Short-Term Medical Cannabis Treatment Regimens
Produced Beneﬁcial Eﬀects among Palliative
Joshua Aviram 1, Gil M. Lewitus 1, Yelena Vysotski 1, Anton Uribayev 2, Shiri Procaccia 1,
Idan Cohen 3, Anca Leibovici 2, Mahmud Abo-Amna 3, Luiza Akria 2, Dmitry Goncharov 2,
Neomi Mativ 2, Avia Kauﬀman 2, Ayelet Shai 2, Or Hazan 1, Gil Bar-Sela 3,4 ,* and David Meiri 1 ,*
1Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel;
email@example.com (J.A.); firstname.lastname@example.org (G.M.L.); email@example.com (Y.V.);
firstname.lastname@example.org (S.P.); email@example.com (O.H.)
2Department of Oncology, Galilee Medical Center, Nahariya 22100, Israel; AntonU@gmc.gov.il (A.U.);
AncaL@gmc.gov.il (A.L.); AkriaL@gmc.gov.il (L.A.); DmitriG@gmc.gov.il (D.G.);
NeomyM@gmc.gov.il (N.M.); AviaK@gmc.gov.il (A.K.); firstname.lastname@example.org (A.S.)
3Cancer Center, Emek Medical Center, Afula 18101, Israel; email@example.com (I.C.);
4Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel
*Correspondence: firstname.lastname@example.org (G.B.-S.); email@example.com (D.M.); Tel.: +972-4-6495723 (G.B.-S.);
+972-77-8871680 or +972-525330031 (D.M.)
Received: 14 November 2020; Accepted: 27 November 2020; Published: 30 November 2020
In the last decade the use of medical cannabis (MC) for palliative cancer treatment has risen.
However, the choice between products is arbitrary and most patients are using Tetrahydrocannabinol
(THC)-dominant cannabis products. In this study, we aimed to assess the short-term outcomes
of MC treatment prescribed by oncologists in relation to the type of cannabis they receive.
A comparative analysis was used to assess the diﬀerences in treatment eﬀectiveness and safety
between THC-dominant (n=56, 52%), cannabidiol (CBD)-dominant (n=19, 18%), and mixed
, 30%) MC treatments. Oncology patients (n=108) reported on multiple symptoms in baseline
questionnaires, initiated MC treatment, and completed a one-month follow-up. Most parameters
improved signiﬁcantly from baseline, including pain intensity, aﬀective and sensory pain, sleep
quality and duration, cancer distress, and both physical and psychological symptom burden.
There was no signiﬁcant diﬀerence between the three MC treatments in the MC-related safety
proﬁle. Generally, there were no diﬀerences between the three MC treatments in pain intensity
and in most secondary outcomes. Unexpectedly, CBD-dominant oil treatments were similar to
THC-dominant treatments in their beneﬁcial eﬀects for most secondary outcomes. THC-dominant
treatments showed signiﬁcant superiority in their beneﬁcial eﬀect only in sleep duration compared
to CBD-dominant treatments. This work provides evidence that, though patients usually consume
THC-dominant products, caregivers should also consider CBD-dominant products as a useful
treatment for cancer-related symptoms.
Keywords: medical cannabis; THC; CBD; palliative cancer treatment; oncology
Cancer patients suﬀer from many conditions resulting from the disease or its treatment.
These include cancer-related pain [
], anxiety [
], depression [
], insomnia [
], decreased quality of
], and increased disability [
]. These comorbidities are some of the underlying causes of cancer
Pharmaceuticals 2020,13, 435; doi:10.3390/ph13120435 www.mdpi.com/journal/pharmaceuticals
Pharmaceuticals 2020,13, 435 2 of 16
patients’ suﬀering while undergoing therapies and some may even lead to worsened prognosis [
To date, there is still no optimal treatment addressing all of these comorbidities .
Currently, Medical Cannabis (MC) is one of the options to alleviate cancer patients’ suﬀering [
While the preclinical literature is vast [
], there is a paucity of clinical literature [
to arbitrary MC treatment regimen decisions based mostly on the oncologist experience and on
patient demands. Many oncologists ﬁnd MC appropriate as the ﬁrst-line therapy for cancer-related
] and a recent study showed that the majority of cancer patients request MC treatment
from their oncologist [
]. Nonetheless, there is not enough data on the negative and positive eﬀects of
MC treatment on cancer patients .
Importantly, cannabis is not a single compound; it is comprised from many compounds in diﬀerent
concentrations, including many phytocannabinoids [
] with diverse biological activities [
The concentration of these compounds (i.e., chemovar) is also vastly diﬀerent between diﬀerent
strains (i.e., cultivars) [
]. This makes traditional treatment by titrating of a single molecule
particularly diﬃcult. Thus far, Randomized Controlled Trials of cancer-related pain focused mainly on
-trans-tetrahydrocannabinol (THC) [
], but currently, probably due to the large media hype
and its more enabling regulation worldwide, there is a major shift of focus to cannabidiol (CBD) [
Today, most countries that approve MC treatment require cultivators to report and adhere only by the
two major phytocannabinoids, THC and CBD .
In this study, we conducted a prospective, short-term study that compared the eﬀectiveness and
safety of the most widely used categorization of MC treatment, conceptualized by Small
et al., (1973)
to THC-dominant as type I cannabis, equal THC and CBD as type II, and CBD-dominant as type III [
A total of 293 patients were enrolled to the study, of them, 228 patients completed the baseline
) questionnaires and initiated MC treatment (Figure 1, CONSORT ﬂow diagram). A follow-up
questionnaire was completed by 147 patients at T
. Of these patients, 108 patients reported on full MC
treatment information, these patients represent the analyzed sample for the current study. About 95%
of the patients provided data online and the rest by telephone calls.
Pharmaceuticals 2020, 13, x FOR PEER REVIEW 2 of 16
and increased disability . These comorbidities are some of the underlying causes of cancer patients’
suffering while undergoing therapies and some may even lead to worsened prognosis . To date,
there is still no optimal treatment addressing all of these comorbidities .
Currently, Medical Cannabis (MC) is one of the options to alleviate cancer patients ' suffering .
While the preclinical literature is vast [9–13], there is a paucity of clinical literature , leading to
arbitrary MC treatment regimen decisions based mostly on the oncologist experience and on patient
demands. Many oncologists find MC appropriate as the first-line therapy for cancer-related
symptoms  and a recent study showed that the majority of cancer patients request MC treatment
from their oncologist . Nonetheless, there is not enough data on the negative and positive effects
of MC treatment on cancer patients .
Importantly, cannabis is not a single compound; it is comprised from many compounds in
different concentrations, including many phytocannabinoids [18,19] with diverse biological activities
[20,21]. The concentration of these compounds (i.e., chemovar) is also vastly different between
different strains (i.e., cultivars) [22–24]. This makes traditional treatment by titrating of a single
molecule particularly difficult. Thus far, Randomized Controlled Trials of cancer-related pain
focused mainly on (-)-Δ9-trans-tetrahydrocannabinol (THC) [25–31], but currently, probably due to
the large media hype and its more enabling regulation worldwide, there is a major shift of focus to
cannabidiol (CBD) . Today, most countries that approve MC treatment require cultivators to
report and adhere only by the two major phytocannabinoids, THC and CBD .
In this study, we conducted a prospective, short-term study that compared the effectiveness and
safety of the most widely used categorization of MC treatment, conceptualized by Small et al. (1973), to
THC-dominant as type I cannabis, equal THC and CBD as type II, and CBD-dominant as type III .
A total of 293 patients were enrolled to the study, of them, 228 patients completed the baseline
(T0) questionnaires and initiated MC treatment (Figure 1, CONSORT flow diagram). A follow-up
questionnaire was completed by 147 patients at T1. Of these patients, 108 patients reported on full
MC treatment information, these patients represent the analyzed sample for the current study. About
95% of the patients provided data online and the rest by telephone calls.
Figure 1. Consort flowchart diagram. T0, Baseline; T1, one-month follow-up; MC, medical cannabis;
BL, baseline; AEs, adverse effects.
Consort ﬂowchart diagram. T
, Baseline; T
, one-month follow-up; MC, medical cannabis;
BL, baseline; AEs, adverse eﬀects.
Pharmaceuticals 2020,13, 435 3 of 16
2.1. MC Treatment Characteristics
MC treatment information was reported by 108 patients at T
and included type I (n=56, 52%;
patients consuming THC-dominant cultivars only; included three products: THC(T)20/CBD(C)4,
T15/C3 and T10/C2), type III (n=19, 18%; patients consuming CBD-dominant cultivars only; included
three products: T1/C20, T5/C10 and T3/C15), and type II (i.e., mixed; n=33, 30%; patients consuming
cultivars with similar THC:CBD ratio that included two products: T10/C10 and T5/C5, or patients
consuming both THC-dominant and CBD-dominant cultivars in the same day) MC treatments.
Sublingual MC oil extract was the most common route of administration for type III and for type
II treatments and less common for type I treatments (n=17, 89%, n=19, 58%, and n=19, 34%,
respectively), whereas patients consuming type I treatments consumed it mostly (n=32, 57%) by
inﬂorescence inhalation. Inﬂorescence inhalation was less common for type III and for type II treatments
(n=2, 11% and n=7, 21%, respectively). Some patients consuming type I and type II (n=5, 9% and
), but not for type III, utilized both administration routes (
=26.02, p<0.001). Overall
reported monthly MC dose was similar for all three treatments (20 (20–20) grams).
THC and CBD monthly doses were signiﬁcantly diﬀerent between the three treatments
=68.28, p<0.001, respectively). Patients consuming type I treatments
consumed 600 (400–725) mg/month of CBD (with weight-adjusted dose of 7.8 (5.7–11) mg/kg/month) and
3000 (2000–3600) mg/month of THC (with weight-adjusted dose of 39 (29–56) mg/kg/month). Patients
consuming type III treatments consumed 2000 (2000–3000) mg/month of CBD (with weight-adjusted
dose of 40 (26–46) mg/kg/month) and 1000 (600–1000) mg/month of THC (with weight-adjusted dose
of 12 (8.4–15) mg/kg/month). Patients consuming type II treatments consumed 2000 (1500–2000)
mg/month of CBD (with weight-adjusted dose of 30 (20–36) mg/kg/month) and 2000 (1400–2000)
mg/month of THC (with weight-adjusted dose of 29 (20–36) mg/kg/month).
2.2. Baseline Demographics and Cancer Characteristics
Sixty-two of the patients in the sample were females (57%) with an average age of 64 (52–72) years.
Demographic characteristics did not diﬀer between the MC treatments (Table 1). Oncology diagnoses
were heterogenous, with breast cancer being the most frequent diagnosis (n=30, 28%), followed by
lung, colon and ovarian cancers (n=15, 14%, n=15, 14%, and n=5, 5%; respectively). Most patients
(n=48, 44%) were categorized as in IV stage cancer where 57 of the patients (53%) were at ﬁrst-line
of oncology treatment, meaning that most patients were diagnosed and started treatment while in
advanced metastatic disease. Chemotherapy was the most prevalent current treatment protocol (n=56,
52%), followed by biological and immunological cancer treatments protocols (n=15, 14% and n=10,
9%, respectively). Most patients (n=76, 70%) were scored by the oncologist as not disabled (scored
based on Eastern Cooperative Oncology Group (ECOG) Performance Status score). Additionally, no
signiﬁcant diﬀerences were found in cancer characteristics between the three MC treatments (Table 2).
Table 1. Demographic characteristics.
Parameters Type I
(χ2)†/Kruskal–Wallis rank ††
Age (years) 62 (49–68) 66 (54–74) 66 (56–72) 64 (52–72) 3.37 †† (0.19)
Unknown 4 2 2 8
No. of patients (%)
Male 25 (45) 6 (32) 15 (45) Male 25 (45)
Female 31 (55) 13 (68) 18 (55) Female 31 (55)
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Table 1. Cont.
Parameters Type I
(χ2)†/Kruskal–Wallis rank ††
Weight (kg) 72 (65–80) 69 (53–77) 66 (55–80) 70 (59–80) 2.12 †† (0.35)
Unknown 7 5 5 17
BMI 25 (22–29) 24 (21–26) 26 (21–28) 25 (22–28) 0.70 †† (0.70)
Unknown 12 7 6 25
No. of patients (%)
Comorbidities (yes) 19 (34) 5 (26) 7 (21) 31 (29) 1.21 †(0.54)
Unknown 1 1 3 5
experience (yes) 17 (30) 5 (26) 7 (21) 29 (27) 0.88 †(0.64)
, Pearson’s Chi-squared test;
, Kruskal–Wallis rank sum test; kg, kilograms; BMI, body mass index; IQR,
inter quartile range; n, number of patients; where missing nis not speciﬁed, there are no missing data; Type I,
THC-dominant treatments; Type III, CBD-dominant treatments; Type II, equal THC:CBD concentration treatments;
#, Signiﬁcance between the three diﬀerent treatment regimens.
Table 2. Cancer characteristics.
Parameters Type I
n=108 χ2(p-Value) #
No. of patients (%)
Solid tumor etiology
Breast 19 (34) 3 (16) 8 (24) 30 (28) 10.81 (0.21)
Lung 9 (16) 2 (11) 4 (12) 15 (14)
Colon 8 (14) 5 (26) 2 (6) 15 (14)
Ovaries 1 (2) 2 (11) 2 (6) 5 (5)
Other 18 (32) 6 (32) 17 (52) 41 (38)
Solid tumor staging
I 3 (5) 1 (5) 3 (9) 7 (7) 4.30 (0.64)
II 8 (14) 1 (5) 6 (18) 15 (14)
III 4 (7) 3 (16) 3 (9) 10 (9)
IV 26 (46) 11 (58) 11 (33) 48 (44)
Unknown 15 3 10 28
Oncological treatment line
1st 30 (54) 8 (42) 19 (58) 57 (53) 2.65 (0.26)
≥2nd 18 (32) 10 (53) 9 (27) 37 (34)
Unknown 8 1 5 14
Oncological treatment †
Chemotherapy 27 (48) 11 (58) 18 (55) 56 (52) 0.67 (0.72)
Biological 8 (14) 3 (16) 4 (12) 15 (14) 0.15 (0.93)
Hormonal 7 (12) 0 4 (12) 11 (10) 2.61 (0.27)
Immunological 6 (11) 1 (5) 3 (9) 10 (9) 0.50 (0.78)
Radiation 1 (2) 1 (5) 0 2 (2) 1.84 (0.40)
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Table 2. Cont.
Parameters Type I
n=108 χ2(p-Value) #
No. of patients (%)
≤1 39 (70) 12 (63) 25 (75) 76 (70) 0.15 (0.92)
≥2 14 (25) 5 (26) 8 (24) 27 (25)
Unknown 3 2 0 5
, Pearson’s Chi-squared test; n, Number of patients; ECOG, Eastern Cooperative Oncology Group Performance
, numbers does not add up to 100% due to concomitant treatments; where missing nis not speciﬁed,
there are no missing data;
, Signiﬁcance between the three diﬀerent treatment regimens; Type I, THC-dominant
treatments; Type III, CBD-dominant treatments; Type II, equal THC: CBD concentration treatments.
2.3. MC Treatment Safety
Fourteen patients stopped MC treatment due to Adverse Eﬀects (AEs), such as dizziness (n=2),
hallucinations (n=2), anxiety (n=1), faints (n=1), fatigue (n=1), nausea (n=1), combination of
bad taste and drowsiness (n=1), and combination of restlessness and weakness (n=1); four patients
did not specify the AEs that led to MC treatment discontinuation. Therefore, these patients are not
analyzed in the T1dataset.
Overall, 24 patients (22%) reported on at least one MC-related AE that did not led to MC treatment
discontinuation. In a descending order, AEs consisted of central nervous system (CNS; n=14, 13%),
gastrointestinal (GI, n=9, 8%), psychological (n=7, 7%), musculoskeletal (n=4, 4%), ophthalmic
), cardiovascular (n=2, 2%), and auditory (n=2, 2%) AEs. No signiﬁcant diﬀerences were
found between the three MC treatment regimens in MC-related AEs by aﬀected systems (Table 3).
Table 3. Medical cannabis treatment regimen-related adverse eﬀects.
Parameters Type I
n=33 χ2(p-Value) #
No. of patients (%)
Overall adverse eﬀects 10 (18) 3 (16) 11 (33) 3.02 (0.22)
Central nervous system 6 (11) 1 (5) 7 (21) 2.94 (0.23)
Gastrointestinal 3 (5) 2 (11) 4 (12) 1.30 (0.52)
Psychological 2 (4) 1 (5) 4 (12) 2.37 (0.30)
Musculoskeletal 1 (2) 0 3 (9) 3.78 (0.15)
Ophthalmic 1 (2) 1 (5) 2 (6) 1.17 (0.56)
Cardiovascular 0 0 2 (6) 4.44 (0.11)
Auditory 0 0 2 (6) 4.44 (0.11)
, Pearson’s Chi-squared test; AEs, adverse eﬀects;
, signiﬁcance between the three diﬀerent treatment
regimens; Type I, THC-dominant treatments; Type III, CBD-dominant treatments; Type II, equal THC:CBD
The most frequent speciﬁc AEs were dizziness and tiredness (n=9, 8%; for both) (Table 4). Due to
the non-frequent reports of speciﬁc AEs, we could not assess the diﬀerences between them for the three
Notably, 21 (13%) patients that are not analyzed in the T
dataset died during the ﬁrst month of
MC treatment. Therefore, their MC treatment type is unknown.
Pharmaceuticals 2020,13, 435 6 of 16
Table 4. Reported non-serious, MC-related adverse events.
Central nervous system No. of patients (%)
Confusion 4 (4)
Disorientation 4 (4)
Impaired attention 3 (3)
Dizziness 9 (8)
Falls 3 (3)
Feeling drunk 6 (6)
Decreased physical sensation 4 (4)
Impaired balance 6 (6)
Impaired memory 5 (5)
Impaired psychomotor functions 5 (5)
Impaired coordination 5 (5)
Increased awareness 5 (5)
Impaired speech 5 (5)
Tiredness 9 (8)
Vertigo 5 (5)
Gastrointestinal No. of patients (%)
Abdominal discomfort 7 (7)
Abdominal pain 6 (6)
Decreased appetite 7 (7)
Increased appetite 3 (3)
Loss of appetite 5 (5)
Bad taste 8 (7)
Constipation 5 (5)
Diarrhea 6 (6)
Dry mouth 6 (6)
Heartburn 5 (5)
Decreased mouth sensation 5 (5)
Mouth ulcers 5 (5)
Nausea 6 (6)
Vomiting 6 (6)
Mouth pain 5 (5)
Thirst 6 (6)
Psychological No. of patients (%)
Unusual thinking 4 (4)
Anxiety 4 (4)
Bad mood 6 (6)
Sweet craving 5 (5)
Depression 4 (4)
Decreased interest 5 (5)
Euphoria 4 (4)
Forgetfulness 4 (4)
Hallucinations 4 (4)
Hyperactivity 3 (3)
Loss of time sensation 4 (4)
Nervousness 4 (4)
Nightmares 3 (3)
Paranoia 3 (3)
Weird dreams 2 (2)
Psychosis * 2 (2)
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Table 4. Cont.
Musculoskeletal No. of patients (%)
Bone pain 3 (3)
Joint pain 3 (3)
Jaw stiﬀness 2 (2)
Decreased motor ability 2 (2)
Limb weakness 3 (3)
Muscle pain 3 (3)
Tremor 1 (<1)
Cardiovascular No. of patients (%)
Hypertension 1 (<1)
Hypotension 2 (2)
Irregular pulse 1 (<1)
Orthostatic hypotension 2 (2)
Palpitations 2 (2)
Ophthalmic No. of patients (%)
Blurred vision 4 (4)
Red eyes 1 (<1)
Vision alterations 1 (<1)
Itchy Eyes 1 (<1)
Light sensitivity 3 (3)
Auditory No. of patients (%)
Ears buzzing 2 (2)
Decreased hearing 2 (2)
Noise sensitivity 1 (<1)
* diagnosed by psychiatrist; some of the adverse eﬀect reports are concomitant.
2.4. MC Treatment Regimens’ Eﬀect
Assessing the eﬀect of MC treatment (the change from T
), for all of the evaluated parameters,
demonstrated that there was a signiﬁcant (p<0.05) improvement for several of the parameters.
Speciﬁcally, signiﬁcant improvement from baseline was reported for weekly average pain intensity,
aﬀective and sensory pain intensities, sleep quality and duration and in MSAS distress, physical
(p<0.01) and psychological indexes. Additionally, a decrease in analgesics consumption was also
demonstrated. Notably, we found no signiﬁcant change from T
for least and worst pain
intensities, weight, body mass index (BMI), pain catastrophizing scale, sleep latency, depression,
disability, QoL, and for anxiety (p>0.05) (Table 5).
For the above-mentioned parameters that improved signiﬁcantly from T
, we analyzed
the diﬀerences between the three MC treatments. We found that the median change from T
between the three MC treatments was signiﬁcantly diﬀerent in MSAS physical index (
p<0.05) and in sleep duration (
=6.02, p<0.05). Speciﬁcally, for MSAS physical index, post
hoc analyses showed a trend for superiority of type III and type I treatments (
2 to 19) and
8 (+0.25 to
20)), respectively) compared to mixed treatments (
1 (+8 to
12)). Moreover, for MSAS
30% clinical improvement, patients consuming type III treatments reported higher
rate of response (
), compared to type I (n=28, 50%) and type II (n=10, 30%) treatments
). For sleep duration, post hoc analyses showed signiﬁcance of superiority for
type I treatments (+0.5 (0 to +2) h) compared to type III treatments (0 (−1 to +0.5) h) (Figure 2).
Pharmaceuticals 2020,13, 435 8 of 16
Table 5. Diﬀerence from baseline in outcome parameters.
Median (IQR) Unknown
Weight (Kg) 72 (60–80) 70 (59–80) 17 0.10 (0.72) Worsening
BMI (weight (kg)/[height (m)]2)26 (22–29) 25 (22–28) 25 0.07 (0.97) Worsening
Weekly least pain intensity (NPS, 0–10) 5 (2–7.2) 3 (1–6) 35 0.16 (0.27) Improvement
Weekly worst pain intensity (NPS, 0–10) 8 (6–9) 6 (5–8) 35 0.20 (0.10) Improvement
Weekly average pain intensity (NPS, 0–10) 7 (3–8.8) 5 (1.5–7) 5 0.22 (<0.05) Improvement
Aﬀective pain intensity (McGill questionnaire, 0–12) 7 (4.5–9) 4 (2–7) 43 0.34 (<0.01) Improvement
Sensory pain intensity (McGill questionnaire, 0–33) 18 (14–24) 13 (7–20) 45 0.28 (<0.05) Improvement
Pain catastrophizing scale (PCS, 0–52) 28 (15–37) 22 (7–36) 17 0.13 (0.47) Improvement
Sleep quality (PSQI global score, 0–21) 12 (9–15) 9 (5.2–12) 30 0.29 (<0.01) Improvement
Sleep duration (h) 5 (4–6.5) 6 (5–7.5) 8 0.25 (<0.05) Worsening
Sleep latency (min) 45 (30–60) 30 (15–60) 11 0.17 (0.10) Improvement
Depression (BDI, 0–63) 17 (10–24) 15 (9–21) 10 0.10 (0.64) Improvement
Quality of life (EQ-5, 0–10) 4 (3–6) 3 (2–5) 5 0.13 (0.37) Improvement
Anxiety (GAD-7, 0–21) 8 (2.8–14) 5 (2–11) 8 0.14 (0.28) Improvement
MSAS distress index (0–100) 44 (25–64) 34 (19–46) 0 0.20 (<0.05) Improvement
MSAS physical index (0–120) 38 (18–50) 27 (12–40) 0 0.23 (<0.01) Improvement
MSAS psychological index (0–60) 24 (14–40) 16 (8–32) 0 0.22 (<0.05) Improvement
No. of patients (%)
Analgesics consumption (yes) 60 (56) 40 (37) 1 6.8 (<0.01) Improvement
BL, Baseline; m, meter; NPS, Numerical pain scale; PSQI, Pittsburgh Sleep Quality Index; BDI, Beck depression
index; EQ-5, EuroQol questionnaire; GAD-7, General anxiety disorder questionnaire; IQR, Inter quartile range; Kg,
Kilograms; BMI, Body mass index; MSAS, Memorial Symptom Assessment Scale; n, Number of patients; Range is
indicated next to each parameter.
While there was a general decrease in analgesic medications consumption, there were no signiﬁcant
diﬀerences between the three MC treatments in the rates of patients that consumed them at T
stopped at T1(χ2(2) =0.28, p=0.87).
As patients can consume either sublingual oil extract or inﬂorescence by inhalation, we also
compared between these diﬀerent routes of administration. No signiﬁcant diﬀerences were found
between patients that consumed only type I cultivars by sublingual oil extract (n=19) and patients
that consumed only type I cultivars by inﬂorescence inhalation (n=32) in the median change from T
of all parameters (p>0.05). In addition, comparative analysis between patients that consumed
only type III cultivars by sublingual oil extract (n=17) and patients that consumed only type I
cultivars by inﬂorescence inhalation (n=32) demonstrated that there was no signiﬁcant diﬀerence in
the median change from T
of most parameters, excluding sleep duration. Overall, we found
superiority for consumption of type I treatments by inﬂorescence inhalation (+1 (0.31 to +2.4) h)
compared to consumption of type III treatments by sublingual oil extract in sleep duration extension
(0 (−1 to +0.5) h) (χ2(1) =0.50, p<0.05).
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Figure 2. MC Treatment regimens significant differential effects. (A) Differences between the three
MC treatments in weekly average pain intensity; (B) Differences between the three MC treatments in
affective pain intensity; (C) Differences between the three MC treatments in sensory pain intensity; (D)
Differences between the three MC treatments in sleep quality; (E) Differences between the three MC
treatments in sleep duration; (F) Differences between the three MC treatments in MSAS general distress
index; (G) Differences between the three MC treatments in MSAS physical index; (H) Differences
between the three MC treatments in MSAS psychological index; CBD, Cannabidiol; THC, (−)-Δ9-trans-
tetrahydrocannabinol; MSAS, Memorial Symptom Assessment Scale; The dashed lines represent the
baseline (T0) values of their corresponding parameters; The box-plot values represent the raw median
change from baseline (T0) to one-month follow-up (T1); n, Number of patients; n.S, Non-significant; Type
I, THC-dominant treatments; Type III, CBD-dominant treatments; Type II, equal THC:CBD
concentration treatments; Median and IQR change from baseline are calculated individually for each
patient, the presented change from BL is the median of all individual patients and not the difference
between the medians of BL and one-month follow-up; p values are adjusted for multiple comparisons;
The direction of the arrows indicates the desired symptoms improvement trajectory.
While there was a general decrease in analgesic medications consumption, there were no
significant differences between the three MC treatments in the rates of patients that consumed them
at T0 and stopped at T1 (χ²(2) = 0.28, p = 0.87).
As patients can consume either sublingual oil extract or inflorescence by inhalation, we also
compared between these different routes of administration. No significant differences were found
between patients that consumed only type I cultivars by sublingual oil extract (n = 19) and patients
that consumed only type I cultivars by inflorescence inhalation (n = 32) in the median change from T0
to T1 of all parameters (p > 0.05). In addition, comparative analysis between patients that consumed
only type III cultivars by sublingual oil extract (n = 17) and patients that consumed only type I
cultivars by inflorescence inhalation (n = 32) demonstrated that there was no significant difference in
the median change from T0 to T1 of most parameters, excluding sleep duration. Overall, we found
superiority for consumption of type I treatments by inflorescence inhalation (+1 (0.31 to +2.4) h)
MC Treatment regimens signiﬁcant diﬀerential eﬀects. (
) Diﬀerences between the three
MC treatments in weekly average pain intensity; (
) Diﬀerences between the three MC treatments in
aﬀective pain intensity; (
) Diﬀerences between the three MC treatments in sensory pain intensity;
) Diﬀerences between the three MC treatments in sleep quality; (
) Diﬀerences between the
three MC treatments in sleep duration; (
) Diﬀerences between the three MC treatments in MSAS
general distress index; (
) Diﬀerences between the three MC treatments in MSAS physical index;
) Diﬀerences between the three MC treatments in MSAS psychological index; CBD, Cannabidiol;
-trans-tetrahydrocannabinol; MSAS, Memorial Symptom Assessment Scale; The dashed
lines represent the baseline (T
) values of their corresponding parameters; The box-plot values represent
the raw median change from baseline (T
) to one-month follow-up (T
); n, Number of patients; N.S,
Non-signiﬁcant; Type I, THC-dominant treatments; Type III, CBD-dominant treatments; Type II, equal
THC:CBD concentration treatments; Median and IQR change from baseline are calculated individually
for each patient, the presented change from BL is the median of all individual patients and not the
diﬀerence between the medians of BL and one-month follow-up; pvalues are adjusted for multiple
comparisons; The direction of the arrows indicates the desired symptoms improvement trajectory.
In this “real-world” study on palliative care in oncology patients, we found a signiﬁcant
improvement in most of the assessed parameters, including reduced pain intensity, improved
sleep, alleviated cancer symptoms and a decrease in pharmaceutical analgesics consumption.
We demonstrated that this improvement from baseline is rapid and apparent, already at one month after
MC initiation. This symptom relief proﬁle is supported by previous studies [
], while it is opposite
to the expected trajectory of symptoms in palliative cancer patients [
]. However, unlike previous
studies that demonstrated an increase of appetite and weight gain [
], as well as anxiolytic [
], and quality of life (QoL) improvement properties [
]; we found no signiﬁcant
short-term improvement for those in the allocated time. These ﬁndings may be explained by the
inherent nature of the parameters, they may require additional treatment duration for the eﬀects to be
apparent. Another possibility is the patients’ demographics, as these are palliative oncology patients
Pharmaceuticals 2020,13, 435 10 of 16
with high rates of advanced metastatic disease. These results can assist oncologists to facilitate patients’
expectations regarding the short-term eﬀects of MC treatment.
Additionally, patients reported a mostly non-serious adverse eﬀects proﬁle. Our ﬁndings are in
line with previous results concluding that cannabinoid treatment for cancer-related pain is safe [
A previous study of recreational cannabis users demonstrated that THC is a major contributor to
the psychoactive eﬀects of cannabis, with dose-dependent properties [
], whereas CBD is generally
described in psychiatric clinical studies as safe or as the phytocannabinoid that attenuates THCs’
psychoactive eﬀects [
]. Moreover, the American Pain Society (APS) guidelines prefer to direct patients
to low-THC and high-CBD content MC cultivars due to THC-related AEs [
]. In our study, we found
no signiﬁcant diﬀerences between MC treatment regimens in MC-related AEs. Thus, the dominance of
THC/CBD phytocannabinoids within the MC treatments, at least for short-term treatment of palliative
cancer patients, does not play a clinical role in the safety proﬁle of MC.
Currently, oncologists in Israel are required to prescribe MC treatment deciding on the
administration route and on THC:CBD ratio of products. We found that most of the prescriptions for
palliative oncology patients were for type I cultivars, which might be explained by previous clinical
trials demonstrating that cultivars with higher THC content provide a better therapeutic response for
pain reduction [
]. In the current study we found that except for sleep duration, type III treatments
were as good as type I treatments. In fact, for most assessed parameters, there was no superiority
of any speciﬁc MC treatment. Additionally, a trend of signiﬁcance was found for both type I and
type III treatments compared to type II treatments for cancer-related physical symptoms reduction,
with higher clinical response rate for type III treatments. Hence, we can assume, based on our results,
that for amelioration of physical cancer symptoms, and for most cancer-related parameters (other than
sleep duration extension), there is no added therapeutic value for type I treatments and physicians
can prescribe type III cultivars. Additionally, Portenoy et al., (2012) showed that lower THC and
CBD concentrations of Nabiximoles were associated with higher pain reduction eﬃcacy in cancer
]. Hence, the higher response rate for physical cancer burden by type III MC may be
attributed to its low THC concentrations, rather than for its high CBD concentrations. Nevertheless,
the THC:CBD ratio is not a good enough predictor for treatment response and other MC components
(e.g., concentration of other phytocannabinoids or terpenoids) should be assessed and matched for
some cancer symptoms. Hence, keeping in mind that we found no superior beneﬁcial eﬀects for type
I MC treatments other than for sleep duration and due to the abuse potential of THC [
], type III
MC treatments may be preferred for palliative oncology patients. Notably, previous clinical trials
that compared cannabis-based medications, such as THC, CBD and equal THC:CBD products for
chronic non-cancer pain patients, demonstrated superiority for equal THC:CBD products [
As whole-plant medical cannabis treatment is more complex than just its THC/CBD concentrations,
with more than 500 components, of which over 100 are phytocannabinoids [
], the comparison to the
relative inferiority of type II treatments in our study cannot be assessed.
This study has few limitations. First, no control or placebo groups were assigned. Hence, prudent
interpretation of the results is needed. Second, self-report bias may have occurred. To diminish this
bias, only validated questionnaires were utilized and patient responses were kept anonymous from
their physician. Third, since we investigated palliative cancer patients, with a short life expectancy
prognosis, a relatively short duration of follow-up was conducted. Future studies should attempt to
extend the follow-up period. Fourth, the heterogeneity of our sample prevents us from making any
generalization of our ﬁndings to a speciﬁc cancer etiology. Fifth, survival bias may have occurred,
since patients that discontinued MC treatment, due to ineﬀectiveness or AEs and patients that passed
away could not contribute their follow-up status. Fifth, selection bias might have also occurred, since
extremely advanced patients might have not been included due to the study design. Lastly, we suggest
repeating this study in a placebo-controlled randomized clinical trial, using standardized cannabis
products with known phytocannabinoid and terpenoid composition.
Pharmaceuticals 2020,13, 435 11 of 16
4. Materials and Methods
4.1. Study Design
This is an intermittent subgroup study of an ongoing, multi-center, prospective study that is
being conducted since January 2019, and was analyzed at September 2020. The institutional Ethics
Committees of the Haemek Medical Center, Israel (#0137–18-EMC) and of the Galil Medical Center,
Israel (#0010–19-NHR) approved the study. This was a pure observational study with no interventional
component whatsoever, so registration at the Clinical Trials Register was not required. Importantly,
no recognizable information on participating patients is published in this article.
Hebrew speaking patients aged
18 years licensed for the ﬁrst time for MC for treating metastatic
cancer pain and for chemotherapy-related nausea, vomiting and/or pain, were eligible for participation
in the study. After explaining the study procedures, participating oncologists who regularly issue MC
licenses on their own clinical discretion obtained written informed consents from eligible patients.
Copies of the consent forms along with the patients’ cancer diagnoses, cancer treatment and contact
information were sent to the study coordination center. To avoid any possible inﬂuence of collected
data on physicians’ decisions regarding clinical management of their patients, prescribing physicians
had no access to data collected on individual patients.
Patients were instructed to complete the study questionnaires at baseline, before MC treatment
; within few days from MC prescription), and at one (T
), three- and six-months following
treatment initiation. In this subgroup analysis, we selected to present only the short-term (T
) eﬀects of
MC treatment. The baseline questionnaire consisted of 174 questions at baseline and a variable number
of about 220 follow-up questions, which were presented in a dynamic format customized to individual
responses where responses on a particular question determined the subsequent questions asked.
In order to further reduce study burden, patients were also given the choice to skip questions. Hence,
each patient completed a unique set of questions and each question received a diﬀerent number of
responses. Data was collected online by the secured survey technology Qualtrics
(Provo, Utah, version
]. Whenever patients had diﬃculties with the use of the web platform, the questionnaires
could be completed by phone, with the assistance of the study coordinator. No ﬁnancial compensation
was oﬀered to participating patients. The STROBE statement checklist for cohort studies is presented
in the Supplementary Materials.
4.2. Study Questionnaires
Physician reported information included cancer diagnosis, classiﬁcation of malignant tumors
(TNM), cancer treatment protocol and the Eastern Cooperative Oncology Group (ECOG) Performance
Status score. Patient reported information included demographics, analgesics consumption,
MC treatment characteristics as well as Hebrew validated oncology-related questionnaires, including
(1) the study’s primary outcome measure of “average weekly pain intensity” on a 0–10 numerical pain
scale (NPS) and the weekly average worst and least pain intensities; (2) Memorial Symptom Assessment
Scale (MSAS) [
]; (3) The short-form McGill Pain Questionnaire (SF-MPQ) [
]; (4) Pain Disability
Index (PDI) [
]; (5) Quality of life—EuroQol (EQ5) [
]; (6) Pittsburgh Sleep Quality Index (PSQI) [
(7) Beck Depression Inventory II (BDI-II) [
]; (8) Pain Catastrophizing Scale (PCS) [
]; and (9) General
Anxiety Disorder (GAD-7) [
]. Using a predetermined list [
], patients were requested to report
adverse eﬀects (AEs) at each follow-up time-point that they could attribute directly to MC treatment.
AEs were later classiﬁed as serious or non-serious, according to the FDA deﬁnition .
4.3. Phytocannabinoids Dose Assessment
Since the Israeli MCU reform [
], MC cultivators in Israel are required to accurately indicate the
THC and CBD concentrations in their products [
]. We calculated the monthly doses of THC and
CBD only for patients that reported fully on their MC treatment regimen, according to the products
that patients reported to consume, alongside with their total and product speciﬁc monthly doses.
Pharmaceuticals 2020,13, 435 12 of 16
For example, if a patient reported on consuming 10 g of THC10/CBD10 product and another 10 g
of THC20/CBD4 product, the patient calculated amount of monthly consumption is 6000 mg and
2800 mg of THC and CBD, respectively. Notably, MC cultivators in Israel are not required to report on
terpenoids concentrations in their MC products.
4.4. Statistical Analysis
R software (V.1.1.463) with atable [
], ggstatsplot [
] and tidyverse [
] packages were used to
analyze diﬀerences between three MC treatments: Type I (patients consuming THC-dominant cultivars
only), type III (patients consuming CBD-dominant cultivars only; Type III) and type II (patients
consuming either hybrid cultivars with similar THC:CBD ratio; Type II, or patients consuming a
combination of THC-dominant and CBD-dominant cultivars in the same month) [
]. Chi square or
Kruskal–Wallis rank tests were conducted to establish similarity of demographic data between the
three treatments. The Shapiro-Wilk test of normality demonstrated non-normal distribution for all
measures. Thus, data is presented as median (IQR, Q1-Q3, i.e., quartiles 25 and 75). Diﬀerences were
considered signiﬁcant at the p<0.05 level. Incidences are presented as numbers and percentages of
patients. Notably, due to the exploratory nature of the study and many potential subgroup analyses,
no sample size was determined a priori.
4.5. Data Sharing
All data requests should be submitted to the corresponding author for consideration. Access to
anonymized data may be granted following review of the request.
In conclusion, this prospective, short-term cohort of palliative cancer patients demonstrated
an overall mild improvement of most investigated parameters, regardless of its phytocannabinoid
dominance. This is the ﬁrst study that investigated the variability between three diﬀerent classes of
regulated and accurately labelled MC products, using precise doses of both phytocannabinoids, THC
and CBD. Keeping in mind our relatively small sample size, short-term follow-up and lack of control
and placebo groups, we could not elucidate any diﬀerences in beneﬁcial eﬀects between MC treatments
for most outcomes, but we were able to demonstrate some diﬀerential eﬀects between them. Thus,
we can cautiously recommend type III treatments and not type I or type II treatments be prescribed
for oncology patients with a high burden of physical cancer symptoms. However, if the patient’s
main complaint is short sleep duration, type I treatments are preferred. Future studies should further
investigate the role of diﬀerent MC treatments in order to better elucidate our understanding of MC
The following are available online at http://www.mdpi.com/1424-8247/13/12/435/s1,
Methods S1: STORBE checklist.
Conceptualization, J.A., G.M.L., G.B.-S. and D.M.; Data curation, J.A., A.U., I.C., A.L.,
M.A.-A., G.B.-S., L.A., D.G., N.M., A.K., A.S. and O.H.; Formal analysis, J.A. and Y.V.; Funding acquisition, D.M.;
Investigation, J.A. and D.M.; Methodology, J.A., G.M.L., G.B.-S., Y.V. and D.M.; Project administration, G.M.L. and
D.M.; Resources, D.M.; Supervision, G.M.L. and D.M.; Validation, J.A. and Y.V.; Visualization, J.A., Y.V., S.P. and
D.M.; Writing—original draft, J.A.; Writing—review & editing, J.A., G.M.L., Y.V., Anton Uribayev, S.P., I.C., A.L.,
M.A.-A., G.B.-S., L.A., D.C., N.M., A.K., A.S., O.H. and D.M. All authors participated in data collection, discussed
the results and commented on the manuscript. All authors have read and agreed to the published version of
The study was funded by the Evelyn Gruss Lipper Charitable Foundation. The funder had no role in
the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in
the decision to publish the results.
We would like to thank Ella Lutbak and Reut Peled in their administrative assistance in
Conﬂicts of Interest: The authors declare no conﬂict of interest.
Pharmaceuticals 2020,13, 435 13 of 16
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