Neurological Sciences

https://doi.org/10.1007/s10072-022-06393-1

ORIGINAL ARTICLE

Cannabis‑based magistral formulation is highly effective

as an adjuvant treatment in drug‑resistant focal epilepsy in adult
patients: an open‑label prospective cohort study
Cristian Eduardo Navarro1,2,3,4 

Received: 18 August 2022 / Accepted: 8 September 2022

© Fondazione Società Italiana di Neurologia 2022

Abstract  
Introduction  The safety and efficacy of a formulation high in cannabidiol (CBD) and low in ∆9-tetrahydrocannabinol (THC)
to treat drug-resistant epilepsy have been examined previously in children, but not in adult population. The aim of this study
was to evaluate whether CBD-rich oil, as an add-on treatment to conventional antiepileptic drugs, was effective, safe, and
well-tolerated in adults with drug-resistant focal epilepsy (DRFE).
Methods  An open-label, prospective cohort, single-center in adult patients with DRFE, were receiving stable doses of
antiepileptic drugs (AEDs). A cannabisbased-magistral formulation (CBMF) (100 mg/ml CBD and THC <1.9 mg/ml) wasa-
dministrated 0.1 ml sublingually every 12 hours, up-titrated weekly. Theprimary outcome was to establish a reduction in
seizures frequency >50% at12 weeks. Adverse-drug reactions monitoring was done. p-value <0.05 wasstatistically significant.
Results  BetweenAugust 2020 and July 2022, 44 (38.6%) patients completed >3 months offollow-up. The median daily dose
of CBD was 200 mg, that of THC was 4 mg, andthat of CBD per kilogram of weight was 3.7 mg. The median number of
seizuresper month before CBD treatment was 11, and after CBD treatment was 2.5(p<0.001). A reduction in seizures >50%
at 12 week was achieved in 79.5%of the patients. The median percentage change in seizure frequency per monthwas 84.1%
at 12 weeks. Five patients reported any adverse-drug reactions.
Conclusion  The CBMF is a highly effective and safety therapy to treat adult patients with DRFE. The reduction in seizures
frequency is maintained over time.

Keywords  Cannabidiol · Cannabis · Drug-resistant epilepsy · Epilepsies partial · Treatment outcome

Introduction  children and young people with other etiologies of drug-

Epidiolex® (99% cannabidiol [CBD] formulation) has
emerged as a new alternative to treat drug-resistant epilepsy,
especially in patients with some epileptic encephalopathies
[1–4]. Besides, its effectiveness has been demonstrated in
* Cristian Eduardo Navarro
cenavarroc@unal.edu.co
1
Unit of Clinical Neurology, School of Medicine, Universidad
Nacional de Colombia, Bogotá, Colombia
2
Master’s Program in Epidemiology, School of Medicine,
Universidad El Bosque, Bogotá, Colombia
3
Grupo de Investigación en Neurología, de la Universidad
Nacional de Colombia–NeuroUnal, Bogotá, Colombia
4
Medical Cannabis and Drug-Resistant Epilepsy Program,
Clínica Zerenia, Bogotá, Colombia
resistant focal epilepsy (DRFE) such as tuberous sclero-
sis complex [5], cyclin-dependent kinase-like 5 (CDKL5)
deficiency disorder, Aicardi syndrome, chromosome
15q11.2–13.1 duplication (Dup15q) syndrome, Doose syn-
drome [6], Sturge–Weber syndrome, SYNaptic GTPase
Activating Protein (SYNGAP1) encephalopathy [7], sodium
voltage-gated channel alpha subunit 8 (SCN8A)–related
epilepsy, epileptic spasms, and epilepsy with myoclonic
absences [8]. The effectiveness of CBD is explained by the
participation of the endocannabinoid system in different pro-
cesses that restore homeostasis, and even control seizures
[9]. The safety and efficacy of a formulation high in CBD
and low in ∆9-tetrahydrocannabinol (THC) (50:1) to treat
drug-resistant epilepsy have been examined previously in
children [10, 11], but data is still sparse in adult population.
The aim of this study was to evaluate whether CBD–rich
oil (50:1), as an add-on treatment to conventional AEDs,

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was effective, safe, and well-tolerated in adults with DRFE,
independent of their age and epileptic etiology.
Methods
Study design and population
An open-label, prospective cohort, single-center study was
conducted at Clínica Zerenia (a reference center special-
izing in medical cannabis therapy) in Bogotá, Colombia.
The inclusion criteria were patients > 18 years old who had
DRFE irrespective of etiology and seizure frequency, and
were receiving stable doses of AEDs for at least 3 months
before enrollment. If patients were taking valproic acid, it
could be suspended to avoid thrombocytopenia and hepato-
toxicity [12]. Since obtaining the serum levels of clobazam
is not feasible in Colombia, its dose was tapered off gradu-
ally in patients who were taking it, considering the exces-
sive daytime sleepiness it induces [13]. For individual sub-
jects with vagus nerve stimulation, the settings had to be
unchanged for a month. Each patient had to have at least
3 months of follow-up to be included in the final analysis.
The exclusion criteria were patients < 18 years-old, with-
out drug-resistant epilepsy or with genetic generalized epi-
lepsy, with cognitive disabilities and without caregivers to
provide accurate information, with suspected non-epileptic
paroxysmal events, with a history of addiction or substance
abuse, pregnant women, and individuals with baseline liver,
renal, or haematological laboratory abnormalities.
The institutional review board approved the study.
Patients provided written informed consent to participate
and to use a cannabis based-magistral formulation (CBMF).
Procedures and intervention
Before initiating CBD-rich oil therapy, patients had a 4-week
baseline period to fill in their seizures-diary. They were
asked to report any type of motor and non-motor seizure.
Episodes of status epilepticus and emergency room visits
were also recorded prospectively in patient diaries.
After this period, patients received the CBMF, which was
prepared by diluting cannabis extracts, using sesame oil and
ethanol as excipients, with added sucralose, and flavoring
agents [14]. The concentration of CBMF was 100 mg/ml
CBD and THC < 1.9 mg/ml (Epidiolex®-like formulation),
and it was produced by Khiron Life Science Corp®. Patients
were given 0.1 ml CBD-rich oil sublingually every 12 h,
up-titrated weekly based on seizure response and toler-
ability. The maximum dose considered was 50 mg/kg/day
as reported in a previous study in adult patients [15]. The
CBMF was added to an unchanged AED regimen; the only
drug to withdraw was valproic acid.
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Neurological Sciences
Every month, each patients had a neurological consultation to
evaluate the use of the CBD-rich oil, to determine the adherence
to the other AEDs, to collect information from the seizures-diary,
to weight the patient, and to enquire about any adverse-drug reac-
tions using the Liverpool Adverse Events Profile (LAEP) [16].
A complete blood count, kidney function test (serum
creatinine, blood urea nitrogen), and liver function test
(transaminases, bilirubin, gamma-glutamyl transferase, alka-
line phosphatase) were performed and serum concentrations
of AEDs were measured for each patient before starting the
CBD-rich oil therapy and every 3 months.
Outcomes
The primary outcome was to establish the effectiveness of
CBD-rich oil, defined as a reduction in seizures > 50% at
12 weeks compared with the baseline (the response rate).
The secondary outcomes were: proportion of patients
with > 50% reduction in seizures at 24 weeks compared with
the baseline; percentage of subjects with > 75% reduction
in seizures at 12 and 24 weeks compared with the baseline;
proportion of patients with > 90% reduction in seizures at
12 and 24 weeks compared with the baseline; proportion of
seizure-free patients; percentage change in monthly seizure
frequency at 12 and 24 weeks; and proportion of subjects
experiencing adverse drug reactions.
The percentage change in monthly seizure frequency at
12 weeks for each patient was calculated using Devinsky’s equa-
tion [15].
Statistical analysis
The study sample size was not predetermined; the entire
cohort of patients recruited since study initiation was consid-
ered. Descriptive statistics (percentage, median, interquartile
range [IQR], mean, standard deviation [SD]) were applied
to age, age at epilepsy diagnosis, years with epilepsy, sex,
etiology of DRFE, time of CBD-rich oil treatment, seizure
frequency, types of AEDs, dose of CBD and THC, dose
of clobazam, patients’ weight, and adverse drug reactions.
The null hypothesis of normality was verified with the Sha-
piro–Wilk test. Quantitative variables were compared using
the paired Student’s t test or the non-parametric Wilcoxon
test, as appropriate. The independence between qualitative
variables was evaluated using the McNemar test. The cor-
relations between the dose of CBD-rich oil and clobazam,
and between the dose of CBD-rich oil and previous seizure
frequency, were analyzed with Pearson’s or Spearman’s
correlation coefficients, as appropriate. A multiple logistic
regression analysis was performed to investigate the associa-
tion between the response rate (> 50% decrease in seizure
frequency at 12 weeks) and CBD dose, with adjustments
Neurological Sciences
for age, sex, etiology of DRFE, years with epilepsy, type of
AED, and seizure frequency before CBD treatment.
A p value < 0.05 was considered statistically significant.
The effectiveness was analyzed by a modified intention-to-
treat principle.
The data were obtained from the clinical record system
Gomedisys® and organized in a Microsoft Excel-Office
365® sheet. The database was analyzed with the IBM SPSS
Statistics® version 28 software.
Role of the funding source
Khiron Life Science Corp.® and the directive board at
Clínica Zerenia had no role in the study design, data collec-
tion, data analysis, data interpretation, writing of the manu-
script, or in the decision to submit the paper for publica-
tion. Khiron Life Science Corp.® did not deliver CBMF to
patients. In Colombia, medical cannabis is an off-label treat-
ment, so it is an out-of-pocket expense. Each patient agreed
to pay for their treatment. The corresponding and main author
had full access to all the data in the study and assume the
final responsibility for the decision to submit for publication.
Fig. 1  STROBE flow diagram
Results
Between August 2020 and July 2022, 114 patients were evalu-
ated at our medical cannabis clinic. Of them, 98 (86%) patients
had DRFE, but only 61 (53.8%) opted for CBD-rich oil treat-
ment (37 patients could not pay for CBMF). Forty-four (38.6%)
patients completed > 3 months of follow-up (34 with > 6 months)
and their data were available for analysis (Fig. 1). Table 1 shows
the baseline clinical characteristics of patients. Their median
age was 30 years (IQR 25–37) and were living with epilepsy
for a mean of 20.8 years (SD 9.8). The most common etiology
of epilepsy was structural (50%, n = 22), followed by unknown
causes (36.4%; n = 16) (Table 2). The median number of AEDs
was 2.5 (IQR 2–3), and the most frequently used drug was lev-
etiracetam, used by 23 patients (52.3%). Only 4 patients (9.1%)
had a vagus nerve stimulation device.
The median daily dose of CBD was 200  mg (IQR
185–345), that of THC was 4 mg (IQR 3.7–6.9), and that of
CBD per kilogram of weight was 3.7 mg (IQR 2.3–5.2). The
maximum CBD dose was 700 mg daily (14 mg/kg/day). The
patients used CBD-rich oil for a median of 10 months (IQR
5–13.75). The median number of seizures per month before
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Table 1  Baseline characteristics Variable Number Mean (SD) Median (IQR)

(percentage)

Male 33 (75)
Female 11 (25)
Age (years) 33.2 (14.7) 30 (25–37)
Age at diagnosis (years) 12.3 (14.6) 12 (2.25–15)
Years with epilepsy 20.8 (9.8) 19.5 (14–27)
Weight (kg) 67.1 (15.8) 65 (52.25–78.75)
Seizures per month without CBD 40.25 (70.3) 11 (4–30)
Number of antiepileptic drugs 2.4 (0.9) 2.5 (2–3)
Clobazam dose before CBD (mg) 40.4 (19.6) 40 (25–60)
Vagus nerve stimulation 4 (9.1)

CBD cannabidiol, IQR interquartile range, SD standard deviation, THC ∆9-tetrahydrocannabinol

patients (n = 35 of 44). The response rate at 24 weeks was

Table 2  Causes of epilepsy and antiepileptic drugs
obtained in 27 of 34 patients (79.4%) with > 6 months of fol-
Variable Number (percentage) low-up. The median percentage change in seizure frequency
Etiology of epilepsy Unknown 16 (36.4)
per month was 84.1% (IQR 50–100) at 12 weeks. The pro-
Structural 22 (50)
portion of seizure-free patients was 27.3% (n = 12) (Fig. 3).
Genetic 5 (11.4)
Table 3 presents each evaluated outcomes at 12 weeks and
Infectious 1 (2.3)
24 weeks. No variable was associated with the response
Metabolic 0 (0)
rate to CBD-rich oil at 12 weeks, as per logistic regression
Immune 0 (0)
analysis.
Antiepileptic drug Brivaracetam 6 (13.6)
Carbamazepine 8 (18.2)
Adverse‑drug reactions
Clobazam 11 (25)
Lacosamide 19 (43.2)
Reasons for withdrawal included unsteadiness (n = 1), feel-
Lamotrigine 14 (31.8)
ings of aggression (n = 1), and tiredness (n = 1); all with a
Levetiracetam 23 (52.3)
LAEP score of 4. These adverse–drug reactions appeared
Oxcarbazepine 9 (20.5)
from the beginning of CBD therapy regardless of the low
Phenytoin 3 (6.8)
dose used. One patient reported feelings of aggression and
Topiramate 7 (15.9)
another had sleepiness after they had achieved the primary
Valproic acid 5 (11.4)
outcome, but when the dose of CBD-rich oil was slightly
Vigabatrin 2 (4.5)
reduced, the symptoms improved and the two patients were
able to continue the therapy. The patient who reported sleep-
CBD treatment was 11 (IQR 4–30), and after CBD treatment iness was taking concomitant clobazam, so its daily dose
was 2.5 (IQR 0–6.75) (median difference p < 0.001). This was decreased from 25 to 15 mg daily. No patients displayed
effect was maintained at 12 weeks and at 24 weeks (Fig. 2). an abnormality in complete blood count, and kidney and
Within the subgroup of patients taking clobazam (n = 11), liver function tests. No cases of thrombocytopenia or hepa-
there was no a significative dose reduction before and after totoxicity were recorded.
CBD use (mean 40.4 mg vs 30.9 mg; mean difference 9.5 Valproic acid was discontinued in one patient (1 of 5)
[95%CI − 0.91–20.0], p = 0.069). after achieving seizures control. None of patients with
The doses of CBD-rich oil and clobazam did not correlate clobazam required its suspension.
at 12 weeks (Spearman’s correlation coefficient =  − 0.125,
p = 0.715), and the dose of CBD-rich oil was not associated
with previous seizure frequency as well (Spearman’s cor- Discussion
relation coefficient = 0.109, p = 0.482).
The present open-label, prospective cohort study shows
Effectiveness outcomes that add-on treatment with CBD-rich oil (CBMF) is safety
and effective for adult patients with DRFE, independent
A reduction in seizures > 50% at 12 weeks compared with of sex, age, time with epilepsy, etiology, seizure frequency
the baseline (the response rate) was achieved in 79.5% of the before CBD treatment, and clobazam doses. The clinically

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Neurological Sciences
Fig. 2  Change in seizure
frequency per month between
baseline and week 12
Fig. 3  A Percentage of patients with seizures reduction > 50% at
12 weeks compared with baseline. B Percentage of patients with sei-
zures reduction > 75% at 12  weeks compared with baseline. C Per-
meaningful response rate at 12 weeks was achieved in 79.5%
of the patients, and it was maintained at 24 weeks. The median
percentage change in monthly seizure frequency was 84.1% at
12 weeks. The median number of seizures per month drasti-
cally decreased from 11 before CBD treatment to 2.5 after
centage of patients with seizures reduction > 90% at 12  weeks com-
pared with baseline. D Percentage of patients with seizures-free at
12 weeks compared with baseline
CBD treatment (p < 0.001). Twelve of the 44 patients (27.3%)
were declared seizure-free, which is the most important out-
come for patients with drug-resistant epilepsy.
The CBD daily dose was not high (median of 200 mg)
considering that the patients were adults with a mean weight
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Table 3  Response rates at 12 weeks and at 24 weeks after treatment
with CBD-rich oil
Outcome At 12 weeks At 24 weeks
Seizures reduction > 50% 79.5% (n = 35/44) 79.4% (n = 27/34)
Seizures reduction > 75% 52.3% (n = 23/44) 52.9% (n = 18/34)
Seizures reduction > 90% 45.5% (n = 20/44) 47.1% (n = 16/34)
Median percentage 84.1% (IQR 50–100) 85% (IQR 50–100)
change in seizure fre-
quency per month
IQR interquartile range
of 67 kg (3.7 mg/kg/day of CBD). The patient with highest
CBD dose (700 mg daily, 14 mg/kg/day) was a 23-year-old
male with a structural DRFE, who had a good tolerance
to THC (14 mg daily in a 50:1 CBMF); his response rate
was 73.3%. Comparing our results with those of previous
studies, including epileptic encephalopathy trials evaluating
99% purified CBD [1–4, 17–19], adults with DRFE who
use a CBMF may need a lower CBD dose. The correlation
between CBD oral dose, serum CBD levels and the response
rate has been evaluated by Malaca et al. [20]. They showed
that there is an inter-individual variability between the CBD
dose and its serum levels, and between the different brands
of CBD–oil and the serum levels of metabolites. It is neces-
sary in the near future to quantify these drug–levels. It could
be possible to adjust the CBD dosage according to the serum
levels and not to the patient’s weight.
Currently, the mechanism by which CBD alleviates sei-
zure frequency is unclear. CBD has affinity to Transient
Receptor Potential Vanilloid-1 (TRPV1), the orphan G
Protein-Coupled Receptor-55 (GPR55) and the equilibrative
nucleoside transporter-1 (ENT-1). The TRPV1 and GPR55
downregulate the pro-inflammatory pathways and the influx
of ­Ca2+ to mitochondria. The ENT-1 enhances the anti-
inflammatory pathways through the role of adenosine as a
negative modulator of glutamate–excitatory transmission
[21]. The antagonism of the N-methyl-D-aspartate recep-
tor and the P-glycoprotein efflux transporter inhibition are
other possible mechanisms of action [22, 23]. The CBD use
has been clinically associated with a significant decrease
in interictal discharges in adults [24, 25]. It has been sug-
gested that CBD–rich extracts could be more effective in
reducing seizure frequency compared with purified CBD
[22]. The synergistic effect between CBD and THC in a
CBMF may enable reduced seizure frequencies in adults
at lower daily doses, which contrasts with the results of
Devinsky et al. [26]. They published the first study evalu-
ating the tolerability and efficacy of CBMF (high-CBD/
low-THC 20:1 and 50:1) to treat seizures in 29 subjects
(children and adults) for 6 months, with a maximum pos-
sible CBD/THC daily dose of 300/6 mg daily. The mean
age was 25 years, but only 10 patients continued the drug
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intervention after 12 weeks. The CBMF doses was lower,
the average THC dose was 0.11 mg/kg/day and CBD dose
was 2.3 mg/kg/day (maximal THC dose 5.9 mg and CBD
dose 117.2 mg). They reported no significant difference in
the seizure frequency between the baseline and the interven-
tion period (Wilcoxon test p = 0.99). The study showed only
21% patients with a > 50% reduction in seizure frequency,
and only 13.8% patients became seizure-free. Unlike our
results, they had 4 patients (13.8%) with a > 50% increase
in seizure frequency. Also, CBMF efficacy did not improve
in patients taking clobazam [26]. On the other hand, Mar-
chese et al. [27] published a retrospective study evaluating a
CBD–oil in a heterogeneous group of 37 patients (children
and adults) with focal epilepsy, generalized epilepsy and
epileptic encephalopathy (22 of 37). Unlike this study, they
used a 24% CBD-rich oil; but the effective CBD dose was
similar (4.2 mg/kg/day), which is lower compared to what
was published. The response rate was achieved in 73% of
patients. The 85% of patients with an epileptic encephalopa-
thy had a reduction of seizures > 50%. Only 56% of patients
with DRFE achieved the response rate, which is a lower
proportion compared with the results reported in the present
study. The adverse events were mild, but they occurred in a
higher proportion (25% of patients).
Previous studies that have demonstrated long-term effec-
tiveness of CBD treatment in adults with DRFE, have not
evaluated a CBMF, and the dose was adjusted according
to the patient's weight [15, 17–19, 28]. In contrast to the
present findings, those trials show a lower proportion of
patients achieving the response rates. Further investigations
are necessary to evaluate whether sublingual administration
is better than oral route due to the greater bioavailability of
CBD. Also, the hypothesis that CBMF has a similar or a
higher potency than a 99% purified CBD formulation (the
entourage effect) remains unproven.
The adverse event profile of CBD-rich oil was favora-
ble in our study, despite its addition to a median of two
concomitant AEDs. Five patients (11.4%) reported adverse
effects, but these were mild and were resolved after stop-
ping or lowering the dose of CBD. The slow dose titration
of CBD-rich oil helps avoid adverse effects, especially at
the beginning of treatment. Unlike other studies [15, 17, 18,
26], we adjusted the dose as 0.1 ml (10 mg of CBD) every
12 h, up-titrated weekly. Actually, our CBD titration scheme
is slower than that published by D’Onofrio et al. [29] and
our approach is more secure with fewer adverse-drug reac-
tions such as unsteadiness (n = 1), feelings of aggression
(n = 2), tiredness (n = 1), and sleepiness (n = 1). No cases
of thrombocytopenia or hepatic failure were reported, most
likely because the number of patients taking valproic acid
was low, and monitoring was rigorous; also, serum level
of valproic acid was evaluated quarterly to avoid an over-
dose. One patient did not require taking valproic acid after
Neurological Sciences
achieving ictal control (1 of 5 patients). Clobazam was used
in 11 of 44 patients (25%) with no correlation with CBD-
rich oil dose. The meta-analysis of randomized and pla-
cebo-controlled trials testing the efficacy of CBD in Dravet
and Lennox-Gastaut syndromes showed that improvement
depends on the dose of CBD and not clobazam status or its
serum levels [30]. Expecting a high risk of hypersomnia
because of the CBD–clobazam interaction [13, 31–34], the
clobazam doses was lowered as needed and as reported by
the patient, but this adjustment was not significantly differ-
ent (mean clobazam doses before vs after CBD = 40.4 mg
vs 30.9 mg, p = 0.069). No patient required clobazam to be
discontinued. These results about safety are in agreement
with those published previously [35].
Limitations
This study was limited by lack of blinding, small sample
size, and lack of a control group. The small sample size is
explained by the significant number of subjects that did not
initiate therapy and were withdrawn (n = 37). Currently in
Colombia, CBD treatment for epilepsy is expensive and not
covered by the healthcare system, so those patients could not
afford it. The placebo effect was not considered to explain the
effectiveness observed in patients who could pay for CBMF.
As previously discussed, it has been described that CBD
possesses affinity for multiple receptors which modulate the
neuronal excitability important to the physiopathology of
seizures. To avoid a conflict of interest, Khiron Life Science
Corp.® was not allowed to sponsor the CBMF treatment.
The entire cohort was heterogeneous regarding the epi-
lepsy etiology, and catastrophic epilepsies were excluded
considering the aim of the study. So, this might explain why
the CBD dose needed was low, because these other types of
DRFE are not very difficult to treat as Lennox-Gastaut and
Dravet syndromes. The number of AEDs required was low
(2.5 [IQR 2–3]), in Colombia is not usual to use > 3 AEDs
in a patient because the benefit is less than 3% [36].
Another possible limitation is the low CBD dose used
compared with other studies; even though the effectiveness
obtained was significant and was maintained over 24 weeks,
a higher CBD dose could improve the response rate further.
The dose limitation is related to the CBMF cost.
Maybe the response rate would change if all non-motor and
nocturnal seizures were counted in detail, but this was not possible
because several patients lived alone or were unaware of their seizures.
This study is benefited from a structured and rigorous
observation period with a continuous slow dose titration
and adverse-drug reaction monitoring to ensure tolerance.
Another point in favor is the restrictive inclusion criteria
which allows conclusions to be drawn only for the adult
population with DRFE.
Conclusion
The present study shows that CBMF (high-CBD/low-THC
50:1) is a highly effective and safety therapy to treat adult
patients with DRFE other than Dravet and Lennox-Gastaut
syndromes. This effectiveness was independent of sex, age,
time with epilepsy, etiology, seizure frequency, and clobazam
doses. The reduction in seizures frequency is maintained over
time. In adults, the dose of CBMF could be established with-
out considering the patient’s weight, because a low CBD dose
and a slow dose titration improve tolerance. Further infor-
mation derived from randomized controlled clinical trials is
needed to confirm the findings presented in this article.
Acknowledgements  To patients and their families who agreed to par-
ticipate in this observational study.
Author’s contributions  Cristian Eduardo Navarro MD MSc: concep-
tualization, review of literature, data collection, data analysis, writing,
and editing the manuscript. The author read and approved the final
manuscript.
Funding  This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Declarations 
Ethical approval  The institutional review board approved the study.
Consent to participate and for publication  Patients provided written
informed consent to participate and to use a cannabis-based magistral
formulation (CBMF).
Conflict of interest Cristian Eduardo Navarro MD MSc works at
Clínica Zerenia in Bogotá (Colombia) which is a reference center spe-
cializing in medical cannabis therapy owned by Khiron Life Science
Corp®. Khiron Life Science Corp.® manufactures the cannabis-based
magistral formulation used in this study.
Informed consent  Informed consent was provided by each patient at
the beginning of the study.
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