Bio 22

REVIEW ARTICLE

Pharmacological evidence of medicinal cannabis in oncology: a systematic review

Danielle Brown1 & Michael Watson1

& Janet Schloss1

Received: 22 December 2017 /Accepted: 25 March 2019 /Published online: 6 May 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019

Abstract Purpose This systematic literature review examines research into the use of medicinal cannabis in cancer management. The aim was to identify the gaps in knowledge on the dose, dosing schedule and absorption of the administration routes of medicinal cannabis use in oncology. Methods A comprehensive search of the literature was conducted across six databases to identify original data reporting the pharmacology of medicinal cannabis in oncology. Results Eighteen articles were selected for review. Of the selected articles, ten were identified as randomised control trials, two experimental studies, two retrospective cohort studies and four case studies. Four articles reported absorption data and one drug interaction study was identified. Conclusions There is little evidence reported in the literature on the absorption of medicinal cannabis in cancer populations. Various reasons are explored for the lack of pharmacokinetic studies for medicinal cannabis in cancer populations, including the availability of assays to accurately assess cannabinoid levels, lack of clinical biomarkers and patient enrolment for pharmaco- kinetic studies.

Keywords Medicinal cannabis . Cannabinoids . Pharmacology . Cancer . Oncology . Integrative medicine

Introduction

Increased legal access to medicinal cannabis has continued the debate surrounding cannabis application in disease manage- ment [1]. Cannabis is by no means a new medicine [2]. In modern history i t was part of the United States Pharmacopoeia and British Pharmacopoeia, until being re- stricted, criminalised and removed in the twentieth century [3]. In 2013, Cannabis spp. were reintroduced in the American Herbal Pharmacopoeia [4].

Clinical trials on medicinal cannabis have focused on the management of the side effects associated with first-line can- cer therapy that can compromise patient quality of life and compliance to potential curative treatments. These include the investigation of medicinal cannabis for chemotherapy- induced nausea and vomiting, cachexia and pain management

[5]. Clinical trials investigating anticancer actions have been limited, with the focus on the tolerability of medicinal canna- bis [5, 6]. Preclinical studies on the anticancer actions of me- dicinal cannabis exhibit promising anticancer properties through the modulation of key cellular pathways involved in cell survival and immunomodulatory factors [7]. Additionally, cannabinoids have demonstrated the ability to sensitise some cancer cells to first-line therapy [8–11]. However, there is no consensus on the effectiveness of medicinal cannabis as an anticancer agent in oncology [5, 7].

With the global cancer burden predicted to increase to 20 million new cases by the year 2025, an understanding the pharmacology of cannabis cannabinoids and metabolites in oncology can assist with the therapeutic application of medic- inal cannabis in cancer populations [12].

Medicinal cannabis is defined for purpose of this review as pharmaceutical cannabis–based medicine (standardised cannabinoid ext rac t s ) f rom Cannabis sp . ; non- pharmaceutical cannabis–based medicine (undefined can- nabinoid extracts) from Cannabis sp., and single-molecule cannabinoids.

Pharmaceutical cannabis–based medicines and single- molecule cannabinoids are approved for use in several

* Danielle Brown name.danielle@icloud.com

1 Endeavour College of Natural Health, Brisbane, Queensland, Australia

Supportive Care in Cancer (2019) 27:3195–3207 https://doi.org/10.1007/s00520-019-04774-5

countries despite a common conclusion within the broader medical community that medicinal cannabis lacks adequate evidence [13]. In cancer populations, nabilone (Cesamet®), a single-molecule cannabinoid is prescribed to manage chemotherapy-induced nausea and vomiting. The cannabis- based medicine nabiximol (Sativex®) is prescribed in the management of refractory cancer pain.

Knowledge of the complexity of cannabis pharmacolo- gy has expanded since the identif icat ion of the endocannabinoid system in the mid 1990s, followed by the discovery of G protein-coupled cannabinoid receptors 1 and 2, and the endogenous ligands (endocannabinoids) anandamide (AEA) and 2-arachydonylglycerol (2-AG) [14–17]. The most recent count of phytocannabinoids identified from the Cannabis sp. numbers over 100 [18]. Of principle medical interest are the decarboxylated phytocannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) derived from Cannabis sp.

Phy tocannab ino id s i n t e r a c t w i t h the human endocannabinoid system which is known to mediate key cel- lular pathways that exert both palliative and modulatory ef- fects in cancer management [19]. When this knowledge is combined with the identification of further pharmacological constituents from cannabis, including terpenoids, the thera- peutic potential of this plant is continuously espoused [2].

Despite the continued understanding of cannabinoid recep- tors and their distribution and the role of endocannabinoids, there is a paucity of evidence on how best to modulate the individual’s endocannabinoid system for therapeutic out- comes. Cannabis pharmacology remains the same irrespective of use [2, 20–23]. However, an understanding of the pharma- cology of medicinal cannabis in respect to administration, dose, absorption and potential drug interactions in cancer pop- ulations is fundamental in the assessment of efficacy, thera- peutic index and safety profile of this medicine [24].

This systematic literature review examines the literature surrounding the administration, dosing and absorption of me- dicinal cannabis reported in oncology across human studies. Eighteen articles have been systematically identified from the years 2000 to 2017. These dates were chosen to reflect the re levant pharmaco log ica l unders tand ing of the endocannabinoid system.

Methodology

A comprehensive search of the literature was conducted to identify original data reporting on the pharmacological study of medicinal cannabis, with the primary endpoint to capture administration, dosage and absorption data of medicinal can- nabis in cancer management. Standard systematic review

protocol was followed in accordance with the PRISMA state- ment [25].

Article eligibility criteria

Inclusion criteria captured all types of cancer and medicinal cannabis, including both pharmaceutical and non- pharmaceutical cannabis–based medicines, and synthetic singu- lar molecule drugs. Original data included in the review re- quired articles to report a minimum of two of the following pharmacokinetic considerations: administration, dosage and ab- sorption. Where medicinal cannabis dosage was described, a minimum of two dosage ranges must have been provided. Articles were excluded on the basis of not reporting original data, full-text availability, not available in English, not cancer specific, not medicinal cannabis as described above, reporting on the synthetic cannabinoid analogue levonantradol and reporting in vivo and in vitro data. Date restrictions on publica- tions were applied to all searches. Full-text screened articles previous to 2000 were excluded in order to reflect a consistent pharmacological understanding of the endocannabinoid system.

Identification and selection of studies

The following six databases, including grey literature sources, were searched within the date range of 2000 to 2017: PubMed (US National Library of Medicine), Scopus (ELSEVIER), CINAHL (EBSCOhost), EMBASE (ELSEVIER), Cochrane Library (Wiley Online Library), AMED (Allied and Complementary Medicine Database). The search terms used were ((cancer OR oncology OR neoplas* OR malignan*)), ((medicinal cannabis OR cannabis OR medicinal marijuana OR marijuana OR cannabinoids OR phytocannabinoids)) and ((clinical trial OR case study OR trial OR study and human)).

Data extraction and appraisal

All relevant sources were used for data extraction includ- ing full-text journal articles, conference proceedings and abstracts. All identified articles were imported into EndNote Bibliography referencing software management program. Duplicates were removed and articles analysed first by title, secondly by abstract and finally in full text, and once again in full text, culminating in a final selection of articles that met inclusion criteria. Discussion between authors was undertaken throughout to reach consensus in the case of uncertainty or disagreement. Articles were characterised by study type and thematically grouped by common characteristics involving multiple readings to identify themes to allow for contrast and comparison of the reported findings within the identified articles [26].

3196 Support Care Cancer (2019) 27:3195–3207

Critical appraisal

Standard critical appraisal tools from the Joanna Briggs Institute (JBI) were used to evaluate the methodological qual- ity of articles selected for inclusion [27, 28]. These included 3 variations: JBI Critical Appraisal Checklist for Randomized Controlled Trials, JBI Critical Appraisal Checklist for Case Reports and JBI Critical Appraisal Checklist for Cohort Studies [27, 28]. This approach was chosen to assess the iden- tified research types for internal validity.

Results

A total of 18 articles were selected for review between 2000 and 2017 (See Fig. 1). All studies reported dose schedules and administration data. Four of the 18 articles reported absorption data [6, 29–31]. Safety assessments were reported in ten arti- cles through the identification of adverse events (AEs). AEs were commonly characterised by somnolence, fatigue, hallu- cinations and toxicity measured by common toxicity criteria with no report of serious adverse events relating to the inter- vention [6, 29–37].

The primary outcomes of the included articles focused on the characterisation of medicinal cannabis as an antiemetic (n = 5) appetite stimulant (n = 3), analgesic (n = 4), anticancer (n = 3) and anticholinergic (n = 1). Other outcomes were

related to its effect as an adjuvant treatment in radiotherapy treatment (n = 1). One study investigated clinical pharmacoki- netic interactions of medicinal cannabis with chemotherapeu- tics in cancer management (n = 1) (See Table 1).

Of the selected articles, ten were identified as randomised control trials (five of the ten were further defined as a pilot trial (n = 3), phase II trial (n = 1) and phase III trial (n = 1)), three experimental studies (non-randomised), two retrospective co- hort studies and four case studies (See Table 2). The partici- pants across all studies included adult, adolescence and young adults (AYA) and paediatric population with multiple cancer presentations.

Intervention

The medicinal cannabis interventions include single-molecule analogues of THC, namely dronabinol (Marinol®) or nabilone (Cesamet®); pharmaceutical cannabis–based medi- cine including nabiximols (Sativex® 2.7 mg THC, 2.5 mg CBD), Bedrocan® tea (18%THC, 0.8% CBD); and non- pharmaceutical cannabis-based medicines reported as ‘hemp oil’ and inhaled cannabis sourced from Cannabis sp. plant.

Cannabis-based medicine (CBM) interventions were used to investigate anticancer, antiemetic, analgesic and appetite stimulant actions. The single-molecule cannabinoid dronabinol was investigated as an antiemetic and appetite stimulant; nabilone for quality of life (QOL) outcomes and

Fig. 1 PRISMA flow diagram outlining the process of articles selected to be included in the review

Support Care Cancer (2019) 27:3195–3207 3197

anticholinergic action. A standardised THC isolate investigat- ed anticancer actions, and similarly non-standardised CBM as inhaled or oil-based product reported anticancer actions.

Dosing

Dose titration was reported in 11 studies reporting variable dosages between participants to achieve an individual dose–effect relationship [6, 30, 34–42]. All variable dos- ages were characterised by a maximum allowable dose over 24 h. Under-dosing of medicinal cannabis was report- ed in two studies [36, 40].

The range in dosing for each intervention was variable dependent on the type of medicinal cannabis and route of administration (See Fig. 2). Oral administration included dronabinol (Marinol®) at 2–5 mg once (QD) or twice (BID) a day to maximum titration of 15 mg for antiemesis [39–41, 43]. As an appetite stimulant in cancer-associated anorexia and chemosensory alterations, dronabinol (Marinol®) was initially given 2.5 mg BID titrated to a maximum of 20 mg per day [32, 44]. CBM was prescribed BID either THC:CBD (2.4 mg:1 mg) or THC (2.5 mg) for cancer-related anorexia [31]. Nabilone (Cesamet®) was dosed between 2 and 4 mg QD for quality of life measures [33, 45]. Bedrocan® was dosed at 1 g, infused as a tea in 200 ml of water QD to investigate potential interaction with anticancer drugs [29]. Hemp oil was extracted from Cannabis indica ‘chronic’; afghan/thai strain was dosed as drops up to 1 ml BID [42]. The oromucosal administration of nabiximols (2.7 mg THC:2.5 mg CBD) was dosed nomore than 8 actuations, over a 3 h, at maximum dose of 48 actuations over 24 h for anti- emetic and analgesic effect [30, 35–37]. Intratumourally ad- ministered THCwas dosed to a maximum of 180 μg a day [6].

As an antiemetic, dronabinol (Marinol®) was administered 1–3 h before chemotherapy [39–41]; for postoperative nausea and vomiting following breast surgery, dronabinol was sched- uled preoperatively [43]; finally, the cannabis-based medicine Sativex® was administered 2 h after chemotherapeutic

treatment [30]. For analgesic effect cannabis–based medi- cines, nabiximols were first titrated to optimal individual dose, and not exceeding more than 4 doses over 3–4 h, or 1 dose before bed and increasing by 2 doses until optimal effective dose was reached [34–37]. As an appetite stimulant, dronabinol (Marinol®) was scheduled at meal time and/or before bed [32, 44]. CBM THC:CBD or CBD only was scheduled before lunch and dinner, with milk for cancer- related anorexia [31]. For quality of life including manage- ment of nocturnal hyperhidrosis, nabilone (Cesamet®) was scheduled before bed for the hypothesised management of hyperhidrosis associated with cancer or scheduled once a day before the first radiotherapy treatment [33, 45]. The CBM Bedrocan® was prescribed once daily, in the evening for drug interactions study [29]. Potential anticancer actions were reported for cannabis-based medicine (hemp oil) or the single constituent THC [6, 42].

Administration route

The route of administration for pharmaceutical and non- pharmaceutical cannabis–based medicines was orally via cap- sule or as ‘hemp oil’ (n = 10) [31–33, 39, 41–45]. oromucosal spray (n = 5) [30, 34–37], a herbal tea (n = 1) [29] and inhala- tion (n = 1) [38]. Single-molecule THC isolate was intratumourally administrated via subcutaneous reservoir (n = 1) [].

Oral administration of pharmaceutical medicinal cannabis via capsule containing single-molecule THC concentrations was used predominantly for antiemesis (n = 5), or as an appe- tite stimulant for chemosensory alterations (n = 1) and cancer- associated anorexia (n = 1). Oral capsules containing THC (2.5 mg) or THC:CBD (2.5 mg:1 mg) investigated appetite in cancer-related anorexia (n = 1). Oral capsules containing THC (1 mg) investigated anticholinergic action (n = 1) and quality of life (QOL) (n = 1). Oromucosal administration of nabiximols investigated pain management (n = 4) and antiemesis (n = 1). Inhalation of non-pharmaceutical CBM

Table 1 Therapeutic action and intervention of medicinal cannabis and number of studies reported in this review. (*Clinical drug interaction study. QOL quality of life)

Action Single-molecule cannabinoids Cannabis-based medicine (CBM)

Dronabinol (Marinol®)

Nabilone (Cesamet®)

THC isolate

Pharmaceutical CBM

Nabiximols (Sativex®)

Bedrocan® Hemp oil, leaf, flower

Anticancer 1 2

Antiemetic 4 1

Analgesic 4

Appetite stimulant 2 1

Anti-cholinergic 1

QOL adjuvant 1

*Drug interactions 1

3198 Support Care Cancer (2019) 27:3195–3207

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ed ia n

Support Care Cancer (2019) 27:3195–3207 3199

T ab

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Pr ef er en ce

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of sl ee p fo r ad va nc ed

ca nc er

pa tie nt s w ith

ch em

os en so ry

al te ra tio

ns .

M ai da

et al .

20 08

C as e re po rt

4 N ab ilo ne

(a nt i- ch ol in er gi c)

PO pa tie nt s 1 an d 2:

1 m g/ da y;

(s yn th et ic si ng le -m

ol ec ul e

T H C = 1 m g)

pa tie nt s 3 an d 4:

1 m g B ID

(t ot al 2 m g)

(s yn th et ic si ng le -m

ol ec ul e

T H C )

C on tr ol le d

N o ab so rp tio

n da ta

re po rt ed

E SA

S qu es tio

nn ai re

on in iti al co ns ul ta tio

n an d

at 48 -h

in te rv al s

th er ea ft er .

A ll pa tie nt s re po rt ed

im pr ov em

en to

f ni gh ts w ea ts

w ith

in 48

h of

in iti at in g

th er ap y w ith

na bi lo ne .N

on e

of th e pa tie nt s ex pe ri en ce d

an y si gn if ic an tb

ur de n of

si de

ef fe ct s fr om

th e ad di tio

n of

na bi lo ne .

C ot e et al .2 01 6

R an do m is ed

do ub le -b lin

d pl ac eb o- co nt ro lle d

tr ia l

46 N ab ilo ne

(Q O L )

PO H S

W ee k 1:

0. 5 m g H S;

(s yn th et ic si ng le -m

ol ec ul e

T H C = 0. 5 m g)

W ee k 2:

0. 5 m g B ID

; (s yn th et ic si ng le -m

ol ec ul e

T H C = 1 m g)

W ee k 3:

co nt .m

ax 4 m g/ da y

(s yn th et ic si ng le -m

ol ec ul e

T H C = 4 m g)

C on tr ol le d

N o ab so rp tio

n da ta

re po rt ed

E O R T C -Q

L Q -C 30 ,V

A S;

w ei gh t; co un to f da ys

on fe ed in g tu be

or ga st ro st om

y; in de pe nd en t

qu es tio

nn ai re to ev al ua te

ap pe tit e, na us ea ,c ou nt

of an tie m et ic

m ed ic at io n, A E s

N ab ilo ne

al on e de m on st ra te d no

si gn if ic an tQ

O L

im pr ov em

en t. N ab ilo ne ’s

to xi ci ty is lim

ite d an d th at th is

m ed ic at io n is w el lt ol er at ed

by pa tie nt s re ce iv in g

ra di ot he ra py

tr ea tm

en ts .

Ly nc h et al .

20 14

D ou bl e- bl in d

pl ac eb o- co nt ro lle d

pi lo tt ri al

16 N ab ix im

ol (a na lg es ic )

un kn ow

n O ro m uc os al

sp ra y

O ne

sp ra y. T itr at io n by

1 to

2 sp ra ys

pe r da y un til

th ey

re ac he d a do se

th at he lp ed

th ei r pa in ;m

ax 12

sp ra ys

V ar ia bl e

N o ab so rp tio

n da ta

re po rt ed

N R S -P I; Sh

or tF

or m -3 6

H ea lth

Su rv ey

(S F- 36 ® ); Q ST

; co lle ct io n of

ad ve rs e

T he re

w as

no st at is tic al ly

si gn if ic an td if fe re nc e be tw ee n

th e tr ea tm

en ta nd

th e pl ac eb o

gr ou ps

on th e N R S- PI .

3200 Support Care Cancer (2019) 27:3195–3207

T ab

le 2

(c on tin

ue d)

A ut ho r

St ud y ty pe

N In te rv en tio

n (a ct io n)

ty pe

A dm

in D ai ly

do se

D os in g

sc he du le

Ph ar m ac ok in et ic da ta

O ut co m e m ea su re s

P ri m ar y ou tc om

es

pe r da y do se

co nt in ue d ov er

4 w ee ks .

M in

do se :

2. 7 m g T H C :2

.5 m g C B D

M ax

do se :3

2. 4 m g T H C :

30 m g C B D

ev en ts ;c on cu rr en t

m ed ic at io ns

an d

ch an ge s du ri ng

st ud y

D em

on st ra te d th at na bi xi m ol s

ar e a sa fe

m ed ic at io n. T he re

w er e no

SA E s an d th e A E s

ex pe ri en ce d w er e m ild

an d

tr an si en ta nd

di d no tl ea d to

w ith

dr aw

al fr om

th e st ud y or

di sc on tin

ua tio

n of

th e

m ed ic at io n.

D ur an

et al .2 01 0 D ou bl e- bl in d pi lo t,

pa ra lle l,

pl ac eb o- co nt ro lle d

ph as e II cl in ic al tr ia l

16 N ab ix im

ol (a nt ie m es is )

C an na bi s sa tiv a L. ,

le af

an d flo

w er

O ro m uc os al

sp ra y

T itr at e to

3 sp ra ys

ov er

2- h

pe ri od ;

O ve r 4 da ys

tit ra tio

n up

to 8

sp ra ys

w ith

in an y 4- h pe ri od

ev er y 24

h M in

do se :2

.7 m g T H C :2

.5 C B D

M ax

do se :2

9. 6 m g T H C :

12 0 m g C B D

V ar ia bl e

Fi ve

bl oo d sa m pl es

w er e

co lle ct ed

fr om

ea ch

pa tie nt

in he pa ri ni ze d

tu be s, ce nt ri fu ge d,

w ith

pl as m a w as st or ed

at − 20

°C un til

an al ys is .T

hr ee

sa m pl es

w er e co lle ct ed

at tim

e 0 (b as al ), 60

an d 24 0 m in

on da y 0.

Pl as m a co nc en tr at io ns

of T H C ,C

B D an d th e tw o

m et ab ol ite s of

T H C

(1 1- O H -T H C an d

T H C -C O O H ) us in g a

m od if ie d pr ev io us ly

de sc ri be d m et ho d

kn ow

n as

th e

tr im

et hy ls ily

ld er iv at iv es

by G C /M

S. T he

lo w er

lim it of

se ns iti vi ty fo r al l

co m po un ds

w as

0. 5 ng

m l− 1 . V A S;

M A N E su rv ey

S at iv ex ®

ad de d to

st an da rd

an tie m et ic th er ap y w as

w el l

to le ra te d an d pr ov id ed

be tte r

pr ot ec tio

n ag ai ns td

el ay ed

C IN

V .A

hi gh er pr op or tio

n of

pa tie nt s in

th e B D S gr ou p

ex pe ri en ce d a co m pl et e

re sp on se

du ri ng

th e ov er al l

ob se rv at io n pe ri od

w ith

no m aj or

A E s re po rt ed .

Po rt en oy

et al .

20 12

M ul ti- ce nt re

ra nd om

is ed

pl ac eb o– co nt ro lle d

gr ad ed

do se

tr ia l

26 3

N ab ix im

ol (a na lg es ic )

C an na bi s sa tiv a L. ,

le af

an d flo

w er

O ro m uc os al

sp ra y

1- w ee k bl in de d do se

tit ra tio

n pe ri od

fo llo w ed

by 4 w ee ks

of st ab le do si ng ;G

ro up

1 (l ow

do se ) tit ra te d

in te rv en tio

n to

be tw ee n 1

an d 4 sp ra ys /d ay .

G ro up

2 (m

ed iu m do se )t itr at ed

in te rv en tio

n be tw ee n 6 an d

10 sp ra ys /d ay .

G ro up

3 (h ig h do se ) tit ra te d to

be tw ee n 11

an d 16

sp ra ys /d ay

M in

do se :2

.7 m g

T H C :2 .5

m g C B D

M ax

do se :4

3. 2 m g

T H C :4 0 m g C B D

V ar ia bl e

w ith

in tr ea tm

en t

ar m s

N o ab so rp tio

n da ta

re po rt ed

D ai ly

N R S- PI

vi a ca ll fr om

an in te ra ct iv e vo ic e

re co rd in g sy st em

(I V R S) .B

PI -S F,

E O R T C L Q -C 30

V er si on

3, 1 PA

C -Q

O L ,

M A D R S. 15

Pa tie nt s

al so

co m pl et ed

a PG

IC at th e st ud y te rm

in at io n

vi si t.

N ot ab le pa tte rn

of un de r- do si ng

pa rt ic ul ar ly

in th e na bi xi m ol s

tr ea tm

en tg

ro up s, w he re th e

pr op or tio

n of

pa tie nt s w ho

w er e no tt ak in g th e ta rg et ed

do se

in cr ea se d m ar ke dl y as

th e ta rg et in cr ea se d.

Jo hn so n et al .

20 10

Tw o- w ee k ra nd om

is ed

do ub le -b lin

d pl ac eb o- co nt ro lle d

pa ra lle l- gr ou p tr ia l

17 7

N ab ix im

ol (a na lg es ic )

C an na bi s sa tiv a L. ,

le af

an d flo

w er

O ro m uc os al

sp ra y

E ac h 10 0 m L

(2 .7

m g/ m lT

H C an d

2. 5 m g/ m lC

B D .

T he

m ax im

um pe rm

itt ed

do se

of al ls tu dy

m ed ic at io n w as

8 ac tu at io ns

in an y 3- h

pe ri od

an d 48

ac tu at io ns

in an y 24 -h

pe ri od .

M in

do se :2

.7 m g T H C ;

2. 5 m g C B D

M ax

do se :1

29 .6

m g T H C :

12 0 m g C B D

V ar ia bl e

N o ab so rp tio

n da ta

re po rt ed

T he

N R S qu es tio

n ‘i nd ic at e

yo ur

le ve lo f pa in ’ as ke d

3/ da y. B PI -S F, an d

E O R T C (Q

L Q -C 30

V er si on

3 w er e

co m pl et ed

by pa tie nt s at

V is it 1 an d at th e en d of

th e st ud y.

T H C :C B D co m bi na tio

n sh ow

ed a m or e pr om

is in g ef fi ca cy

pr of ile

th an

th e T H C ex tr ac t

al on e as

an ad ju nc tiv

e fo r

ca nc er -r el at ed

pa in .

Jo hn so n et al .

20 13

O pe n- la be lm

ul ti- ce nt re

fo llo

w -u p st ud y

43 N ab ix im

ol (a na lg es ic )

C an na bi s sa tiv a L. ,l ea f

an d flo

w er

O ro m uc os al

sp ra y

E ac h 10 0 m L

(2 .7

m g/ m lT

H C an d

2. 5 m g/ m lC

B D )

V ar ia bl e

N o ab so rp tio

n da ta

re po rt ed

Pa tie nt

di ar ie s, B PI -S F,

E O R T C Q L Q -C 30

sc or es

S om

e pa tie nt s w ill

co nt in ue

to ob ta in

re lie f of

ca nc er -r el at ed

pa in

w ith

lo ng -t er m

us e of

T H C /C B D sp ra y, w ith

ou t

Support Care Cancer (2019) 27:3195–3207 3201

T ab

le 2

(c on tin

ue d)

A ut ho r

St ud y ty pe

N In te rv en tio

n (a ct io n)

ty pe

A dm

in D ai ly

do se

D os in g

sc he du le

Ph ar m ac ok in et ic da ta

O ut co m e m ea su re s

P ri m ar y ou tc om

es

T he

m ax im

um pe rm

itt ed

do se

of al ls tu dy

m ed ic at io n w as

8 ac tu at io ns

in an y 3- h

pe ri od

an d 48

ac tu at io ns

in an y 24 -h

pe ri od .

M in

do se :

2. 7 m g T H C :2

.5 m g C B D .

M ax

do se :1

29 .6

m g T H C :

12 0 m g C B D

in cr ea si ng

th ei rd

os e of

th is or

ot he r pa in -r el ie vi ng

m ed ic at io ns

ov er

tim e,

su gg es tin g th at th e ad ju va nt

us e of

T H C /C B D sp ra y in

ca nc er -r el at ed

pa in

co ul d

pr ov id e be ne fi tt o ca nc er

pa tie nt s

G uz m an

et al .

20 06

Pi lo tp

ha se

I tr ia l

(c oh or t)

9 T H C (a nt ic an ce r)

un kn ow

n In tr a- tu m -

ou ra ly

T H C so lu tio n (>

96 .5 %

T H C ,

< 1. 5%

of its

is om

er D 8- T H C ,<

0. 5%

bu ty l- T H C an d < 0. 5%

pr op yl -T H C ) w as

ad m in is te re d to

th e pa tie nt s

fo rd

if fe re nt tim

es st ar tin

g at

da ys

3– 6 af te r su rg er y at a

ra te of

0. 3 m l m in

w ith

a sy ri ng e pu m p co nn ec te d to

th e su bc ut an eo us

re se rv oi r.

A ve ra ge

10 -d ay

cy cl e

(r ep ea te d)

V ar ia bl e

Pl as m a an d ur in e

co nc en tr at io n of

T H C

de te rm

in ed

da ily

in pa tie nt s 1 an d 2 du ri ng

th e fi rs t7

da ys

of ad m in is tr at io n. T he

co nc en tr at io ns

of T H C

an d tw o m et ab ol ite s

w er e be lo w de te ct io n

lim its

in al la na ly se s

pe rf or m ed

in pl as m a

an d ur in e.

Fl uo re sc en ce

po la ri sa tio

n im

m un oa ss ay

ki t

(A xS

Y M

C an na bi no id

A ss ay ,A

bb ot t, A bb ot t

Pa rk ,I L ,U

SA ;d et ec tio

n lim

it, 50

ng m l− 1 ), a

cl on ed

en zy m e do no r

im m un oa ss ay

ki t

(M ic ro ge ni cs

C E D IA

D A U M ul ti- L ev el T H C ,

M ic ro ge ni cs ,

Pl ea sa nt on ,C

A ,U

SA ;

de te ct io n lim

it, 50

ng m l− 1 ) an d ga s

ch ro m at og ra ph y/ m as s

sp ec tr om

et ry

(d et ec tio

n lim

it, 10

ng m l− 1 ).

T um

ou r ce lls

cu ltu

re s- co lla ge na se

D M E M .W

es te rn

bl ot ,

co nf oc al m ic ro sc op y.

T H C do es

no tf ac ili ta te tu m ou r

gr ow

th no r de cr ea se s pa tie nt

su rv iv al in th is co ho rt of

br ai n

tu m ou r pa tie nt s ex pr es si ng

ca nn ab in oi d re ce pt or s.

P O pe ri -o ra l, H S be fo re be d, B ID

tw ic e da ily ,Q

ID fo ur

tim es

da ily ,I V in tr av en ou s, TH

C te tr ah yd ro ca nn ab in ol ,V A S V is ua lA

na lo gu e Sc al e, E C O G P S E as te rn

C oo pe ra tiv

e O nc ol og y G ro up

P er fo rm

an ce

S ca le ,A

E ad ve rs e ev en ts ,E

O R TC

-Q LQ

-C 30

E ur op ea n O rg an iz at io n fo rR

es ea rc h an d T re at m en to fC

an ce rQ

ua lit y of

L if e Q ue st io nn ai re ,C

30 N R S- P IP

ai n In te ns ity

N um

er ic al R at in g S ca le ,G

C /M

S ga s

ch ro m at og ra ph y m as s sp ec tr om

et ry ,F A A C T Fu

nc tio

na l A ss es sm

en t of

A no re xi a/ C ac he xi a T he ra py ,P

O N V po st op er at iv e na us ea

an d vo m iti ng ,E

SA S E dm

on to n Sy

m pt om

A ss es sm

en t S ys te m ,M

A N E

su rv ey

M or ro w as se ss m en to fn au se a an d em

es is ,B

P I- SF

B ri ef P ai n In ve nt or y- Sh

or tF or m ,P A C -Q

O L P at ie nt A ss es sm

en to fC

on st ip at io n Q ua lit y of L if e, M A D R S M on tg om

er y- A sb er g D ep re ss io n R at in g

S ca le ,P

G IC

Pa tie nt

G lo ba lI m pr es si on

of C ha ng e

3202 Support Care Cancer (2019) 27:3195–3207

(n = 1), hemp oil extract (n = 1) and intratumoural injection of THC (> 96.5% THC, < 1.5% of its isomer D8-THC) (n = 1) investigated anticancer actions. Cannabis tea (18% THC and 0.8% CBD) was given orally in a clinical interaction study (n = 1).

Absorption

Of the 18 studies identified, four measured the absorption of medicinal cannabis in oncology through validated cannabi- noid assays [6, 29–31]. A 2007 clinical drug interaction study measuring the interaction of medicinal cannabis tea (Bedrocan®) with the chemotherapeutic agents, irinotecan and docetaxel, concluded that at the stated dose of medicinal cannabis, no interactions were observed [29]. Urine cannabi- noid levels were measured semi-quantitatively, having a threshold for detection of below 50 ng/ml (undetected) and above 50 ng/ml (detectable) to assess patient compliance to the intervention. Pharmacokinetic studies were centred on the chemotherapeutic agents to assess potential interactions [29].

A pilot phase I clinical trial investigating anticancer actions of inter-cranial delivery of THC investigated plasma and urine concentration of THC daily during the first 7 days of admin- istration for two patients and resulted in undetectable levels of cannabinoids and metabolites [6]. A phase II clinical trial in- vestigating chemotherapy-induced nausea and vomiting screened for plasma concentrations of THC, CBD and the two metabolites of THC (11-OH-THC and THC-COOH) [30]. CBD and THC were detected at pre-dose on day 1 for two of seven patients in the cannabis-based medicine group, and the inactive metabolite 11-nor-9-carboxy-delta-9-

tetrahydrocannabinol (THC-COOH) was detected in five pa- tients. A phase III random, double blind placebo controlled clinical trial investigating cancer cachexia that measured, al- though did not report the findings of urinary cannabinoid tests taken at week 0, 2, 4 and 6 [31].

Cannabinoid testing included preliminary urinary samples employing a fluorescence polarisation immunoassay kit to assess the presence of THC, CBD and THC metabolites 11- OH-THC and THC-COOH (AxSYM Cannabinoid Assay, Abbott Laboratory, Abbott Park, IL, USA; detection limit, 50 ng ml 1; TDx/FLx® cannabinoids assay; Abbott Laboratories, Abbott Park, IL). Oral fluid sample testing for the presence of metabolites 1-11-nor-Δ9-THC, THC-COOH, 11-OH-9THC, Δ8THC, cannabinol and cannabidiol (Microgenics CEDIA DAU Multi-Level THC, Microgenics, Pleasanton, CA, USA) as well as conformational gas chromatography/mass spectrometry (GS/MS).

Critical analysis

Standard critical appraisal tools from the Joanna Briggs Institute (JBI) were used to evaluate the methodological qual- ity of articles selected for inclusion. All articles beyond one sample number were subject to differences within participant groups, and subject to confounding variables during the inter- vention period, including concomitant medications. Randomised control trials (RCTs) met most of the critical analysis criteria. Limitations were commonly noted due to sample size. Five of the ten in total RCTs reported sample size calculations. Three of the five RCTs that reported sample size calculations achieved the necessary sample size required to

Fig. 2 Illustrative example of dosing and scheduling of medicinal cannabis in oral single–molecule medicinal cannabis, oral cannabis–based medicine (CBM) and oromucosal CBM *Tetrahydrocannabinol **Cannabidiol

Support Care Cancer (2019) 27:3195–3207 3203

conduct the proposed data analysis with confidence [34, 37, 44]. The remaining two RCTs either finished short due to insufficient differences between intervention and placebo [31] or did not meet sample size calculations, and as such statistical analysis was not performed for some outcomes [39]. Experimental and cohort studies measured exposure on- ly with no control group, or own control. Case studies met all criteria of the JBI tool, reporting intervention criteria where available. All articles meet the overall criteria for the respec- tive JBI critical appraisal tools.

Discussion

The collection and analysis of pharmacokinetic data stream- lines the development of newmedicines [46]. Much of what is known on the pharmacokinetics of medicinal cannabis has been determined via the examination of healthy subjects will also apply to cancer populations. For example, it is understood that differing routes of administration demonstrate varying rates of absorption, and therefore determine the dose and scheduling of a therapeutic outcome [21].

Individual tolerability to cannabinoid therapy is dependent on a number of biological parameters. These include first pass metabolism and secondary enterohepatic pathways metabolised via cytochrome P450 (CYP450) isoforms which are common metabolic pathways [47].

The lipophilic nature of cannabinoids can affect individual tolerability and therapeutic outcomes of medicinal cannabis, and when administered with fats or polar solvents, the absorp- tion of cannabinoids is improved [21, 48]. Furthermore, the pharmacodynamics involved with previous exposure to can- nabinoids can affect individual tolerability to medicinal can- nabis, while individual body composition can influence the level of cannabinoids detected in plasma over an extended timeline [21]. Pharmacogenetic considerations of the endocannabinoid system also provide an insight into polymor- phisms involved in cannabinoid metabolism offering a novel insight into cannabinoid therapy and individualised approach to medicine [49].

Almost all medicinal cannabis interventions reported in this review use oral-administered single-molecule cannabinoids or pharmaceutical cannabis–basedmedicine, the exception being two articles that reported results on inhaled and oil-based ex- tract of non-pharmaceutical cannabis–based medicines [38, 42]. Pharmacokinetic biomarkers of cannabis use have fo- cused on the acute administration of inhaled cannabis which may not be applicable to other routes of administration [50]. Moreover, limits of quantification (LOQ) for both invasive and non-invasive methods of detection of cannabinoids result in only the indication of the presence of limited cannabis analytes above a specified level of sensitivity [51, 52].

Pharmacokinetic data collection often involves invasive multiple sampling procedures that can raise issues concerning patient perception of non-therapeutic pharmacokinetic inter- ventions [46, 53]. This can result in low rates of participation for these type of trials that theoretically may impact research translation in to clinical practice [53].

Clinical guidelines for the pharmaceutical medicinal can- nabis interventions Marinol® (dronabinol) and Sativex® (nabiximol) recommend a low starting dose and slow titration [13, 54–56]. Dose titration is used to identify an individual dose effect and to navigate the therapeutic window of a can- nabinoids to avoid adverse events [13]. However, dose titra- tion is not without challenges and can result in prescriptive and patient under-dosing, potentially impacting on reported efficacy of the cannabis intervention and patient quality of life [13].

For example, a retrospective chart study (n = 58) on medic- inal cannabis (dronabinol) in paediatric chemotherapy– induced nausea and vomiting reported that dose scheduling was followed in just 19% of cases, with 55 of 58 patients receiving a lower than recommended dose [40] . Furthermore, dronabinol was prescribed incorrectly as a res- cue medication in 45% of cases [40]. In this instance, out- comes of a lower dose of medicinal cannabis were reported as favourable for the majority of patients (60%).

Although the role of the endocannabinoid system in cancer remains unclear, various cancer cell lines have demonstrated i r r egu la r cannab ino id recep to r exp res s ion and endocannabinoid levels that vary dependent on the cancer presentation [57]. Increased expression of cannabinoid recep- tors has been associated with cancer aggressiveness; however, cannabinoid receptors are not reliable marker of cancer pro- gression or predictability [7, 57, 58]. Endocannabinoids and enzymes involved in cannabinoid synthesis and metabolism similarly do not provide consistent data for use as tumour markers, or as an indication of tumour progression [57].

Cannabis-based medicines derived from whole plant ex- tracts have an expanded phytochemical profile beyond the commonly standardised cannabinoids that has been coined the entourage effect. The synergy of constituents, including terpenoid-derived cannabis-based medicines may influence the pharmacokinetics through multi-target effects, improving bioavailability and modulating potential adverse events asso- ciated with medicinal cannabis [17, 59, 60]. Moreover, cannabis-based medicines have broadly demonstrated in- creased efficacy and patient compliance when compared to single-molecule cannabinoids [59, 61, 62]. The generalised outcome associated with the entourage effect does not specify what indication the CBM was prescribed for; however, in moving forward, it is an element to consider in cannabis phar- macology and patient-centred outcomes.

Determining guidelines for cannabis-based medicine, giv- en the complexity of the phytochemical profile, and the

3204 Support Care Cancer (2019) 27:3195–3207

confounding variables of both the plant and the patient can be difficult. For example, different batches of ‘hemp oil’ (non- pharmaceutical cannabis–based medicine) extracted from Cannabis indica ‘chronic’; afghan/thai strain used to treat acute lymphoblastic leukaemia (ALL) demonstrated dose- and batch-dependent positive response in the reduction blast cells count—a biomarker of ALL [42]. Nuances within the confirmation of cannabis species have lead experts to argue that without biochemical analysis of individual plants within the species, claims, for example that Cannabis indica has a higher CBD to THC ratio when compared toC. sativa have no scientific validity [63].

Potential complementary effects of medicinal cannabis with first-line treatments in oncology have been reported in preclinical studies. Reduced therapeutic resistance and en- hanced chemosensitivity to antineoplastic agents in glioblas- toma multiforme cell lines has been observed with CBD treat- ment, while a THC and CBD combination induced glioma cell death and anti-proliferation of tumour xenografts in combina- tion with the antineoplastic agent, temozolomide [64, 65]. Similarly, CBD has been shown to enhance the anticancer effects of radiation [66, 67]. To date, only one clinical study has investigated the pharmacological interactions of antineo- plastic agents with a medicinal cannabis tea, Bedrocan® [29].

Limitations

A number of conference papers were identified that met the required inclusion criteria; however, these were not included without further peer reviewed publication being available. Date restriction due to the exclusion of articles previous to 2000 in order to reflect a consistent pharmacological under- standing of the endocannabinoid system may have limited the identification of absorption studies. Guidelines on pharmaco- kinetic studies, including subject participation, particularly among paediatric population, may have limited potential ab- sorption studies. Heterogeneity of participants and small study numbers may have limited the statistical significance of pri- mary outcomes.

Conclusion

A lack of clear biomarkers and an ability to accurately assess what the body does to the drug on administration of medicinal cannabis makes it difficult to establish clarity for precise indi- vidual dosing and scheduling. Similarly, biomarkers are lack- ing in terms of disease state and the modulatory effect of medicinal cannabis on the endocannabinoid system. As access to medicinal cannabis increases, the continued understanding of the complex pharmacology of this plant and the ability to modulate the endocannabinoid system can best inform

prescriptive practices and support patient centred outcomes in cancer populations.

This review highlights gaps in the literature reporting me- dicinal cannabis dosage and prescriptive practices in oncology that may impact efficacy investigations and patient quality of life. Evidence from this review suggests future studies should emphasise investigations into the administration, dosing schedules and absorption of medicinal cannabis to further ex- plore its application in cancer management. The context of this knowledge will allow a better assessment of the efficacy of medicinal cannabis in oncology.

Acknowledgments This research was supported by FIT-BioCeuticals Ltd. and Endeavour College of Natural Health, Australia.

Compliance with ethical standards

Ethical statement This article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interest The first author is a recipient of tuition scholarship for Honours candidature (Endeavour College of Natural Health, Australia) from FIT-BioCeuticals Ltd. The authors have full control of all primary data and agree to allow the journal to review the data if requested.

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