Regulatory Models for Cannabis In order to be able to develop and regulate a drug, it is necessary to meet safety and efficiency requirements, in addition to passing certain clinical trials. After this, the drug is approved, commercialized and recognized as medical. For cannabis and other medicinal substances to be included in the current pharmacopoeia, new regulatory models are required.
To begin, let’s clarify the difference between two terms used interchangeably, but that actually have different meanings. When using the term “drug”, we refer to a chemically active substance that affects the body, causing biological changes through chemical reactions that modify cellular activity. These substances are used for diagnostic, therapeutic or preventive purposes.
Pharmaceuticals are the combination of one or more drugs, along with a series of excipients, which will be put in the market and eventually used for industrial or clinical purposes. Hence, pharmaceuticals are the commercial version of drugs, and exist in different formats: pills, dragées, granules, suspensions, liquids, etc. Although both have the same functions, their pharmaceutical presentation is different.
As mentioned before, in order to be able to develop a drug and eventually regulate it, it needs to meet certain safety and efficiency requirements, in addition to passing a series “clinical trial phases”. At the moment, this is the only way that regulatory agencies can supervise drugs, which, once commercialized, will become pharmaceuticals.
In order to be able to include cannabis, and other substances derived from plants with medicinal benefits, in the current pharmacopoeia, other regulatory alternative models different from those in existence need to be implemented.
Evidence-Based Medicine and Clinical Trials
“Evidence-based Medicine” or EBM is an approach to medical practice intended to optimize decision-making by highlighting the importance of the use of evidence obtained through scientific research. It demands that medical recommendations be based on firmly established facts, that is, on scientific data resulting from controlled clinical trials, meta-analysis or systematic reviews, among others.
Let’s apply this to the case of cannabis. In order for cannabis to be recognized as a pharmaceutical, clinical trials would need to be carried out by randomly assigning different treatments to a group of patients. After giving cannabis to one group, and a placebo to another, the results of both treatments would be compared and a conclusion about the efficacy of each would be rendered. Once a sufficient number of patients have been treated and the efficacy with respect to the placebo has been observed to be statistically significant, the drug would be approved as a pharmaceutical.
For over six decades, this has been the prevailing way of understanding medicine, and clinical trials have been considered the main pattern for drugs to become pharmaceuticals based on the data yielded by these trials. Furthermore, by considering clinical trials as the only way to regulate a drug, evidence-based medicine has replaced clinical experience and other medical or scientific non-biomedical disciplines.
EBM is criticized, among other things, for being difficult to implement in real-life conditions since clinical trials are based on uncommon settings regarding the selection, treatment and observation of the participating subjects. Moreover, its poor reliability is also observed; the argument about statistically-proven evidence is not convincing.
Furthermore, there is no scientific evidence proving that EBM should be preferable to data produced by other disciplines. Science does not compete with a single field; it is rather a method by which completely valid results can be obtained through different methodologies that do not necessarily involve clinical trials.
Legislation Makes the Process More Difficult
To all this, it must be added that drug legislation not only hinders research on cannabis and other narcotic substances or drugs, but also prevents that cannabis and other substances derived from plants with therapeutic benefits may enter the pharmaceutic market.
The truth is that there is no drug legislation that prohibits the scientific or medical use of cannabis or any other drug. As a matter of fact, it is administrative rules that are responsible for hindering research considerably and that other drugs become pharmaceuticals. In Spain, for example, the law that regulates clinical trials is the Guarantees and Rational Use of Medicines and Medical Devices Law.
In 2006, a regulation came into force in Europe according to which clinical trials can only take place when treating patients with drugs that have met very specific manufacturing standards known as Good Manufacturing Practices for Medical Products (GMP). Because of this regulation, the ability to develop and regulate a drug, so that it becomes a pharmaceutical, is in the hands of the pharmaceutical industry, to the detriment of independent research due to the costs involved of having to manufacture them under very specific conditions.
The Case of Cannabis…
Before delving further into the case of cannabis, and in order to better understand it, let us recall some of the most important methods used in EBM to demonstrate that a drug is effective. In the second place, we find randomized controlled clinical trials, and in the first, the most ideal method, the so-called, and already mentioned, “meta-analysis”, which is nothing more than a combination of clinical trials analyzed by using a very complex statistical technique.
The cannabis plant contains more than 400 chemical compounds, among which are terpenes, flavonoids and cannabinoids. The latter are compounds synthetized naturally by the plant itself. To date, 104 cannabinoids have been discovered, each with its own characteristics and properties. Although tetrahydrocannabinol (THC) is the best known among them and the one responsible for the psychoactive effects of cannabis, there are others that are starting to be known. This is the case, for instance of cannabidiol (CBD), which acts as antipsychotic and anxiolytic, or cannabinol (CBN), which has 10% psychoactivity compared to THC.
So far, enough clinical trials with cannabis or cannabis products have been conducted to reasonably argue that it has therapeutic uses. We have two recent and extensive reviews of the data obtained during these trials. In the review that goes from 2005 to 2009, 37 clinical trials involving more than 2,500 patients, were collected. In another more recent review, which runs from 2010 to 2014, 32 clinical trials involving more than 3,000 patients were collected.
This means that there are more than 5,000 patients who were treated with cannabis or cannabinoids in over 60 clinical trials. From 2014 until now, more trials have been carried out. As it is to be expected, not all the results have been positive. Cannabis is not a magic medicine, and as it is the case with any other drug or pharmaceutical, in some instances it yields positive results and in others, negative.
In an attempt to determine the level of evidence of the controlled clinical trials, these get sifted through the statistical sieve known as meta-analysis. The results obtained, indicate that the efficacy of cannabis is moderate, for instance, in the treatment of chronic pain and spasticity. They even show a low level of evidence in what concerns the treatment of nausea and vomiting caused by chemotherapy or sleep disorders. Moreover, they conclude that cannabinoids are associated with an increase in short-term effects considered non-severe.
However, when the clinical trials are analyzed from a clinical point of view, keeping into account clinical observation and the benefits obtained by patients in the context of their illnesses instead of considering the results of meta-analysis, we discover that the level of evidence goes from low to moderate or high.
… And Its Contradictions
The case of cannabis is also quite particular, because the plant affects everyone differently, our bodies react to it in their own distinct ways. It is known that, even in the clinical trials with Sativex to treat multiple sclerosis, some patients react to it and others don’t. Therefore, before starting a clinical trial, patients who react to cannabis are separated from those who don’t. Hence, flexible methods are beginning to be created for clinical trials because if they were exclusively understood under the rigidity of meta-analysis many pharmaceuticals in use today would not have been approved.
Moreover, cannabis produces adverse effects, but they are milder than those of other medications. We speak of a product that, regardless of its effectiveness, is quite safe to use. We have enough information based on clinical trials to affirm that cannabis-based medication is very safe.
We say cannabis-based medication because, when it comes to evaluate the effectiveness of cannabis, there are very few clinical trials that have tried it in its pure form. The bureaucratic and legal issues are an obstacle for doing research with the plant. The majority of clinical trials have been performed with isolated cannabinoids, which do not have the same effects when used in conjunction with other cannabinoids, this due to the so-called “entourage effect”.
In fact, there are countries where the entire plant has been regulated as in some states of the United States, Canada, Argentina, Uruguay, Czech Republic, Germany, Italy, the Netherlands, Poland, and Israel. Other countries that have some form of regulation in place usually approve cannabinoids such as THC or some form of cannabinoid-based pharmaceuticals.
Thus, to regulate or to create a medical cannabis program, it is not necessary to go through the clinical trial phases, at least that is what the experience of other countries shows. In fact, The Single Convention on Narcotic Drugs of 1961, which prohibits the use of cannabis, does not prohibit the possession or use of narcotic drugs for medical or scientific purposes.
In addition, in 2014, The International Narcotics Control Board (INCB), the body responsible for overseeing drugs, published a report explaining the control measures applicable to medical cannabis use programs. In other words, the document discusses the requirements that countries around the world should meet in order to implement such a program. It makes clear that the Single Convention allows member states to use cannabis for therapeutic purposes, hence, the regulation of cannabis is only a matter of the political will of each country.
Another important aspect worth noting is that cannabis is not altogether efficient when studied in controlled clinical trials, because these are based on a main variable. However, medical cannabis users use it less for its curative properties than for its ability to improve their quality of life. The pain may decrease with it but will not be eliminated, so opiates will always be required; at the end of the day cannabis will help decreasing opiate consumption. For this reason, meta-analysis will not conclude that cannabis is effective in improving quality of life, because this is simply not a main variable in any clinical trial.
Of what there is in fact more and more evidence is that cannabis can replace many prescription drugs. It can replace or help reduce the use of medication against pain, anxiety or sleep-related problems, among others. Furthermore, it is proving very helpful in the face of the opiate crisis currently taking place in the United States, where 90 people die each day from opiate overdose. American states with access to medical cannabis have a lower rate of this type of incident.
The Ibogaine Case
Ibogaine has a somewhat similar history. The Tabernanthe Iboga shrub is an African plant, which grows mostly in the Congo, Gabon, and Equatorial Guinea. It is native to Equatorial Africa, an area where traditionally some tribes such as Pygmies and Bushmen use the bark of the root to go hunting or for their magical religious rituals. The bark of the root is cut, crushed and made into a powder.
Its active ingredient is called ibogaine, which has a remarkable ability to treat physical dependence associated with the withdrawal symptoms of heroin, methadone and other opiates, and for this reason, it is used as treatment for these addictions. It is legal in most countries.
Although there have been few studies on this substance, the research is conclusive in what concerns its anti-addictive effects, and recently two observational studies have been published confirming that ibogaine is also useful in the treatment of opioid dependence.
Once again, there has not been a single controlled clinical trial or meta-analysis that arrives at the same conclusion, but this does not mean that ibogaine is not being used by patients and doctors. As a matter of fact, although this substance has not met the usual requirements for drugs to become pharmaceuticals, in countries such as Canada, the Brazilian state of Sao Paolo, Nigeria, South Africa, and in New Zealand, there are already specific places that allow the use of ibogaine for the detoxification of opiate dependence.
Again, this means that regulation allows certain drugs to be regulated without having to undergo standard procedures, simply because there are a sufficient number of patients and doctors who are using it in medical practice.
The Case of CBD
And to finish, let’s briefly review the case of cannabidiol, which is the object of much publicity. Again, CBD has been regulated in countries such as Brazil and many American states, not on account of clinical trials carried out to test its efficacy. To date, there are very few trials conducted with CBD, although there are a few more underway.
It has been the experience of patients and their relatives, together with the pressure they have put on governments by mobilizing, which at the end has forced the authorities to regulate CBD. This is a new example of a drug that does not necessarily have to follow standard regulation models.
One of the contradictions presented here is that CBD is not controlled in the 1961 convention either, so there is no reason why CBD could not be in the market. But the same document forbids any type of extraction of the cannabis plant. Even so, some countries have bypassed international legislation and allow the extraction of CBD from the cannabis plant, such as the Czech Republic, Germany, the United Kingdom, Belgium, Italy, and the Netherlands, which can also export to other countries in the European Union. The sale of CBD products cannot be prohibited, because the free trade agreements of the EU would be violated.
And there is yet another paradox; in the US, in almost every state where there are medical cannabis programs, and in others where there is none, there are specific CBD regulations. At the same time, the DEA has decided to include CBD in Schedule 1 of Controlled Substances.
Although the level of evidence is low due to the few studies or clinical trials that have taken place, there is a subculture very close to CBD, and also very widespread, which prescribes this substance for many diseases and ailments without data evidencing its efficacy in humans. We are referring to a product whose effectiveness has not yet been demonstrated by science, but its safety has, in the case of most illnesses. Nonetheless, courageous people, patients and many physicians have gone ahead to advance both science and the laws.
Society Moves Ahead
Cannabis, ibogaine, and CBD are three different products of plant origin with different legal status, different levels of implementation in medical practice and different regulations depending on the country. But there are other psychoactive plants, such as ayahuasca or peyote, very little studied, whose use is increasing because people find them beneficial.
Therefore, it is essential that alternative regulatory models be established to be able to use these substances, these drugs, in contemporary medicine. It has been demonstrated that, in many occasions, evidence based on the patient is more relevant than evidence based on science. The former must be scientifically researched so that regulatory agencies take it into account.