Open Journal Systems

REVIEW ARTICLES

Received: November 24^th 2015

Accepted: January 26^th 2016

Cannabis: effects in the central nervous system. Therapeutic, societal and legal consequences

Víctor Manuel Rivera-Olmos,^a Marisela C. Parra-Bernal^b

^aProfesor Emérito Distinguido, Departamento de Neurología, Baylor College of Medicine, Houston, Texas, EUA

^bUniversidad de Guadalajara, Guadalajara, Jalisco, México

Communication with: Víctor Manuel Rivera-Olmos

Telephone: (832) 407 0668

Email: vrivera@bcm.edu

The consumption of marijuana extracted from Cannabis sativa and indica plants involves an important cultural impact in Mexico. Their psychological stimulatory effect is widely recognized; their biochemical and molecular components interact with CB1 and CB2 (endocannabinoid system) receptors in various central nervous system structures (CNS) and immune cells. The psychoactive element Δ-9-tetrahydrocannabinol (THC) can be reproduced synthetically. Systematic reviews show evidence of therapeutic effectiveness of therapeutic marijuana only for certain symptoms of multiple sclerosis (spasticity, spasms and pain), despite attempts for its widespread use, including refractory childhood epilepsy. Evidence indicates significant adverse effects of smoked marijuana on the structure, functioning and brain connectivity. Cannabis exposure during pregnancy affects fetal brain development, potentially leading to later behavioral problems in children. Neuropsychological tests and advanced imaging techniques show involvement in the learning process in adolescents with substance use. Also, marijuana increases the cognitive impairment in patients with multiple sclerosis. Social and ethical consequences to legally free marijuana for recreational use may be deleterious transcendentally. The medicinal or psychoactive cannabinol no addictive effect requires controlled proven efficacy and safety before regulatory approval studies.

Keywords: Cannabis; Medical marijuana; Drug legislation; Drug and narcotic control

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In the sixteenth century, the leaves and seeds of hemp (cannabis) were originally used to produce fibers for fabrics and ship ropes; they were later brought to New Spain by Hernán Cortés in about 1521, and the plant started to be cultivated in the region starting in 1545.

The cannabis plant was already known for over two millennia in China and India, where in addition to its textile utilities, the leaves of the botanical variety indica were processed to be smoked to experience their attractive psychedelic effect. In the form of hashish (Cannabis sativa), which is extracted from marijuana plant resin, it is presented as blocks that, when pulverized, can be used to produce cigarettes or devices for inhalation. This variety spread throughout Persia, the Middle East, North Africa, and its (illegal) consumption continues in Europe and the United States.

Cultural and historical impact in Mexico. Therapeutic accessibility

Due to the influence of African slaves who arrived in Mexico between the seventeenth and nineteenth centuries, and the medicinal effects ancestrally assigned to the plant by popular folklore, it tended to be used secretly in some social levels. Since traditional healers were called "Marías" or "Juanas", with the passage of time the conjunction of terms resulted in the linguistic mix: mariguana, a commonly used word in Spanish, while in English and certain Romance languages ​​the term adheres to the original etymology: marijuana. 

Through history, the regular consumption of marijuana went from being a ritual medicinal act to having a recreational and psychologically stimulating use, being considered in the nineteenth and early twentieth centuries "a bad habit" of "dangerous" social groups: lepers, prisoners, and soldiers.

During the Mexican Revolution of 1910, marijuana use was common both by rebel and federal forces (it was popularly recognized as "mota" or "yerba" [herb]), as well as by government soldiers during the so-called Cristera War between 1928 and 1929.¹

Subsequently, its effects were promoted in Mexico by bohemian intellectuals, artists, and writers since 1920, giving rise to the "rooftop culture" in Mexico City, where "they smoked, discussed, and created" to this day.²

Through cultivation, which is illegal in Mexico especially in industrial quantities, illegal export to the United States (USA), where there is high demand in most states, has been a matter of transnational concern, becoming element of the activities of so-called drug traffickers.

Cannabis: effects on the central nervous system (CNS) and legal consequences  

In Mexico during recent decades, social activism for the liberation of marijuana has been developed by some organizations, such as the so-called Psychoactive Cultural Law and the Mexican Cannabis Movement. The Conde initiatives, introduced in the LX Legislature of the Mexican Congress (2006-2009) by Federal Congresswoman Elsa Conde, did not produce results at that time. More recent political and constitutional efforts, such as the proposal on the right to produce and consume cannabis for personal recreational purposes promoted by the Sociedad Mexicana de Autoconsumo Responsable y Tolerante (SMART), which was presented for discussion at the First Chamber the Supreme Court of Justice of the Nation in November 2015, has caused a great interest in the subject and nationwide controversy.

The legalization of marijuana for recreational use is based on the premise of the need to decriminalize a habit that is theoretically less dangerous and less toxic long-term than smoking and alcoholism, and of course than other illicit drugs, narcotics, and mind-altering substances.

Other groups promote the adoption of formulations of cannabinoids (marijuana derivatives) for medical use, including cannabidiol (CBD). Most of these products are primarily proposed on an anecdotal basis, rather than with evidence.

To properly and rationally assess this public health concern, the Comisión Federal para la Protección Contra Riesgos Sanitarios (COFEPRIS) of the Secretaría de Salud, a body with the responsibility for the approval and monitoring of drugs (and new therapeutic molecules), according to its current statuary structure, would require controlled studies showing convincing and acceptable efficacy and safety data applied to any cannabinoid proposed as a medication. 

There are very few cannabinoids that have met the challenge of controlled trials. Nabilone is the only synthetic cannabinoid of Δ-9-tetrahydrocannabinol (THC) so far approved in Mexico. It is used as second-line treatment for refractory nausea and vomiting caused by cancer chemotherapy and as an adjunct in chronic pain management. Nabilone is categorized in Group II of Restricted Drugs in Section I, Narcotics (Article 226 of the Ley General de Salud, Mexico).  

Two CBD products that have been attributed beneficial effects in the management of certain types of difficult to control childhood epilepsy remain under study and have been given the name of "orphan drugs" by the FDA (the US Food and Drug Administration), adhering to strict institutional and regulatory standards. For humanitarian and compassionate reasons, and because of huge media interest, although studies in the US seeking to establish their actual efficacy and safety have not been completed, in 2015 COFEPRIS approved the use of one of these compounds by a judicial investigation in favor of a Mexican patient. The drug was donated by the pharmaceutical company producing it and sent from the US. This attempt at treatment should be under strict pediatric neurological monitoring.  

The current cultivation of marijuana has been developed with great technical sophistication. THC is the major pharmacologically active chemical component in marijuana plants, mainly in the leaves and unfertilized female flowers.

Depending on the cultivation process and botanical manipulation, the concentration of THC in marijuana plants has increased from 3 to 3.5% in 1980 to over 20% in the last decade.³ CBD is present in a smaller proportion in the leaves and mostly in the stem (hemp), which is virtually free of THC. Chemical analysis has shown only traces of this molecule in hemp,⁴ which was used as material for making paper, fibers, and fabrics, now out of use. The concentration of CBD in certain anatomical elements of the plant has been used industrially for the production of oils that are offered today as another modality for oral medical use, with presumably minimal or absent psychoactive effects. Other constituents without apparent psychoactive properties are: cannabigerol and cannabinol. 

The compounds of marijuana and cannabinoids activate endocannabinoid receptors in the CNS, mainly CB1 and CB2. CB1 receptors are found in high concentration in the hippocampus, cerebellum, basal ganglia, prefrontal cortex, and the limbic system.⁵ (Table I). CB2 receptors are located in immune cells and regulate cytokine discharge.⁶

It is possible that endocannabinoid receptors also interact with neurotransmitters in the CNS, making the pathophysiological effect even more complex.

The international pharmaceutical industry has produced oral cannabis extract (OCE), several CBD products, and synthetic THC compounds. Oral administration as a tablet or oil (favored in pediatrics) produces more consistent and measurable pharmacodynamic and kinetic effects than when smoked, vaporized, or aerosolized by oromucosal spray.

The effect (feeling) of smoking a marijuana cigarette is experienced by the subject after a few seconds or minutes, with a maximum effect after 30 minutes and duration of action of between 2 and 3 hours. The maximum plasma concentration of THC occurs within the first 10 minutes and decreases to approximately 60% of the peak level at 15 minutes and 20% at 30 minutes after repeated inhalation. If the cigarette is shared with other smokers, systemic absorption of THC is between 25 and 27% of the total content.⁷

Medical evidence of effectiveness of cannabinoids

Systematic reviews based on evidence to evaluate randomized controlled therapeutic trials have been conducted by the American Academy of Neurology (AAN),⁸ the Swiss Federal Office of Public Health (SFOPH),⁹ and the Division of Drug and Alcohol Abuse of the School of Medicine, Harvard University.¹⁰

The Subcommittee of the AAN for (Therapeutic) Guideline Development reviewed 1729 documents of the most referenced literature sources in MEDLINE, Web of Science, and Scopus, among others, concentrating data from 63 formal articles, selecting 33 that met the criteria of Class I, II, and III studies providing analyzable evidence.

By assigning levels of evidence to the results of studies using cannabinoids analyzed as "effective", "probably effective", and "possibly effective", CBD and THC showed positive results with different levels of quality in spasticity secondary to multiple sclerosis (MS), as well as central neuropathic pain and painful spasms in MS (Table II).

Results of that review showed results of "probably ineffective", "uncertain efficacy" or “insufficient quality of evidence" for CBD and THC in bladder dysfunction and tremor in MS, Huntington's disease, dyskinesia related to dopamine in Parkinson's disease, Tourette syndrome, cervical dystonia, and epilepsy. Smoked marijuana was classified as "ineffective" or of "uncertain efficacy" in disease entities in which it was studied as a specific treatment modality (Table III).

The analysis by SFOPH was based on 79 studies (6462 participants), but only 4 were considered to have low risk of bias. The findings were similar to those obtained by AAN.

The clinical review discussed by the Substance Abuse Department of Harvard University addressed 28 randomized studies registered in MEDLINE published between 1948 and 2015. The results confirm the effects already mentioned in certain symptoms of MS, such as spasticity and neuropathic pain. All systematic reviews conducted and reported today have independent and consistently arrived at the same conclusions.

Current reviews show robust evidence of therapeutic effects on spasticity and neuropathic central pain but only in MS, without having demonstrated effects on spasticity developed after stroke and hemiplegia, post-traumatic myelopathy, and other etiologies. The main limitations of neuropathic central pain management with OCE include the fact that its effect has not been confirmed to persist beyond 6 weeks, although the studies were designed with 1 year of follow-up.¹¹

While objectively the long-term benefit of marijuana consumption for therapeutic purposes has not been demonstrated consistently, potential adverse effects associated with chronic use are unknown. The notion has also been challenged that the effectiveness of OCE is superior to standard drugs, because no head-to-head comparative studies have been conducted.

The effect of cannabinoids on malignancies was investigated in vitro and in experimental animals, but their clinical indication as primary or adjuvant treatment is not justified given the absence of evidence-based studies.

Its potential usefulness in the management of cancer pain is theoretically feasible but lacks proof from specific studies.

One of the medical aspects that has received great publicity in view of the emotional impact involved is the use of cannabinoids in children with rare catastrophic epilepsies and extreme resistance to treatment, clearly represented by Lennox-Gastaut and Dravet syndromes. For the pilot study using Epidiolex, a natural product in the form of an oil, processed and purified to provide essentially 100% CBD, the FDA granted the product the designation of orphan drug and an identification code as an IND (Investigational New Drug). Epidiolex was administered to 19 children with severe refractory epilepsy in whom on average 12 antiepileptic drugs per patient had failed. Using uncontrolled subjective scales, managed and evaluated by the parents themselves, after 3 months, 33% of patients with Dravet syndrome were reported free of attacks.¹²

Controlled studies with long-term efficacy and safety data are essential to document the real benefit for patients with this type of epilepsy.

Two placebo-controlled studies are being carried out at present, so objective information and more solid and reliable data will be available in the near future.

In some cases, under media pressure and the natural expectations (realistic or not) of patients and their families to obtain extraordinary therapeutic options to address their suffering, humanitarian justifications have resulted in prosecutions, motivating unofficial decisions from regulatory agencies, approving access to cannabis in individual instances for some patients with intractable epilepsy despite the lack of scientific evidence of its enduring effect and lack of long-term toxicity, and despite the fact that the compound has not been legally approved (as in the case of the girl who receives Epidiolex under the provisions of the Third District Court to COFEPRIS). 

Aspects of safety and health concerns. Adverse effects

In the community, and in most countries, there is the traditional concept that the use of smoked marijuana, either sporadically for recreational use, or chronically for physiological dependence, is illegal, inappropriate, and dangerous to health. Nowadays, its use is more common, flexible, and acceptable, as its promoters have organized effective campaigns for social tolerance and legal approval.

Despite the apparent trend to a new sociological attitude towards cannabis, the noteworthy behavioral and psychiatric effects exhibited by some consumers remain an observational concern that is not only hearsay, but also has clinical implications.

Proponents of legalization for recreational and medicinal use show as an example the fact of its legitimization in Canada, Argentina, Colombia, Chile, Uruguay, some countries in Europe, and 20 of the 50 states of the United States of America, four of which have absolute legalization for recreational use and free cultivation (Alaska, Colorado, Oregon, and Washington). This phenomenon of global acceptance and spread of cannabis use, however, entails the appearance of certain clinical circumstances and consideration to be adequately assessed and considered to protect the community.

US government data (National Institute of Drug Abuse, NIH) derived from monitoring attitudes on drug use among middle school and high school students, although indicating that rates remained stable between 2013 and 2014, show that the proportion of eighth graders (equivalent to first year of secondary school in the Mexican education system) who smoke marijuana was 6.5%, up to 21.2% for seniors (equivalent to the last year of high school). Of the whole group of these school ages (13 to 16), 6% reported smoking marijuana daily. 

Increased accessibility of cannabis has apparently been reflected in consistent clinical situations reported in specialized events. The American Academy of Addiction Psychiatry reports a significant increase in visits to emergency services due to health problems related to cannabis, in smoked or edible forms. Between 2007-2012, in states that have legalized recreational and/or medical marijuana, most notably in Colorado, one of the first states to legalize marijuana and its many forms of consumption, emergency room visits increased by 50.4%. However, the greatest increase, of 55%, was found particularly in Hawaii.¹³

Psychiatric diseases associated with cannabis reported as emergencies have included (using terminology from the DSM-5 of the American Psychiatric Association): Cannabis Use Disorder, Cannabis Intoxication, and Cannabis Withdrawal.¹⁴ Another study analyzed 229 patients with the schizophrenia clinical spectrum, with follow-up 10 years after the first hospitalization, showing a high incidence of cannabis use (66.2%) in this cohort, while the correlation with symptoms of psychosis and its early development occurred independently of comorbidities present.¹⁵ It has been estimated that 1% of marijuana smokers are at risk of developing severe psychiatric effects, including hallucinations and suicide.

In susceptible patients with a family history of schizophrenia, cannabis use may unmask some subclinical symptoms.¹⁶ Acute psychosis in schizophrenics exposed to marijuana is considered a psychiatric emergency.

Studies in 1577 Canadian adolescents, aged 12-21, with a high polygenic risk score for schizophrenia who are smokers of marijuana, showed decreased cerebral cortical thickness (using magnetic resonance techniques) compared with young people from the comparison group who had never smoked (137 = -2.36; p = 0.2);¹⁷ the abnormal correlation was more notable in males. The authors used data from 3 large studies (Canadian Saguenay Youth Study, IMAGEN, and ALSPAC), each addressing a different aspect for the final correlation, inferring from the results presented that cannabis appears to interfere with the maturation of the cerebral cortex.

The 2015 guidelines produced by a committee of the American College of Obstetricians and Gynecologists (ACOG) insist that women should abstain from smoking marijuana during pregnancy and lactation, due to the potential effects of its active components in the brain development of the fetus. Epidemiological studies by ACOG suggest that between 2-5% of women use marijuana during pregnancy, which increases to 15-28% in young urban women with economic problems. The conclusions presented by the ACOG committee’s systematic literature review include that children exposed to marijuana in utero tend to have impaired vision and coordination, more lapses in attention span, and behavioral problems than children who were not exposed.¹⁸ 

Criminal behavior has been reported in adolescent boys (average age 14) who are at increased risk of becoming marijuana users if they were born from mothers who smoked during pregnancy.¹⁹

The increase in consumption and accessibility of certain artisanal forms of cannabis has been linked to reports of stroke (S). In some cases, brain hemorrhage has occurred after smoking the synthetic marijuana popularly known as Spice,²⁰ which was considered harmless.

Smoking marijuana regularly has been reported as a direct cause of multi-segmental occlusive ischemic events, which develop during or immediately after smoking or sharing a cigarette (joint).²¹ This temporal relationship occurred in 81% of cases, while 22% suffered another CV event subsequent to re-exposure to cannabis. The association of other vascular risk factors in these cases was minimal. 

It is argued that these phenomena are due to the vascular spasmodic effect induced by cytokine discharge and activation of CB2 receptors of the endocannabinoid system.

When THC concentrates in the CNS primarily through the inhalation of marijuana smoke, a complex set of physio-neuro-psychological phenomena takes place in the individual, with variable duration and intensity dependent on the inhaled dose, the premorbid emotional state, and a multitude of individual factors such as: body mass, metabolism, liver and lung function, presence of other pharmacological agents, and especially alcohol associated.    

Acute marijuana reaction (albeit temporarily) affects the individual between just a few minutes (peak effect in ≥ 30 minutes) up to 4 hours, and rarely for longer periods. During the effect, various reactions (very individualized) develop normally including: euphoria, anxiety, depression, distortion of reality, occasionally a psychedelic effect, frontal disinhibition, lack of social control, dizziness, incoordination, reduced reaction time, and elements of ataxia.

THC blood concentrations of 2 to 5 ng/ml are associated with substantial impairment to operate a motor vehicle. After alcohol, THC is the psychotropic substance most frequently found in the blood in 4-14% of drivers who have been injured or killed in traffic accidents.²² However, in view of the technical limitations of consistently and uniformly measuring serum THC levels, it is likely that the actual epidemiology of accidents associated with marijuana use are underestimated.²³ 

The effect of cannabis in the subcortical structures of the brain has been studied in 483 twins and siblings through the Human Connectome Project, from the US National Institutes of Health (NIH), of which 262 reported having smoked marijuana during their lifetime. Cannabis was related to a smaller size of the left amygdala (2.3%; p = 0.007) and right ventral striatum (3.5%; p < 0.005). In view of the genetic factors involved, the authors attributed these findings to a predisposition with possible associated environmental effects.²⁴

Using various imaging techniques, such as structural magnetic resonance imaging (MRI), visualizing morphology based on voxels, diffusion tensor imaging, and functional anisotropy, 48 adult marijuana smokers were studied at the University of Texas in Dallas.²⁵ The study showed that chronic cannabis smokers have less brain volume due to orbitofrontal cortex reduction (a commonly affected area in substance users), but also show a marked increase in structural and functional connectivity. Researchers interpret this finding as possibly reflecting a complex neuroadaptative compensation for the loss of gray matter, but which eventually degrades. The measurement of IQ in this group showed lower values.

In Santiago de Chile, researchers studied differences between 40 middle and high school student marijuana users and 40 nonusers, both groups between 15 and 18 years old. The inclusion criterion for consumers was a minimum of 4 episodes of consumption only during the last month and minimum regular consumption for 18 months. Compromise was found matching neuroimaging and neuropsychological testing, affecting the learning of the consumer group. Neuro-SPECT showed hypoperfusion in various regions: bilateral subgenual (left hemisphere > right), bilateral frontal, anterior cingulate gyrus, and Brodmann area 36, ​​which projects on the hippocampus. Numerous but consistent neuropsychological disorders were detected in the domains of attention, concentration, hierarchizing, visuospatial integration, immediate retention, and visual memory. These abnormalities that directly affect the learning process in smokers, showed statistically significant differences with non-smokers.²⁶

According to the Multiple Sclerosis International Federation (MSIF), multiple sclerosis (MS) is considered the second leading cause of neurological disability in young adults after head trauma, which is recognized globally including in Mexico. The most common cause of work disability in MS is cognitive dysfunction, which affects between 40 to 60% of this population,²⁷ particularly the group with the secondary progressive form. This dysfunction has been associated with the development of cerebral atrophy secondary to the neurodegenerative and demyelinating progress of the disease.

MS is the only neurological condition in which CBD has shown positive effects on the management of some of its symptoms with evidence-based studies. Encouraged by the preliminary observations and the potential that the neurodegenerative process could be inhibited by cannabinoids as suggested by experimental studies in animals,²⁸ a 36-week placebo-controlled, double-blind study was conducted in 498 patients using oral dronabinol (THC). The study used as primary goals periodic evaluations using the Extended Disability Status Scale (EDSS for short) as an objective neurological measurement and the MS Impact Scale-29 (MSIS-29) as a subjective measurement provided by the patients themselves. Brain atrophy measurements using magnetic resonance were used as a secondary goal. The study did not reach statistical significance and was negative for all goals.²⁹

Considering the incidence of cognitive dysfunction in MS and the interest and popularity of using cannabis therapeutically in this disease, in addition to its legal accessibility in Canada, the Multiple Sclerosis Society of Canada funded a study designed to integrate psychometric assessments with various imaging techniques: functional magnetic resonance (fMRI) at rest and structural MRI (lesional tissue volumes and with normal appearance and measured by diffusion tensor). The study design was cross-sectional, involving 20 marijuana-smoking MS patients (2-3 times a week, 3-5 times a week, or daily), compared with 19 non-smoking MS patients. The two groups were compatible in various demographic variables: education, degree of disability, and whether or not they were working. Neuropsychological studies performed in these patients were aimed at visual functions, memory, information processing speed, and attention span. 

While no differences were found between groups regarding the dysfunction of brain neural networks evaluated by fMRI or structural MRI, the psychometric correlation with imaging studies shows abnormalities in parietal regions and anterior cingulate lobes, areas involved in the operation of memory. This was mainly evident in MS patients who were chronic marijuana smokers. The differences between the compared groups showed statistical significance in the correlation between neuropsychological dysfunction and brain areas affected by certain advanced imaging techniques.³⁰ The authors conclude that, seeing as brain structures are already affected by MS, exposure to marijuana further compromises cognitive dysfunction.

In addition, chronic use of marijuana affects sleep architecture, both in younger consumers (15 years) and adult chronic consumers (over 18 years). Non-restorative sleep is affected significantly (OR: 1.67) in adults, and severe insomnia can develop. 

Experiences abroad after legalization

Except for the typically liberal European experiences, there is as yet no data on the long-term consequences of the liberation of cannabis in the community.

Each country of the European Union has complicated sui generis laws and regulations that could not easily be adapted for other cultures and constitutional designs. Existing laws approved in the US, Canada, Europe, and even in certain Latin American countries do not necessarily reflect a general feeling or reality. Under certain circumstances, legal permission for limited or open cultivation of marijuana plants or manufacture of products derived therefrom (without sanitary regulation) could potentially create an industry (and monopolies) that would be difficult to control from the health point of view, posing a safety risk to the community.

The effects of these laws on the health of some societies in Europe, some US states (on November 3, 2015, the state of Ohio voted against legalization), Canada, and elsewhere continue to be analyzed and monitored. The major difference tends to be the legal acceptance of smoked marijuana versus cannabinoid medical products that have no long-term psychoactive and addictive effects, based on Class I and at least Class II evidence, approved by regulatory agencies because of its proven efficacy and safety profile. This consideration must completely preclude the first.

Conclusions

World literature and the results of evidence-based studies show that the use of products derived from marijuana or CBD may be useful in treating symptoms of spasticity, neuropathic pain, and spasms only in MS; but they are not effective in other neurological disorders and other diseases. THC is effective in nausea and vomiting caused by chemotherapy and as an appetite stimulant in emaciating diseases such as AIDS and cancer, and may be an adjunct in pain management. The use of CBD in cancer pain has not been studied.

There is preliminary evidence that the use of CBD in children with extremely rare epilepsies refractory to control may have a therapeutic effect in intractable attacks, but evidence-based controlled studies are ongoing and have not been completed. The recommendation is that CBD use in these cases should be within a framework of controlled study, where the real effectiveness can be determined and safety aspects monitored.

Smoked marijuana has a proven scientific profile of great negativity from the point of view of public health, with absolutely no rational basis for medical consideration.

It should be emphasized that for the benefit of the community, it is not responsible or ethical to expose the general population to consumers of substances or psychoactive drugs with the justification to respect their rights of personal choice. The objective data about the potential deleterious effects of marijuana on the developing CNS in learning in adolescents and in brain structure and function are overwhelming.

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