CANNABIS: THE PLANT AND THE MEDICINE. A HISTORICAL PERSPECTIVE
Cannabis: origin and spread
The history of hemp (cannabis) and its use dates back to about the 3rd millennium BC in written history, and according to paleobotanical studies, possibly
to circa 12 millennia back. The plant has been appreciated for its varied uses, such
as fiber, rope, cloth, paper, food, medicine, religion, and recreational[7],[8].
The origin of this plant is generally placed in Central Asia, and from there, it is
believed to have spread, over five millennia, to China, India, Japan, Persia, Arabia,
Europe, Africa, and the Americas[8],[9],[10],[11].
The hemp plant is known by many names, like marijuana, hashish, dagga, bhang, locoweed,
grass, maconha, cañamo, etc. It was first identified and labeled by Carl Linnaeus (Cannabis sativa Linnaeus 1753). Later, two other distinct species were recognized (Cannabis indica Lamarck 1785, and cannabis ruderalis Janischevsky 1924). They differ fundamentally in terms of size and content of psychoactive molecules[7],[10],[12],[13].
Psychoactive properties discovery
The psychoactive properties of cannabis were known to the Aryans (3,000-600 BC), who
introduced the plant to the Scythians, Thracians, and Dacians, whose 'shamans' burned
cannabis flowers to induce trance. The Scythians (2,000-1,400 BC) often inhaled the
vapors of hemp-seed smoke, both as a ritual and for recreation, as reported by Herodotus
(490-425 BC). Through the Aryans, the ancient Assyrians (900 BC) also knew such effects[9],[10] and used it in some religious ceremonies, they called qunubu [kanab] (meaning “way to produce smoke”), then converted to Greek as κάvvαβις (kánnabis), a Scythian or Thracian word, and subsequently to Latin as cannabis, the origin of the modern word[9],[10],[14].
Pharmacological developments
Cannabis’ chemistry is complex and contains a large number of active compounds, many
working on the 'EC system,' localized in the central and peripheral nervous system[7],[15] ([Chart 1]).
Chart 1
Pharmacological developments - chemical composition of cannabis and the endocannabinoid
system.
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•Cannabis composition. The plant contains a large number of chemically active compounds, such as cannabinoids,
terpenoids, flavonoids, and alkaloids. The most active components, which give its
peculiar characteristics, are the ‘cannabinoids.’ Once considered the main active
constituent in cannabis, ‘cannabinol,’ was isolated in the 1890s. Later, in the 1930s,
‘cannabidiol’ (CBD) was obtained. Then, in 1964, the primary psychoactive substance
Δ-9-THC (l-delta-9-trans-tetrahydrocannabinol), was identified[24],[25]. Subsequently, other cannabinoids were recognized, with some biological effects
of their own or by modifying the results of Δ-9-THC. Currently, 538 natural compounds
from Cannabis sativa are known, and more than 100 are identified as phytocannabinoids,
which can be divided into ten subclasses, among which cannabigerol, cannabichromene,
cannabidiol, tetrahydrocannabinol, Δ-9-tetrahydrocannabivarin, cannabicyclol, cannabinol,
and other similar compounds. The proportion of these substances in the plant varies
according to the species and to where it is grown. Thus, in temperate climates, the
plant contains a small proportion of Δ-9-THC (with psychoactive properties) and a
relatively high one of CBD (without psychoactive properties), while in hot climates
(grown for its psychoactive effects), it contains a high proportion of delta-9-THC
and relatively little CBD[6],[7],[9].
•Endocannabinoid system. The site of action of the cannabinoids is the ‘endocannabinoid system,’ localized
in the central and peripheral nervous systems, consisted of endogenous ligands, receptors,
and synthesis and degradation enzymes, as proposed by Di Marzo et al. (1994)[15]. Its main receptors, comprising cannabinoid type-1 (CB1) and cannabinoid type-2
(CB2), were identified respectively in 1990 and 1993, and at the same period, the
two endogenous CB receptor ligands were also discovered (AEA and 2-AG)[7],[25].
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History of therapeutic use
Medicinal cannabis (or medical cannabis) concerns the use of Cannabis sativa (and of other species) - defined as the unprocessed plant, a part of it, or a plant-derived
preparation - for therapeutic purposes[16],[17].
The medical use of cannabis dates back about 3,000 years BC, in China, prescribed
for fatigue, rheumatism, and malaria. Its use as a medicine is extensively reported
in the Egyptian Ebers Papyrus dated to about 3,000 years ago, and in Assyrian clay
tablets (>650 BC). Its medical use in India probably began around 1,000 years BC,
as an analgesic, anticonvulsant, hypnotic, and tranquilizer. Historical and archeological
evidence suggests that, in Europe, Scythian invaders brought the plant in 450 BC[10],[13],[16],[18]. It was also well known among the ancient Greeks and Romans, as mentioned by Herodotus
(about 400 BC)[7],[13]. Its use in the Americas probably began in South America, reaching Brazil in the
XVI century, brought by African slaves, mainly Angolans[13],[18]. The effective introduction of cannabis in Europe occurred in the midst of the XIX
century through the works of the French psychiatrist Jacques-Joseph Moreau, who wrote
on the psychological effect of its use, and the Irish physician Willian Brooke O’Shaughnessy,
who described its use for rheumatism, convulsions, and mainly for muscular spasms
of tetanus and rabies. The medical use of the drug spread from Britain and France,
reaching all Europe and then North America[13],[18].
Following a rapid rise of cannabis usage in 1900s medicine, it began to decline due
to controversies over legal, ethical, and societal implications, therapeutic indications
based on limited clinical data, as well as anti-cannabis laws, which practically abolished
any modern efforts to investigate possible therapeutic applications of the medicine[18],[19]. However, in the past two decades, an increasing interest was seen in the therapeutic
potential of cannabis derivatives for neurological disorders, with a strong stimulus
for research in several areas, such as epilepsy (Lennox-Gastaut and Dravet syndromes),
multiple sclerosis (MS) symptoms, neuropathic pain, movement disorders (e.g., Parkinson disease - PD), dementias (e.g., Alzheimer disease - AD), among other manifestations[6],[19],[20].
Regarding Brazil, one must remember the pioneering studies of Carlini’s group, with
cannabis and tetrahydrocannabinols[21], followed by reviews of Zuardi et al.[13] and, more recently, studies from the same group, coordinated by Chagas et al., emphasizing
the use of CBD in patients with neurological diseases (PD)[22],[23].
Despite persistent controversies, the use of cannabis for medicinal purposes represents
the revival of a plant with long historical significance reemerging in present-day
health care. The properties of cannabis foreshadow transformations of neurological
treatment into a new reality of effective interventional and even preventative care[10],[13].
CANNABINOIDS AND THE BLOOD-BRAIN-BARRIER
Potential therapeutic actions of the cannabinoids delta-9-THC and CBD are based on
their activity as an anti-inflammatory, anti-seizure, as well as analgesic and antiemetic.
Results from laboratory and human studies suggest that it could be a promising experimental
animal model of epilepsy and produce antipsychotic effects in experimental novel agents
for CNS diseases, including schizophrenia and epilepsy. Due to THC and CBD lipophilicity
and their neurological actions, they are natural candidates as new medicinal approaches
to treat CNS diseases. However, their penetrability and disposition in the brain are
different, and these patterns are related to their role in the blood-brain-barrier
(BBB). Several findings indicate that CBD can modify the deleterious effects on BBB
caused by inflammatory cytokines and may play a pivotal role in ameliorating BBB dysfunction
consequent to ischemia and hyperglycemia. Cannabinoids can positively influence the
brain’s immune response, playing a role in the prevention of BBB damage. In this regard,
it has been hypothesized that the activation of the EC system could play a key role
in preventing interactions between immune and endothelial cells and in neuroprotection
through the maintenance of tight junctions. These findings suggest that CBD could
be part of a new strategic approach useful to treat inflammatory diseases of the CNS[24],[25],[26],[27],[28].
Cannabinoids may also interfere in BBB pump-efflux regulation, playing an essential
role in drug resistance in the clinical management of neurological or psychiatric
diseases such as epilepsy and schizophrenia[27],[28],[29].
In addition to their use as therapeutic agents in epilepsy, pain, and movement disorders,
cannabinoids effects upon BBB may justify their use in neurodegenerative diseases.
Cannabinoids’ positive impact on cognitive function could be considered through the
aspect of protection of BBB cerebrovascular structure and function, indicating that
they may purchase substantial benefits through the protection of BBB integrity.
Emerging evidence suggests beta-amyloid (Aβ) deposition in the AD brain is the result
of impaired clearance, due in part to diminished Aβ transport across the BBB. The
modulation of the cannabinoid system may reduce Aβ brain levels and improve cognitive
behavior in AD animal models. Bachmeier and coworkers investigated the role of the
cannabinoid system in the clearance of Aβ across the BBB using in vitro and in vivo models of BBB clearance. They examined Aβ transit across the BBB in the presence
of cannabinoid receptor agonists and inhibitors and determined the expression levels
of the Aβ transport protein, lipoprotein receptor-related protein1 (LRP1) in the brain
and plasma of mice following cannabinoid treatment. Cannabinoid receptor agonism or
inhibition of endocannabinoid-degrading enzymes significantly enhanced Aβ clearance
across the BBB (2-fold).
Moreover, cannabinoid receptor inhibition negated the stimulatory influence of cannabinoid
treatment on Aβ BBB clearance. Additionally, LRP1 levels in the brain and plasma were
elevated following cannabinoid treatment (1.5-fold), providing a rationale for the
observed increase in Aβ transit from the brain to the periphery. These findings provide
an insight into the mechanism by which cannabinoid system modulation has been shown
to reduce Aβ brain burden and abrogate AD pathophysiology and cognitive decline[30],[31].
Still, within the scope of cognitive impairment and BBB integrity, it is known that
type-2 diabetes (T2D) increases the risk of dementia by 5-fold, and evidence suggests
that the heightened inflammation and oxidative stress in T2D may lead to disruption
of the BBB, which precedes premature cognitive decline. Compromised integrity of the
BBB in T2D is both an early and critical event preceding cognitive decline and potentially
dementia, so targeting the BBB may be a novel therapeutic approach for diabetes-associated
dementia. Brook et al., in a recent review, point out the role of BBB dysfunction
in T2D associated dementia and consider the potential therapeutic use of cannabinoids
as a protectant of cerebrovascular BBB preventing neurocognitive impairment[26].
Cannabinoids in epilepsy (children and adults)
The first records of the use of marijuana for medical purposes date back to 2737 BC
in China[32]. However, the EC system was only discovered in 1992[33]. The global interest in the use of medical marijuana in epilepsy grew exponentially
in the 21st century after Charlotte Figi’s story gained notoriety in the United States of America[34], and Anny Fischer’s, in Brazil. Since then, several articles produced without strict
scientific structure have been published, many of them just roughly drafted, and until
2014, Cochrane and American Academy of Neurology reviews did not show scientific evidence
that would substantiate the use of marijuana for epilepsy[35],[36]. Still, CBD has been investigated and found useful in the treatment of patients
with epilepsy for several decades, particularly in the pediatric age group. In recent
years, there has been a growing interest in the use of CBD as an adjunctive treatment
in patients with refractory epilepsy[37].
A controlled series of patients being treated with Epidiolex - drug comprised of CBD,
a compound derived from marijuana and indicated for epilepsy - was published. At this
time, Devinsky et al.[38] showed the results for 214 patients treated with highly pure (99%) CBD in 10 epilepsy
centers in the United States from January 2014 to January 2015, including children
and young adults, with severe forms of epilepsy. This study showed a median reduction
of 36.5% in the frequency of seizures per month.
In 2017 Devinsky et al.[39] conducted a double-blind, placebo-controlled, randomized trial to evaluate the efficacy
of Epidiolex for seizures in 120 children and adult patients with Dravet syndrome.
In another double-blind, placebo-controlled study, Thiele et al. assessed the effectiveness
of Epidiolex for atonic seizures in 225 patients with Lennox-Gastaut syndrome. This
study showed that patients who experienced a reduction of at least 50% in the drop
seizure frequency were mostly in the CBD group, 43%, compared to 27% in the placebo
group[40]. These two randomized, controlled studies which evaluated the efficacy of pharmaceutical-grade
CBD in children with Dravet and Lennox-Gastaut syndromes showed similar efficacy to
other antiepileptic medications[39],[40]. CBD was approved for use in the treatment of patients with epilepsy with the diagnosis
of Lennox-Gastaut Syndrome and Dravet Syndrome by the FDA in 2018 and by the European
Medicines Agency (EMA) in 2019. The approval was based on the previous commented studies
in which CBD, as an addiction drug, was shown to be superior to placebo in reducing
epileptic seizures[38],[39],[40]. In these studies, the median percentage reduction from baseline in seizure frequency
was 44%, data statistically significant when compared to the placebo group. Based
on these studies, the FDA approved the first commercial presentation of highly purified
CBD (Epidiolex®; GW Pharmaceutical, Cambridge, UK).
CBD has also been shown to be effective in the treatment of patients with focal epilepsy
associated with other clinical conditions, such as Tuberous Sclerosis Complex[40]. Still, in these patients, CBD has an off-label indication. The recommended dose
of CBD for refractory epilepsy treatment was 10 to 25 mg/kg/day (about 200 to 300
mg/day) [37].
More recently, de Carvalho Reis et al. systematically examined the efficacy and adverse
events profile of CBD and medicinal cannabis. They observed a statistically meaningful
effect of CBD compared to placebo. Furthermore, CBD proved more effective than a placebo,
regardless of the etiology of the epileptic syndromes and dosage[41].
Concerning the efficacy of CBD for epilepsy, a study that assessed its use for patients
with tuberous sclerosis should also be emphasized. After three months of treatment,
patients who took CBD experienced a mean reduction of 48.8% in seizure frequency and,
after 12 months, a decrease of 50% or more in 50% of the patients. It was also observed
that among patients who took clobazam (CLB) (12/18) concomitantly, the response rate
was 58.3%, compared to 33.3%[10] in patients who did not take it[42].
In all mentioned studies, adverse events were frequent, occurring in almost 90% of
patients[40]. The most common adverse events observed were somnolence, decreased appetite, diarrhea,
behavioral changes, skin rash, fatigue, convulsive episodes, status epilepticus, lethargy,
gait disorder, sedation, as well as changes in the dosages of concomitant antiepileptic
medications[38],[39],[40],[41],[42],[43]. These events were described as mild or moderate, with a small percentage of patients
discontinuing treatment[38]. Severe adverse events were reported in up to 30% of patients, including one case
of sudden unexpected death in epilepsy (SUDEP), although regarded as unrelated to
the study drug[41]. Adverse events in CBD using were more common under short-term than under long-term
treatment[41].
Animal studies demonstrate adverse effects related to the male reproductive system,
with reduced spermatogenesis, changes in embryological and fetal development, reducing
peripheral organ weight and neurotoxicity[43], and its use in a gestational age patient should be considered with thrift.
CBD has complex and variable pharmacokinetics, with a low oral bioavailability, which
increases up to four times when ingested with a high-fat diet[44]. Metabolism is hepatic, and CBD did not significantly modify plasma levels of most
antiepileptic drugs (slightly increases the serum level of phenobarbital and phenytoin
and reduces the serum level of ethosuximide)[45]. The exception is the association of CBD and CLB, which is particularly effective,
with a bidirectional interaction, in which both have an inhibitory action on metabolism,
with CBD inhibiting the metabolism of CLB and its primary metabolite, and CLB inhibiting
metabolism of CBD and its metabolite, 7-hydroxy-CBD[46]. This association leads to a serum level increase of both drugs, enhancing their
therapeutic effect, but with a potential increase in side effects such as drowsiness,
sedation, respiratory hypersecretion, and infections[43],[47]. The significant consequence of this interaction is somnolence, which can be addressed
by reducing the dose. Concerning other medications, the interactions seem to be less
evident, albeit not completely known.
There may also be an increase in liver enzymes when CBD is associated with sodium
valproate[48]. Some studies have shown an increase of ≥3 times the upper limit of normal in the
serum levels of alanine or aspartate aminotransferase for approximately 15% of patients
taking CBD, which proved to be the main reason for the treatment to be discontinued.
There is a potential risk of hepatoxicity, increased by the concomitant use of valproate.
In all the cases, the laboratory abnormalities could be reversed by reducing the dose
of one concomitant antiepileptic medication, mainly valproate or CLB, or after the
reduction or discontinuation of CBD[49],[50],[51].
An increase in the levels of zonisamide, eslicarbazepine acetate, topiramate, and
rufinamide could be observed with the concomitant use of CBD[50],[51].
The interaction of CBD with antiepileptic medications seems common in patients with
epilepsy, especially with clobazam and valproate[49]. These two medications may significantly influence the levels of efficacy and safety
of CBD and must be carefully considered in daily medical practice.
Currently available CBD presentations are marketed as supplements and therefore are
not subject to regulatory regulations for medicines. Some presentations, in addition
to containing high concentrations of THC, do not have the correct level of CBD. Thus,
the Mayo Clinic suggests that a checklist should be made to assess whether the chosen
presentation is reliable, considering: production quality control (manual of good
manufacturing practices, and organic certificate with European, Australian or Canadian
standards), international certification by the National Science Foundation); assess
whether the company has an independent program to report adverse effects; the product
must have organic certification and be tested, guaranteeing a THC concentration >0.3%,
without pesticides and heavy metals[52].
Despite all new antiepileptic drugs that have been developed in recent years, approximately
30% of patients with epilepsy continue with their seizures uncontrolled. In this context,
current scientific data allow us to infer that CBD has a potential role in the treatment
of these patients. However, drug interactions, safety profile, and efficacy are not
yet proven[6]. In this way, we must discuss with patients/family the indications of off-label
CBD use, considering potential risks and benefits, and choose formulations that have
a higher content of CBD with THC levels below 0.3% ([Chart 2]).
Chart 2
Cannabidiol and epilepsy.
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In summary:
1. The efficacy of CBD in the treatment of patients with epilepsy is similar to that
of other antiepileptic medications;
2. CBD is more effective in convulsive episodes, especially in certain childhood epileptic
syndromes such as Dravet and Lennox-Gastaut;
3. CBD causes adverse events, what may limit its use;
4. CBD may be an alternative in refractory epilepsy;
5. The use of CBD must be limited to the well-known pharmaceutical drugs.
6. Consider potential risks and benefits, discuss with patients/family the indication
of off-label CBD use.
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Cannabinoids in multiple sclerosis
The use of cannabis in MS started as a complementary symptomatic treatment, especially
for those symptoms not entirely controlled by standard therapies. Several patients
admit recurrent use of products derived from cannabis (PDC) to relieve symptoms such
as spasticity, pain, insomnia, anxiety, ataxia, and tremor. In a cohort at the University
of British Columbia in Vancouver, Canada, a city where recreational marijuana use
is allowed, a study found that around 30% of patients interviewed used some cannabis-derived
product to treat pain, insomnia, moodiness, or spasticity without their doctor’s knowledge.
Some side effects reported were forgetfulness and lack of attention. Interestingly,
35% of these PDC users had never tried traditional symptomatic medications, and 56%
had previously tried only one symptomatic standard therapy. The reasons for this search
for alternative treatments are still unclear and, therefore, this behavior should
be studied[53].
Cannabinoid type 1 (CB1) and type 2 (CB2) receptors are expressed in the central and
peripheral nervous system and in the immune system. CB1 is more expressed in the CNS
in areas associated with pain control, as well as the cerebellum, hippocampus, peripheral
nerves, dorsal root ganglion, and neuromuscular junction. CB1 stimulation decreases
neurotransmitter release, affecting nociceptive pathways, memory, psychic activity,
and motor control. CB2 receptors are expressed in cells of the immune system as macrophages,
neutrophils, and lymphocytes, which explains some of the anti-inflammatory activity
of cannabinoids, which can also stimulate other receptors such as opioid and serotonergic
receptors. THCs have high affinities for the CB1 receptor, which explains their actions
on psychic activity, including a change in mood and consciousness. In contrast, CBD
has little affinity for CB1 and CB2 receptors and may assume an antagonistic role
by competing with them in the presence of THC, decreasing their potency. The main
effect of CBD is on non-cannabinoid receptors, including ion channels[2].
There are no consistent studies for the therapeutic indication of cannabis in the
form of cigarettes in any of the symptoms of MS. A recent meta-analysis indicated
a slight efficacy of the treatment for spasticity, pain, and urinary retention in
patients with MS (pwMS). But in most of them, the primary endpoint of these studies
was based on subjective self-assessment scales. Objective scales, such as Ashworth’s
applied by neurologists, did not show improvement in spasticity. Another issue is
that there are different PDCs with different formulations being tested, for example,
products with only synthetic or natural THC or even mixtures of THC and CBD in different
ratios such as 1:1 or 2:1 rate, which prevented a real comparison of their effectiveness
and side-effects[54],[55],[56],[57],[58],[59].
There are class I, II, and III studies of compounds extracted from cannabis to treat
some different symptoms, such as spasticity and pain. More than 85% of pwMS can suffer
from some type of spasticity during their lifetime, which can contribute to their
disability, especially in the more advanced stages of the disease. A preparation combining
THC and CBD, in the ratio of 1:1, exclusively for oral use and used in the maximum
dose of up to 12 puffs per day, nabiximol (SativexTM) showed an improvement of more than 20% in the spasticity parameters after four weeks
of use compared to placebo. He then received FDA approval for the treatment of severe
and refractory spasticity in MS[57],[59].
In neuropathic or central pain, it can affect around 70% of patients, in the form
of headache (43%), neuropathic pain in the upper or lower limbs (26%), low back pain
(20%), painful spasms (15%), and trigeminal neuralgia (3.8%). The studies were carried
out in short periods, with variable efficacy. Nabiximols showed improvement in pain
when compared to placebo in patients with MS. Another study demonstrated effectiveness
in controlling chronic neuropathic pain in the association of nabilone with gabapentin.
Oral cannabis extracts have shown conflicting results, and although it is not possible
to conclude their effectiveness definitively, these data suggest that this may be
a therapeutic option in patients who have not responded to conventional treatments[60],[61].
In the treatment of tremors, the use of nabiximols or oral preparations of THC, CBD
or THC/CDB, proved to be ineffective, and there is currently no indication for its
use to relieve these symptoms. For urinary symptoms, nabiximols showed a likely improvement
in reducing the frequency, but with no effect on urinary incontinence[59].
Retrospective studies indicate some benefit of using CBD for anxiety and insomnia
after one month of treatment. These results suggest that this therapeutic option can
be considered in pwMS, however, controlled and long-term studies need to be carried
out to prove its real efficacy and safety[58],[59].
Some precautions must be taken regarding the indication of PDC in MS, as their side
effects can be aggravated due to the peculiarities of the disease. Symptoms such as
cognitive impairment, fatigue, and mood changes, which can vary from depression to
suicidal ideation, must be evaluated before indicating these substances in MS. The
main side effects of cannabis use are mainly related to THC and high dosage used,
which include vertigo, drowsiness, and nausea. In the long run, it can affect cognition
and balance. The most severe effects are induction of psychosis and schizophrenia
in at-risk individuals, heart disease (myocardial infarction, hypertension, heart
failure, and stroke), and cannabinoid hyperemesis syndrome, which can be enhanced
if associated with smoking[53],[54],[56],[59].
Mainly, regarding cognitive functions, patients are vulnerable to a time-dependent
decline, control of disease activity, and type of MS (remitting-recurrent or progressive
forms), affecting their quality of life and work capacity. Studies comparing patients
who use PDC (inhaled or ingested) with those who do not use it demonstrated a significant
worsening in information processing speed, working memory, and cognitive functions.
Those who use PDC are twice as likely to have changes in the neuropsychological assessments
of those who do not. Proving these findings, a recent study assessing patients who
extensively used cannabis and who had previously altered neuropsychological tests,
demonstrated significant improvement 28 days after ceasing its use in all cognitive
domains. In addition, it was shown by functional brain magnetic resonance imaging
(MRI) associated with the symbol digit modality test (SDMT), increased blood oxygen
level-dependent activation (BOLD) in 4 regions of the neural network involved with
SDMT performance after the cessation of cannabis use. In the phase 3 study of the
effectiveness of nabiximol to treat spasticity, the cognitive functions evaluated
by the PASAT test did not change with treatment during the study. However, more complete
neuropsychological tests are needed to assess the presence of this side effect[62],[63].
Cannabinoids in movement disorders
Recently, there has been a growing interest in the medicinal use of cannabinoid derivatives
in treating PD and other movement disorders.
Some studies have been published to seek a definitive answer on the use of cannabinoid
derivatives, especially CBD, in patients with abnormal movements, with a greater interest
in patients with PD due to its high prevalence.
One of the first studies carried out in PD patients treated with CBD for four weeks
demonstrated a decrease in psychotic symptoms without worsening motor function or
inducing adverse effects[64]. Another study showed that although CBD does not improve the motor function of patients
with PD or their overall symptom score, treatment for six weeks improves the quality
of life of these patients, suggesting that this effect may be related to anxiolytic,
antidepressant, and CBD antipsychotic drugs[63],[65]. In 2015, Kluger et al. published a review of the preclinical and clinical studies
that existed until then on the therapeutic potential of cannabinoids in various movement
disorders. The conclusion was that there is not enough data to indicate certain benefits
from the use of these substances in patients with involuntary movements, such as tics,
dystonia, and blushing[66]. A similar conclusion was found for patients with PD because, although observational
and uncontrolled studies suggest some positive response in motor symptoms (tremor
and bradykinesia), these results have not been reproduced in controlled studies. For
dystonia, two controlled studies with a small number of patients showed no benefit
in the abnormal movements of patients treated with CBD compared to the control group[67],[68]. A recent review showed that regarding motor symptoms, only one study, with a small
sample of patients, demonstrated the benefit of CBD use for treat L-Dopa induced dyskinesia[69].
In conclusion, despite the widespread by the lay media of the possible benefits of
cannabinoids in movement disorders, especially PD, there are reports of some improvement
in non-motor symptoms such as psychosis, sleep disorders, and pain, as well as improvement
in scales that assess quality of life, there are no scientific data to support this
indication. Most of the studies are uncontrolled, with a small number of patients,
short follow-up, and without data on cognition and long-term evolution. The few existing
controlled studies have shown no effect on PD motor symptoms, nor in patients with
chorea or dystonia.
Cannabinoids in chronic pain
Chronic pain affects 28% of the general population, and it is the leading cause of
years lived with disability from all diseases worldwide[70]. There are several chronic pain syndromes, grouped according to the primary pathophysiological
mechanism related to their occurrence. They are classified as:
-
Nociceptive/inflammatory pains.
-
Neuropathic pain (central or peripheral).
-
Nociplastic pain (primary headaches, fibromyalgia, and nonspecific low back pain)[71].
In one study, chronic pain was the leading cause of seeking a physician’s prescription
for medical marijuana[72]. However, evidence for the routine use of cannabinoids in chronic pain is still
limited[73]. In some pain syndromes, such as peripheral neuropathic pain, the evidence leans
against its effectiveness, especially considering a large number of first-, second-,
and third-line treatments available, which were already approved and known to be useful
for the treatment of this pain syndrome[74].
Nevertheless, the use of cannabinoids may be proposed for the treatment of some specific
cases in which there is no well-established evidence-based treatment, such as spinal
cord injury-related pain, central post-stroke pain syndromes, neuropathic pain related
to the use of chemotherapy or due to traumatic peripheral nerve. Additionally, the
prescription must be based on a clear rationale, as an adjuvant treatment, and within
an individualized plan treatment.
As with opioid prescriptions, patients should be frequently monitored to detect possible
adverse behavioral, mood, appetite, or systemic events (i.e., bronchitis, risk of an accident while driving). Unlike opioids[75], there are still no straightforward ways to identify patients at higher risk of
developing cannabinoid-related abuse or addiction disorder. Therefore, care must be
taken in instances of dysfunctional (nociplastic) pain syndromes (i.e., fibromyalgia, primary headaches), personal history of abuse of licit or illicit
drugs, or personal/family history of severe psychiatric illness. In these situations,
substance misuse is more frequent, regardless of their pharmacological classes, and
thus special attention should be paid.
Frequently, patients with chronic pain may seek cannabinoid prescription for relief
of symptoms that are not directly related to their pain, but rather to improve sleep,
anxiety, concentration, mood, well-being, or muscle relaxation. The identification
of this primary objective is essential to analyze whether cannabinoids would be the
best treatment available for the demand and, thus, guide patients to the most appropriate
form of pharmacological or non-pharmacological treatment. This “targeting of the bothersome
symptoms” is also essential to monitor the real effects of cannabinoids, should they
be initiated.
As with any psychotropic agent, when prescribing cannabinoids, careful history taking
should be performed to accurately identify the patient’s demands, needs, and expectations
regarding the treatment and use of this class of medication. Currently, the monthly
cost of most cannabinoids legally approved for clinical use is high, and this factor
needs to be taken into account when prescribing a drug for use in the medium and long
term.
Cannabinoids in muscular diseases
The role of the endocannabinoid system (ECS) in muscle physiology was initially identified
in animal models as responsible for the functions related to energy expenditure and
glucose uptake[76],[77]. In addition to this role related to muscle energy dynamics, Iannotti and collaborators
later demonstrated, through studies using gene silencing techniques associated with
pharmacological tools, that the ECS has, mainly via stimulation of CB1 receptors by
endogenous or exogenous cannabinoids, effects on the proliferation of myoblasts[78],[79],[80].
In this sense, it is possible to infer that the ECS possibly influences the pathophysiology
of several myopathies, especially in muscular dystrophies. Studies with an animal
model of Duchenne muscular dystrophy (DMD) treated with phytocannabinoid agents -
CBD, cannabivarin (CBDV), and tetrahydrocannabivarin (THCV) - showed a sustained improvement
in the motor performance of treated animals when compared to controls[81]. Among the possible mechanisms involved are the anti-inflammatory effect, the autophagy
recovery, and also an increase in the myoblast’s differentiation[81]. Considering their impact in human satellite cells, myotubes generation in both
healthy and DMD muscle samples was seen not only with CBD and CBDV but also with THCV[82]. Another cannabinoid derivate, tetrahydrocannabinol, was investigated in animal
models regarding its effects in reducing acute muscle pain. Both local and systemic
administration had an antinociceptive effect[83].
Evidence from animal models has shown that CB2 receptors play a role in the inflammatory
muscle response during the muscle repair course. Its activation attenuates the inflammatory
response and favors the anti-fibrotic/pro-fibrotic balance in the muscle repair process,
whereas its blockade results in the opposite effects[84]. Additional CB2 receptor functions may be seen in regenerated myotubes from muscle
ischemia-reperfusion models where they seem to play a protective effect by relieving
oxidative stress and accelerating early myogenesis. The levels of CB2 receptor protein
were also higher during the differentiation of C2C12 myoblasts, an immortalized mouse
myoblast cell line, suggesting the participation of the CB2 receptor in the muscle
regeneration process[85].
This evidence regarding the immune response modulation may also find a direct effect
on the pathophysiology of inflammatory myopathies, for example. In vitro evidence of the action of a CB2 receptor agonist agent on peripheral blood mononuclear
cells of patients with dermatomyositis (DM) demonstrate its ability to reduce the
secretion of IL-31 (interleukin related to the innate and adaptive immune response
in the skin)[86]. This same CB2 agonist agent proved to be tolerable and safe for patients with DM
in phase II studies[87],[88] and, at the moment, a phase III study, for this same patient profile, is in progress[89].
Considering the available in vivo evidence supporting the use of cannabinoids for myopathies, apart from the phase
II studies mentioned for patients with DM, the scientific background of their possible
benefit in humans is restricted only to a few reports/case series[90],[91],[92]. That said, it is paramount to state that, in the present moment, there is no sufficient
evidence to recommend a systematic cannabinoid prescription for myopathic patients.
Cannabinoids in neurological rehabilitation
The indication and use of cannabinoids in a neurological rehabilitation environment
is hugely restricted, with no established level of evidence for this use, except for
patients with spasticity such as paraplegias or MS. Spasticity is a deficit that impacts
on worsening functional capacity, resulting in problems in activities of daily living.
Chronically, spasticity can lead to muscle pain, spasms or stiffness, reducing mobility,
and to contracture leading to bone and joint deformities. Evidence in the literature
is moderate about the impact of cannabinoids on spasticity due to MS or paraplegia,
as well as adverse events such as dizziness, drowsiness, and nausea. A larger number
of randomized clinical trials are needed to evaluate cannabinoids for spasticity and
chronic pain in this patient population, as well as for other indications[93].
Future studies on the use of CBD derivatives, such as Sativex, are being carried out
to assist in neurological rehabilitation with a focus on improving spasticity, trunk
control, and patient gait, associated with rehabilitation training with robotic assistance[94].
In the environment of patients undergoing neurorehabilitation who progress to palliative
care or end-of-life care, cannabinoids can be used exceptionally, despite the more
significant experience of use still being in oncological diseases. The purpose of
use in this scenario would be to control pain. However, there is still limited evidence
of the role of this drug in patients with neurodegenerative diseases, also indicated
for the improvement of symptoms other than pain, such as sleep problems, fatigue,
anxiety, and depression, nausea, and vomiting. Side effects of using cannabinoids
are drowsiness, dizziness, dry mouth, anxiety, euphoria, paranoia, toxic psychosis,
tachycardia, orthostatic, hypotension, slow reaction time, headache, blurred vision,
cognitive impairment, and depression, with around 20% of patients discontinuing treatment
due to side effects[95].
Cannabinoids in dementia
There is evidence suggesting that cannabinoids may modulate core pathophysiological
mechanisms of AD, such as amyloidosis and tau-related neurodegeneration. Data from
both animal and in vitro studies indicate that cannabinoids may reduce the hyperphosphorylation of Tau protein[96]. Moreover, it seems that cannabinoids may also reduce the production of beta-amyloid
peptide[96]. Interestingly, cannabinoids may regulate microglial activation, leading to reduced
neuroinflammation and oxidative stress[96],[97], which have been recently recognized as key neurobiological processes related to
the pathophysiology of AD. Although interesting, it should be pointed out that these
results come from experimental studies with animal and in vitro models; these findings have not been demonstrated in clinical practice.
Few studies have investigated the possible benefit of cannabinoids in the management
of patients with dementia. Observational studies suggest that cannabinoids may be
useful in the symptomatic control of behavioral changes in patients with AD or other
dementias[97],[98]. However, there are no randomized, multicenter, double-blind studies with a large
number of patients supporting the use of these drugs in clinical practice. There is
no evidence that cannabinoids slow the clinical progression of AD. Therefore, eventual
benefits are essentially symptomatic and not curative.
In summary, although some results are suggesting that cannabinoids may be of scientific
interest in neurodegenerative diseases, there is a lack of evidence to support their
clinical use in patients with dementia. Therefore, their use is not recommended for
treating patients with AD and related disorders. Further studies are warranted to
establish the clinical value of cannabinoids in dementia practice.
Cannabinoids and sleep disorders
The use of cannabinoids for sleep disorders has been tested in a few clinical trials
(CT). Most of the CT are about studies in patients with insomnia, but some investigated
the use of CBD in obstructive sleep apnea and, rarely, in other disorders as parasomnias.
A summary of these findings is stated below:
Insomnia
In a meta-analysis involving 19 CT, a total of 3,231 patients with insomnia associated
with various comorbidities (chronic pain, fibromyalgia, MS, etc.) had been evaluated,
using different types of cannabinoids: Nabiximol (13 studies); Sativex (THC/CBD) (2
studies); THC (inhaled cannabis) (2 studies); dronabinol/nabilone (2 studies)[99]. However, only two of them had a low risk of bias. The meta-analysis found 8 CT
that demonstrated improvement in sleep quality with the use of cannabinoids from 2
to 15 weeks compared to placebo (weighted mean difference [WWD] -0.58, 95%CI -0.87
to -0, 29). The benefit was seen mainly with nabiximol[99],[100].
In a crossover CT with 32 patients with insomnia associated with fibromyalgia, the
use of nabilone 0.5 mg daily compared to 10 mg amitriptyline improved insomnia symptoms
(mean difference from baseline, -3.25, 95%CI -5.26 to -1.24) and the perception of
restorative sleep (mean difference from baseline, 0.48, 95%CI 0.01-0.95) in the 2
weeks that followed[100].
There is little evidence that the use of cannabinoids, such as Nabiximol and Nabilone,
improves short-term sleep quality in patients with insomnia associated with chronic
pain, fibromyalgia, and MS. However, no evidence supports its use for insomnia disorder.
Obstructive sleep apnea
There are two controlled placebo CT with a total of 95 patients[101],[102]. One of them involved 22 patients with obstructive sleep apnea (OSA) and showed
a greater benefit of using dronabinol (maximum dose of 10 mg/day) versus placebo in reducing the rate of sleep apnea/hypopnea (AHI) (mean line difference
base -19.64, p=0.02) with three weeks of follow-up. The other study involved 73 adult
patients with moderate or severe OSA who received a placebo (n=25), 2.5 mg dronabinol
(n=21), or 10 mg dronabinol (n=27) daily, 1 hour before sleep during six weeks. In
comparison with placebo, dronabinol reduced dose-dependent AHI by 10.7±4.4 (p=0.02)
and 12.9±4.3 (p=0.003) events/hour, with doses of 2, 5, and 10 mg/day, respectively[102].
Although promising preliminary results with dronabinol were showed, there is still
no reliable evidence that favors the use of cannabinoids for OSA treatment[103].
Parasomnias
Two CT using nabilone versus placebo demonstrated a reduction of more than 70% in the frequency of nightmares
associated with post-traumatic stress syndrome[104],[105].
An open study with four patients with REM behavior disorder (RBD) associated with
PD, the use of cannabidiol (75-300 mg) led to a complete reduction of symptoms in
three out of the four patients[106].
There is still no clear evidence to demonstrate the benefits of using cannabinoids
to treat parasomnias. More CT with a larger number of patients and longer follow-up
are needed.
Cannabinoids in traumatic brain injury
The neuroprotective antioxidant effects of cannabinoids are particularly relevant
in their ability to counteract “glutamate excitotoxicity,” which leads to neuronal
demise after traumatic brain injury (TBI). Anecdotally, cannabis, particularly chemovars
combining THC and CBD, has been beneficial in the treatment of chronic traumatic encephalopathy
(CTE) symptoms: headache, nausea, insomnia, dizziness, agitation, substance abuse,
and psychotic symptoms. CTE, previously known as dementia pugilistica, or “punchdrunk
syndrome” has garnered a great deal of attention due to its apparent frequency among
long-term American football players but including victims of repetitive head injury
from causes as diverse as other contact sports, warfare and even “heading” in soccer.
Neuroprotective benefits of phytocannabinoids, particularly CBD, further outlined
below, provide support for trials of these agents in post-traumatic syndrome and CTE
prevention[107].
However, as in other neurological diseases, more research is needed, especially controlled
studies with long-term follow-up, to support these results.
Cannabinoids in vestibular disorders
The use of cannabinoids for vestibular disorders has not been tested in human clinical
trials (CT). Most of the information about the ECS and the vestibular system is based
on studies in mice[108],[109]. The pharmacological actions of cannabinoids in the context of nausea and vomiting
are limited. More research is needed to understand their effectiveness in the treatment
of nausea and vomiting.[110],[111],[112] There are not CT about cannabinoids and dizziness treatment[113]. On the other hand, dizziness and vertigo are commonly reported adverse side-effects
in CT of medical cannabinoid [113],[114],[115] The are case reports that smoking cannabis can suppress pendular nystagmus in patients
with MS[115],[116]. Anecdotal and empirical use of CBD for some refractory vestibular disorders was
reported by some of the authors of this review, but the results are not consistent.
There is a lack of evidence about the medical use of CBD for vestibular disorders
and nausea; Dizziness is a possible side effect of the medicinal use of CBD.
CANNABINOIDS IN NEUROINFECTION
HIV
Several factors impact the quality of life of HIV patients, including vomits, anorexia,
and pain. Anorexia in these patients can be caused by stomatitis, intermittent or
chronic diarrhea, and opportunistic infections, such as cytomegalovirus, microsporidia,
and cryptosporidium. Increased appetite and vomit control are fundamental for a better
prognosis. Dronabinol, a synthetic form of THC, directly acts in the vomiting and
appetite control centers in the brain, thereby increasing appetite and preventing
vomiting[117]. Although it has been used for the treatment of anorexia associated to weight loss
in patients with HIV/AIDS, indicators like increasing appetite, reducing nausea, and
improving functional status were mostly assessed in single studies, and associations
failed to reach statistical significance[118].
Neuropathic pain due to HIV-associated sensory neuropathy is the most common peripheral
nerve disorder complicating HIV infection. It is directly associated with a decrease
in daily functioning in HIV-infected individuals. Two clinical trials assessed the
impact of smoked cannabis on neuropathic pain in HIV; both studies found that smoked
cannabis was well tolerated and effectively relieved chronic neuropathic pain from
HIV-associated sensory neuropathy (achieving at least or greater than 30% pain relief)
[119],[120].
There is low-quality evidence that cannabinoids studies improve weight gain in HIV
patients and moderate-quality evidence that it improves neuropathic pain in these
patients.
Cannabinoids in headache
There are no clinical studies that support the therapeutic use of cannabinoids in
any of the main primary headaches, such as migraine, tension-type headache, and cluster
headache. In migraine, studies in an animal model have shown contradictory results,
whereas in cluster headaches, there are only isolated reports of efficacy[121],[122],[123],[124],[125],[126]. Even though some painful neuropathies of the cephalic segment, such as trigeminal
neuralgia, burning mouth syndrome, and persistent idiopathic facial pain seem to respond
to the use of cannabinoids, their use is not recommended by the guidelines or consensus
regarding the treatment of headache, due to the lack of conclusive data.
The prescription of medical cannabinoids must be discussed with each patient and family.
Neurologists have to know adverse effects and possible pharmacological interactions
among prescribed medications. There are many cannabinoids compounds with few known
information, which could be promising in many neurological diseases. We need to clarify
misunderstood conceptions about the medical use of cannabidiol and derivative synthetic
cannabinoids. We have to research cannabinoids’ actions in neurological disorders,
with randomized, blind, and controlled trials to confirm their beneficial effects,
remembering that many usually prescribed substances for some conditions are used off-label.
Safety in using Cannabis-based treatment
Use of cannabis-based products can be associated with several adverse events and these
must be considered before prescribing them as a medicines. The adverse events may
be related to the route of administration or to its content, but also to user’s behavior,
drug to drug interactions, family history, and other medical conditions. One of the
challenges in prescribing a cannabis-based treatment, besides the lack of evidence
for some alleged indication, is the fact that some of the preparations of cannabis-based
medicine are faced as herbal medicine and considered harmless.
A basic knowledge from the prescriber is expected concerning the associated risks
in these therapies. Different onset of action, duration and self-titration possibilities
are observed depending on the administration route, faster to slower in smoked, vaporized,
inhaled, oil, oil-capsule, and edible respectively, as quick as 5 min to few hours
to initiate the effect, and 2 to 12 hours of duration ([Table 1]). Because of its slow start of action there is an increased risk of higher dosage
in edibles presentation, despite some patient ideas of a safer use experience with
edibles[127].
Table 1
Cannabinoids route of administration and characteristics.
|
Route of administration
|
Onset (min)
|
Duration (h)
|
Amenable to self-titration
|
|
Smoked
|
5
|
2–4
|
++++
|
|
Vaporized
|
5
|
2–4
|
++++
|
|
Oral (oil, capsule, edible)
|
30–60
|
8–12
|
+
|
|
Oromucosal
|
15–40
|
2–4
|
++
|
Cannabinoids should be avoided as much as possible in patients below 25 years-old,
in those with family history of psychotic symptoms, in patients that describe a bad
experience in previous exposition to marijuana, or who are heavy drinkers, heavy tobacco
smoking, with poor cardiac conditions, hypotension, and not to be used in pregnant,
in those who intend to get pregnant or breastfeeding women[128].
Respiratory complications in inhaled or vaporized forms as rhinitis, chronic bronchitis,
and pulmonary hemorrhage and coagulopathy in synthetic presentations of inhaled cannabinoids
are described[129],[130]. Local injury in oromucosal after prolonged use of THC/CBD oromucosal spray is referred
by some MS patients. This usually is transitory and prompted recovered after a brief
interruption[131].
The THC/CBD content is not uniform throughout all the presentations, leading to a
higher risk of a lower or a higher dosage comparing with the desired one. Cannabinoids
interaction with liver metabolized drugs, using several enzymes of the P450 CYP system,
is well known[132]. Amongst antiseizure medications there is evidence showing an increase in levels
of topiramate, rufinamide, zonisamide, eslicarbazepine and N-desmethylclobazam, this
last one with increased sedation, in epilepsy patients[51]. Concomitant use of anticoagulants like warfarin carries an increase in bleeding
risk. Other associations to be avoided are St John wort (Hypericum perforatum), rifampin, ketoconazole, and some antiviral drugs[51].
Another concern regarding cannabis-based medicine is the driving skills. It is well
known that THC impairs the ability to drive, and the time lapse between THC use and
safety drive is considered between six to eight hours after consumption[133],[134]. That may not be the case for pure CBD content medicines, but few studies addressed
that at this moment. A 2018 literature review evaluating the driving skills specifically
in MS patients having THC/CBD mucosal spray for spasticity treatment did not find
any evidence of increase in motor vehicle-accident in those patients, with reference
to improvement in motor and cognitive abilities related to driving[134].
The Lower-Risk Cannabis Use Guidelines (LRCUG) published in 2017 summarizes behaviors
that can decrease or increase the associated risk of cannabis use and is a good line
to follow to offer a safer experience to cannabis treated patient[128].
Finally, while we wait for good evidence publications, in favor or against cannabis
medicine, knowing the mechanisms of action, the pharmacology, the restrictions and
contraindications may be more helpful to our patients than been excited to any new
biased indication.
