By Hari Bhathal
Dr. Hari Bhathal is the director of Neurocenter Barcelona, part of the Teknon Medical Center. He has a degree in Medicine and Surgery from the Universidad Autónoma de Madrid and a specialization in neurology from M.I.R.. He completed his subspecialty in epilepsy at the Montreal Neurological Institute.
Subsequently, he has developed his expertise in several prestigious centers, being employed mainly in epilepsy units. He also developed his work at the Hospital Nacional de Parapléjicos (National Hospital for Paraplegics), where he deepened his knowledge of neuropathic pain and spasticity and their treatment.
Throughout his career, he has participated in multiple clinical trials, mainly in epilepsy, as Principal Investigator. In the field of cannabinoids, he has been Principal Investigator in clinical trials with CBD for Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis, and Rett syndrome. He has advised patients with different neurological diseases about the possibility of treatment with cannabinoids.
The cannabis plant has been cultivated for about 8000 years because of the different properties it offers. In antiquity it was mainly used as an industrial product: as construction material, cordage, textiles, and food (oils). Its second, psychotropic, use was not only recreational, but also involved religious rites, shamanism, and divination in different cultures and civilizations. The third main use of cannabis is medical, and in neurology, the first documents attesting to it date back to 2000-1000 BC, mainly in treating epilepsy and pain.
Cannabis contains approximately 100-150 terpenophenolic compounds, the most abundant being THC and CBD. These are the compounds that have most attracted the attention of the scientific community for their possible therapeutic qualities. The chemical structure of cannabinoids and the mechanism by which they act on the brain have been studied since the 1960s. Cannabinoids have specific receptors in the organism (CB1 and CB2), and at the level of the brain they produce retrograde signalling in the neuronal synapse, with a negative feedback effect. This produces anti-inflammatory, analgesic, and anti-epileptic effects. These studies have been carried out on animals and in vitro. Cannabinoids have different routes of administration (oral, inhalation, transdermal), and are preferentially deposited in fatty tissue and in the brain. Side effects are generally considered mild, except in psychiatry, as it can produce paranoid delirium, dissociative states, and panic attacks.
Interest in the therapeutic use of cannabis was reborn in the early 1970s, especially for ailments and diseases without effective pharmacological treatments. It was approved for compassionate use for treatment-resistant glaucoma and chemotherapy side effects (Dronabinol). With the discovery of CB1-CB2 receptors and endocannabinoids (anandamide) in the early 1990s, research has seen an exponential increase. In neurology, Sativex (THC+CBD) was approved for use in muscle spasticity associated with multiple sclerosis. The medical use of cannabis, both regulated and unregulated, is soaring. Pressure from patients who use cannabis for therapeutic purposes, and from the scientific community, is having an effect, and the regulatory agencies (FDA and EMEA) have approved clinical trials for diverse, mainly neurological, diseases.
There are many neurological diseases that affect patients severely – but without having adequate pharmacological treatments that control the symptoms well. These disorders are usually pain, epileptic seizures, and cognitive impairment: areas where therapeutic cannabis has been traditionally used. If, in addition, scientific research shows that the action of cannabinoids is mainly at the level of the nervous system, study and experimentation at the level of neurological diseases are useful.
Regulatory agencies require that the therapeutic properties of a substance be based on scientific evidence through randomized, double-blind clinical trials. Only in this way can they approve the molecule for use and for its distribution through official medical and pharmaceutical channels to ensure proper use. This use is, of course, to help the patient (efficacy) without harming them (toxicity). In neurology, the diseases approved for study are epileptic encephalopathies, neuropathic pain, and neurodegenerative diseases.
Epilepsy
Most epilepsies are adequately controlled with the available antiepileptic drugs. However, 30% of epileptics, despite treatment, still have seizures that affect daily functions: these are known as drug-resistant epilepsies. The most serious of these are epileptic encephalopathies. These are diseases that appear within the first year of life, and produce severe and frequent seizures resistant to antiepileptic medication. In addition, they have a serious impact on neurological development, causing psychomotor retardation.
The first epileptic encephalopathy to be successfully treated with CBD was Dravet syndrome (severe myoclonic encephalopathy in infancy). After several families successfully treated their children with this disease, and several neurologists in the US started open trials with their patients and noted its efficacy, regulatory agencies decided to test CBD via randomized clinical trials. The results have been convincing in terms of efficacy in the reduction of seizures (in some cases with total elimination of seizures), with some overall neurological improvement, and an acceptable level of side effects. Following these results, in 2019 the agencies have approved a pharmacological preparation of CBD (Epidiolex) for use in Dravet syndrome.
The next epileptic encephalopathy to begin clinical experimentation with CBD was Lennox-Gastaut syndrome. Here, too, the results of the clinical trials were positive. Efficacy was found to be superior to placebo in reducing the number and frequency of seizures, with an acceptable rate of side effects. The pharmacological preparation of CBD has also been approved for use in this disease.
Other epilepsies being studied with CBD are tuberous sclerosis, infantile spasms, and Rett syndrome. Although we do not yet have firm results regarding its efficacy and tolerability, we already have a considerable number of patients who have been treated.
These positive data in the most severe epilepsies show that CBD has undoubted anti-epileptic activity. In future, research and experimentation on its use will likely be extended to other drug-resistant epilepsies, adding to our therapeutic arsenal for these highly treatment-resistant epilepsies.
Chronic neuropathic pain
Chronic neuropathic pain is another condition that currently has poor therapeutic results. It is defined as a pain with certain particular characteristics: unpleasant tingling, cramping, burning, and electric-like shocks. It is usually persistent and resistant to pharmacological treatment. It significantly affects mood, sleep, and the ability to concentrate intellectually, and thus the patient's daily functioning in all spheres of daily life.
Unlike visceral or musculoskeletal pain, produced by injury to these organs, neuropathic pain is caused by direct injury to some structure of the nervous system. It may be due to lesions of the areas of perception in the brain, or to lesions of the spinal cord, nerve roots, and peripheral nerves. At the central level (brain and spinal cord) the most common causes are stroke, migraine, trauma, and central sensitivity syndromes (fibromyalgia, among others). At the peripheral level (which is much more frequent than at the central level), the usual causes are compression due to hernias (lumbosciatica) and tumours, trauma, neuralgia (trigeminal and due to herpes virus), as well as peripheral neuropathies of metabolic origin (diabetes, autoimmune diseases). Clearly, there is a multitude of causes, and the fundamental treatment is to remedy the root cause as soon as possible.
When the initial treatment of the cause is not effective, neuropathic pain tends to become chronic. A variety of pharmacological, physical, psychotherapeutic, and sometimes surgical therapies are then applied, preferably using a multidisciplinary approach (under the joint supervision of a team of several medical specialists).
Currently, the most commonly used cannabinoid for neuropathic pain is CBD, and to a lesser extent THC, with promising results in small uncontrolled observational studies. The clinical studies conducted to date suffer from a small number of patients, different routes of administration, and highly variable THC/CBD ratios. Results are therefore divergent and not easily reproducible. It is necessary to design a randomized double-blind clinical trial once doubts about the route of administration, THC/CBD ratio, and dosage are cleared.
Multiple Sclerosis/Spasticity
Multiple sclerosis was the first neurological disease for which cannabinoids were approved for use – specifically, to improve spasticity and muscle spasms suffered by patients with advanced stages of the disease. Several clinical trials proved its efficacy beyond doubt, which led in 2010 to the approval of a THC+CBD spray (nabiximol) for this therapeutic indication.
Further observational studies in multiple patients with sclerosis suggest that nabiximol used for spasticity also produces improvement in other symptoms of the disease such as neuropathic pain, bladder dysfunction, fatigue, and sleep disturbances.
Neurodegenerative diseases
Neurodegenerative diseases are largely caused by oxidative stress that ultimately leads to selective neuronal death. The most common and well known are Alzheimer's disease and Parkinson's disease. These diseases are inexorably progressive, and currently we have no curative therapies: only treatments that improve the symptoms.
With the discovery of the mechanism of action of cannabinoids, which act with inhibitory feedback signals at the neuronal synaptic level, it was also observed that they act on oxidative stress pathways. Thus, it has been thought that CBD could be a candidate for neuroprotective treatment in these diseases, preventing neuronal death. Preliminary in vitro studies are promising, but the few clinical studies to date have not been positive.
This possible neuroprotective effect, which could prevent selective neuronal death, has also been postulated as a treatment for similar diseases such as amyotrophic lateral sclerosis, Huntington's disease, and perinatal anoxic encephalopathy.
Other neurological diseases
Because of the knowledge of the endocannabinoid system at the cerebral level, and the therapeutic success in epilepsies and spasticity, the study of cannabinoids has been extended to many other neurological diseases.
Its application to movement disorders is being studied: tremor, dystonia, and tics (specifically Tourette syndrome).
Due to its possible neuroprotective effect, it is thought that its use in the early stages of stroke and craniocerebral trauma would be beneficial.
Conclusions
We have witnessed the enormous interest that cannabinoids have aroused in the last two decades in relation to neurological diseases. Basic research in this field has grown exponentially. Along with pressure from patient associations and medical communities, regulatory agencies have encouraged clinical trials that have demonstrated efficacy against several neurological conditions based on scientific evidence. The success in this field is encouraging researchers to look for more neurological diseases where the use of cannabinoids can be beneficial. We believe that it is a new therapeutic approach that can provide new solutions to conditions that are very resistant to treatment.
