., according to a federal law, Cannabis is still included in Schedule-1 along with heroin and cocaine, as, according to the FDA, the U.S. drug agency, it has addictive properties while being devoid of adequate therapeutic benefits offsetting the danger of addiction. However, while according to the United States federal law the production, sale and use of cannabis is prohibited in all respects, in 16 U.S. states and the District of Columbia (including Washington) the cultivation and sale of cannabis is allowed for the compassionate treatment of patients suffering from advanced or terminal stage chronic diseases like cancer, AIDS, multiple sclerosis, anorexia etc.
In 2011, Obama had sought to mitigate this contradiction between the restrictive federal law and lax state laws, a source of incurable conflict of laws, by urging district attorneys not to enforce the federal law and therefore not to prosecute the medical use of cannabis in States where such use is legal. However, as is known, federal law prevails over States law. Moreover, especially in a number of more permissive states, such as California, Colorado, Michigan and Montana, the Medical Cannabis has become a shortcut to produce, market and consume cannabis for pleasure and leisure purposes.
In states where the cannabis therapeutic use is permitted, Cannabis is bought in special Cannabis dispensaries, full-fledged supermarkets for all existing varieties of Cannabis, by exhibiting a Cannabis Card issued by physicians enrolled in a special register. This mechanism has allowed the creation of a huge business that involves not only growers, retailers and doctors, but a myriad of secondary players, such as companies that manufacture vaporizers, restaurants that prepare food based on marijuana oil and butter, pastry shops that make sweets from Cannabis and so on. The spread, beyond any realistic compassionate or therapeutic need in states where the cannabis use is legal, has convinced Obama to crack down on the therapeutic use of Cannabis.

Figure 1: Inside a Medical Cannabis Dispensary in California.

What's wrong with the Medical Cannabis system made in U.S.A..? The answer is simple: the fact that it has allowed the use of Cannabis herbal preparations for therapeutic purposes (marijuana, hashish, etc.). This resulted in the intake of Cannabis active ingredients through smoking or vaporization. In practice, state laws legalizing Medical Cannabis do in in fact encourage its use for recreational purposes.

Not least, because smoking, as it fails to ensure a predictable and reproducible dosage of the active ingredient in cannabis, the THC, is a pharmacotherapeutic nonsense.As is known, in fact, the amount of THC absorbed through smoke varies widely depending on the THC content in the preparation, whether there is any tobacco in it, the depth and length of inspiration, for how long the smoke stays in the lungs; in practice, on a series of individual and environmental variables that it is impossible to control.The same applies, at least in part, to vaporization, which in any case involves once again dispensing herbal preparations with no control on their mode of use.Therefore, while it is true that inhalation is the most effective route for THC absorption, its dosage by this route is not reproducible nor predictable in advance.Indeed, no controlled clinical-therapeutic trial has ever been undertaken using Cannabis herbal preparations administered by smoking or vaporization.

Thus, if one excludes the use of standardized Cannabis extracts ( Sativex ) which provide a per application dose for spray application and absorption through the buccal mucosa, the only rational therapeutic use of cannabinoids is the oral administration of synthetic analogs, a ground that has already been successfully explored with opiates and that led to the introduction of narcotic analgesics with high oral bioavailability, such as methadone, meperidine, fentanyl etc...
This route is also open for cannabinoids, as a long series of THC synthetic analogues is nowadays available, which are powerful and with high oral bioavailability, some of which have already been introduced in the illegal market to strengthen the effectiveness of cannabis preparations low in THC.

Cannabis and social risk

Against the background of this contradictory scenario, there comes the policy change taking place in the Netherlands, which in October of 2011 included marijuana with a THC concentration exceeding 15%, in the stupefacients' Table, and, therefore among hard drugs, and, since 1 May of this year, has banned the sale of Cannabis to non-residents in the South and, from January 2013, throughout the whole country, including Amsterdam.The Netherlands decision follows that taken in the United Kingdom in 2009 which reclassified cannabis from being a legal substance (Table C) to being an illegal one(Table B).

In Italy, the Cannabis, its extracts and active ingredients (delta 8 - and delta9-THC) are included along with heroin and cocaine in Table 1, due to their addictive properties.
Following Ministerial Decree of 18.04.2007, the Cannabis active ingredient, THC, its isomer, trans-THC, and its analogue, nabilone, have been included in Table 2, which comprises drugs capable of producing addiction, like morphine, but with therapeutic utility. It should be noted that cannabis and its preparations (marijuana, hashish, hashish oil) are included in Table 1 but not in Table 2, which rules out the possibility for Cannabis and its preparations to be sold and used for therapeutic use.

The decision of the Tuscany Region to facilitate import of cannabinoid drugs for therapeutic purposes is therefore in line with current legislation and does not mark a turning point. Also from a general therapeutic point of view the actual therapeutic advantage is very limited. Cannabinoids are second-line drugs , used as a complementary therapy in treatments based on drugs that have proven their efficacy in controlled trials and through a long post-marketing experience. This is the case of pain therapy, for which first-line drugs are opioids and narcotic analgesics while cannabinoids may play, in selected cases, the role of adjuvants, enhancing the effect of narcotic analgesics. The same applies to the treatment of spasticity in multiple sclerosis, in which the Cannabis extract applied as an oral spray, has proved to be more effective than placebo in controlled clinical trials. Therefore, the media impact of the Tuscany Region opening to cannabinoid drugs transcends the health field and relates to politics rather than medicine.

The American experience shows that Cannabis legalization for therapeutic purposes, if extended to its vegetable derivatives and not subject to appropriate checks by the health system, is actually a shortcut for a non-therapeutic use on a large scale. For this reason, the decision of the Tuscany Region to facilitate dispensing cannabinoid drugs, if restricted to non-herbal preparations (e.g. Sativex) or analogues of natural cannabinoids (e.g. nabilone) and carried out under strict medical supervision, limited to the diseases and conditions recognized as benefiting from the use of cannabinoids on the basis of controlled clinical trials, and monitored with regard to any non-medical use, should have no impact or consequences on consumption or the legal status of cannabis plant preparations used as drugs.

In practice, contrary to what the supporters of free cannabis may think, the two phenomena, the therapeutic use of cannabinoids and the ''recreational'' use of marijuana are destined to diverge, just as it happened with narcotic analgesics, drugs with a double identity, which are criminally prohibited when produced, prescribed and used for recreational purposes (i.e. as a drug) but which can be prescribed as analgesic in a variety of clearly specified conditions. Therefore, while, on the one hand, cannabinoids acquire a medicine status, albeit as second-line medicines intended for palliative therapies (with all the caveat mentioned above), on the other hand, the restrictions on the use of cannabis for recreational purposes increase due to a change in the perception of social risk associated with it.

Explaining the change

This change is the result of two processes: 1) scientific advances in understanding the Cannabis mechanism of action, 2) the selection and marketing of varieties of Cannabis that are cultivated in greenhouses or in hydroponic conditions and which have a THC concentration (15-20%) 20 -40 times higher than that of endemic Cannabis (0.5-1%)..

As for the scientific aspects, until the '70s it was thought that the active ingredient in cannabis, the THC, acted as alcohol by changing the state of aggregation of lipids and proteins in neurons membranes due to its high lipid solubility. It was instead discovered that in the brain of mammals including humans there is a finite number of saturable binding sites, to which THC binds with high affinity and in a stereospecific way and whose brain distribution is consistent with its central effects. In the brain these receptors (CB1 and CB2) are actually the most abundant in their class (G-protein linked receptors) exceeding those of well-known neurotransmitters such as dopamine, serotonin and norepinephrine. Similarly to morphine and opiate receptors, the reason for CB1 receptors presence in the human brain is not to enjoy the rewarding effects of cannabis nor to become dependent on it, but because they play an important role in brain functions. There are in fact a series of endogenous agonists of CB1 receptors (anandamide,2-Arachidonoylglycerol) which are produced locally by specific enzymes acting on lipids that make up the neurons and glia (Arachidonic acid) membrane and which influence the transmission of information in specific brain areas and in neuroplasticity phenomena involved in learning and brain development.

Cannabis produces its acute and chronic effects as its active ingredient, THC, alters the function of this important central system which uses the endogenous cannabinoids as mediators.
This role of the cannabinoid system explains the relationship, documented by a series of epidemiological studies, between early cannabis use and onset, even after many years, of schizophrenic psychosis. This association is not due to an increased consumption of cannabis by schizophrenic patients as a form of self-medication since, as demonstrated by a recent prospective study, cannabis consumption precedes the onset of psychotic symptoms and anticipates its clinical appearance.
The high density of CB1 receptors in the basal ganglia explains the fact that the impairment of the endocannabinoid transmission alters normal behavior ( habit ) based on motor patterns ( skills ) learned through practice and explains why cannabis can alter driving along a usual route. Under the effect of cannabis a person tries to compensate for the impairment of the automatic mode reverting to a typical beginner mode, the goal-directed mode, which no longer depends on stimuli that precede the action (stimulus-response modality) allowing for a rapid and coordinated development, but on the outcome of the action itself (action-outcome modality) which makes the action inadequate, slow and uncoordinated, precisely as the action of a person who is learning to drive. Alcohol, which is often associated with cannabis, primarily affects the action-outcome modality , thus eliminating even this kind of default mode and severely compromising driving.
Epidemiological studies show that driving under the influence of cannabis doubles the risk of fatalities and amplifies the effect of alcohol, in that their combination results in higher risk than the sum of each factor taken individually.



Figure 2: Distribution and density of cannabinoid receptors in the human brain. Density is mapped by colour. Higher density areas (red, orange and yellow) are the dorsolateral prefrontal cortex, which explains the deterioration of cognitive functions due to Cannabis, the globus pallidus and substantia nigra, which explain the rewarding and reinforcing effects and the alteration of extrapyramidal features (habit), the cortex of the anterior cingulate gyrus, which explains the effects on the tone of mood (increased under cannabis influence, decreased during abstinence), and the amygdala and hippocampus, which explain the effects on memory and anxiety. Taken from: K. H. Taber, R. A. Hurley, Endocannabinoids: Stress, Anxiety, and Fear ; The Journal of Neuropsychiatry and Clinical Neurosciences, 2009;21:iv-113

THC acts on CB1 receptors and stimulates the central neurons that release the dopamine neurotransmitter in a specific area of the brain, the nucleus accumbens shell; all addictive drugs that create dependence in humans share this property. Substances that do not produce psychic dependence, such as caffeine, do not possess this property. From this point of view THC shows close similarities with heroin, since its effect on dopamine and the ability to be self-administered by experimental animals and man are blocked, as is the case for heroin, by naloxone, an antagonist of opioid receptors. THC, unlike heroin, does not directly stimulate opioid receptors, but rather it releases endogenous opioids and this explains the fact that some actions of THC are mediated by opioid receptors.

The new Cannabis "qualitative leap"

These relationships between the endogenous opioid system and the Cannabis active principle are of great importance in light of the second factor determining the change in perception of the Cannabis social danger, namely the marketing of varieties of cannabis with a THC concentration that is 15 - 20 times higher than that of endemic Cannabis. The introduction of these varieties has literally changed the status of Cannabis as a drug. It is somehow similar to the situation when heroin was introduced to replace opium or volatile, cocaine base for smoking (crack ) was introduced as a substitute for cocaine hydrochloride for sniffing.

The introduction of Cannabis varieties from hydroponics or greenhouse growing (e.g. skunk) revealed the true nature of Cannabis, such as its impact on driving, the ability to induce dependence (with a sharp increase in the Netherlands and England, where the skunk varieties are particularly widespread, of people needing drug addiction treatment), the long-term impairment of cognitive functions and memory, and finally, the onset, in predisposed individuals, of symptoms of schizoid personality disorder. All this was widely expected on the basis of scientific knowledge on cannabis. Now, the last frontier in this field is the introduction of synthetic and volatile derivatives of cannabinoid receptors, which, under the name "Spice", .... could be freely purchased on the Internet until they have been included in Table 1, together with heroin and cocaine.

In short, gone are the hippies days, when cannabis was the sweetest fruit of the Garden of Eden ...