Trends in Food Science & Technology 115 (2021) 31–41

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Trends in Food Science & Technology

journal homepage: www.elsevier.com/locate/tifs

Innovative and emerging applications of cannabis in food and beverage

products: From an illicit drug to a potential ingredient for health promotion
Gabriela Boscariol Rasera, Andre Ohara, Ruann Janser Soares de Castro *
Department of Food Science and Nutrition, School of Food Engineering, University of Campinas, 80 Rua Monteiro Lobato, Campinas-SP, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Background: The use of cannabis for recreational purposes as a psychoactive substance and/or for the treatment
Cannabinoids of diseases is a controversial topic, surrounded by many different points of view. The fact is, the scientific
Health promotion community has invested in research that has elevated cannabis into an extraordinary status; making it
Cannabis-based products
increasingly socially acceptable and its products and derivatives marketed globally. The global cannabis market
Food ingredient
size was estimated to be valued at USD 20.5 billion in 2020, with a projected growth to USD 90.4 billion by 2026.
Scope and approach: This review aimed to synthesize the basic aspects related to therapeutic cannabis use by
providing information that highlights its application as an emerging ingredient in the food and beverage in­
dustry. Additionally, the legal status, chemical and biological properties, therapeutic and recreational effects and
the major future challenges for the application of cannabis-based products are discussed.
Key Findings and Conclusions: Cannabinoids, the most relevant class of active compounds in cannabis, have been
reported to display a wide variety of biological effects that can be considered beneficial or harmful to human
health. As medicinal agents, these compounds have been suggested as treatments for a number of diseases. Due to
the rapid evolution of the market and the constant need for reinvention, the food and beverage industry has
found, within this sector, an innovative possibility to formulate different products using cannabis as an additive.
Finally, aspects related to food security cannot be overlooked and are necessary to guarantee a safe and reliable
supply of cannabis-based products to the population.

1. Introduction
The origins of medicinal cannabis usage and scientific work is
attributed to the legendary Chinese Emperor Shen Nung, who lived in
the third millennium BC. The ancient emperor advocated the use of
“hemp elixir” in his flora pharmacopeia; which became the standard
reference work for Chinese medicine. By the second century AD, Chinese
medicine was the most advanced in the world and Hua Tuo, a famous
doctor, is said to have found that cannabis resin mixed with wine was an
effective analgesic. Therefore, it would be expected that with such in­
terest in medicinal cannabis use, the Chinese would be the first to report
any psycho-active effects of cannabis consumption.
The use of cannabis as a hallucinogenic/psycho active agent was
predominantly for spiritual or shamanistic exercises conducted by
ancient religious groups. However, shamanism started to decline and
became increasingly restricted in China, and ancient sources rarely
describe or mention shamanism; and consequently, the psychoactive
uses of cannabis in Chinese history. Despite this, there is evidence that
suggests past and continued medicinal and religious use throughout
history; predominantly in India and Asia. Nowadays, cannabis is still
widely used in India for medicinal purposes but is more closely associ­
ated with religious practices (Zuardi, 2006).
Another traditional place for cannabis use is the Arab world, where
hashish (from the Arabic for grass) was developed; made by squeezing
the resin glands or trichomes of the female cannabis plant. Hashish has
played an important historical role in the medical treatment of mi­
graines, syphilis, and as an analgesic and anesthetic in Arab territories
during the Roman empire. Interestingly, only in the sixteenth century
did the habit of smoking travel from Europe into the Middle East, due to
the arrival of tobacco from the western hemisphere. From then on,
hashish, which was traditionally only eaten, started to be smoked
instead (Chouvy & Afsahi, 2014; Booth, 2005).
Several of the medicinal properties of cannabis do not derive from
modern findings, but depend on the revival of empirical observations
made from its medical use over the centuries from all the major ancient
cultures (Chinese, Indian, Scythian, Egyptian, Greek, Latin, Arabic)

* Corresponding author. University of Campinas, 13083862 Campinas, Sao Paulo, Brazil.

E-mail address: ruann@unicamp.br (R.J.S. de Castro).

https://doi.org/10.1016/j.tifs.2021.06.035
Received 8 December 2020; Received in revised form 19 May 2021; Accepted 18 June 2021
Available online 21 June 2021
0924-2244/© 2021 Elsevier Ltd. All rights reserved.
G.B. Rasera et al.
(Pisanti & Bifulco, 2017). Therefore, cannabis was historically intended
to be used as a medicine and for religious purposes; consumed orally in
the form of tinctures, oils, and beverages.
Considering the modern therapeutic descriptions of cannabis prop­
erties, the main discoveries date back to the 19th century with the work
of William Brooke O’Shaughnessy (O’Shaughnessy, 1843) and
Jacques-Joseph Moreau (Moreau, 1845). Both researchers treated
mental patients with cannabis and hashish; observing analgesic and
myorelaxant effects that helped patients sleep, suppressed headaches,
and increased appetite. The Golden Age of Cannabis in Medicine
happened during the second part of the 19th century and up to the first
decades of the 20th. Several studies were carried out, increasing the
number of publications and cannabis applications in commercial prep­
arations produced by several pharmaceutical laboratories worldwide
(Pisanti & Bifulco, 2017).
The use of medical cannabis began to decline around the end of the
19th century, due to legal and cultural issues. The legal aspect of
cannabis trade and usage will be summarized in the next section of this
review. Despite the moral, social and pervasive prejudice towards
cannabis and its derivatives that lasted during the 20th century, the
scientific work on cannabis did not end entirely; the breakthrough of
scientists Yehiel Gaoni and Raphael Mechoulam marked the beginning
of a new era (Mechoulam & Gaoni, 1967). In 1967, those researchers
identified for the first time the chemical structure of the main canna­
binoid present in the plant, named Tetrahydrocannabinol (THC).
The discovery of cannabinoid receptors and the characterization of
endocannabinoids and the endocannabinoid system in the 1990s
(detailed description given later in this review), as well as papers
reporting on phytocannabinoid’s effective biological target renewed
recent scientific interest in Cannabis. This has led to the publication of
several papers demonstrating the pharmacological potential of this plant
(Pisanti & Bifulco, 2017). Over the past two decades, research efforts
have centered on the development of synthetic drugs capable of inter­
acting with the endocannabinoid system, beyond studying the phar­
macological properties of phytocannabinoids (Citti et al., 2019; Lu &
Mackie, 2016; Pisanti & Bifulco, 2019).
Historically, cannabis was intended to be consumed orally as a
medicine; however, for recreational purposes, dried cannabis flower has
been popularly consumed through smoking or vaporization. During the
last decade, several countries have changed their cannabis policies,
adopting laws that allow for its well-documented medicinal use and
decriminalizing or even legalization for recreational purposes (Kilmer,
2017). Nowadays, other forms of cannabis value added products, such as
high-power extracts, vape cartridges, topicals, edibles, and beverages
are being increasingly developed and gaining market-share (Blake &
Nahtigal, 2019).
Common cannabis edibles such as infused chocolate, baked goods,
beverage mixes, candies, and gummies are usually considered non-
dangerous. However, from the food science perspective, little research
has been done to assess how ingestion differs from other cannabis con­
sumption methods; with regards to therapeutic effectiveness, subjective
effects and safety. Moreover, common methods used in the pharma­
ceutical and food industries should be extensively revised in order to
preserve the bioactive cannabinoids (Blake & Nahtigal, 2019; Giombi
et al., 2018).
In this review, general aspects about cannabis, such as worldwide
legal status, chemical and biological properties and therapeutic effects;
in addition to studies involving the application of cannabis as an
ingredient in the food and beverage industries and the major future
challenges for the development of cannabis-based products are reported.
2. Legal status and current trends
The international control of the cannabis trade started in 1912,
together with the first international drug control treaties on opium and
coca. These treaties were revised in 1925 and the USA, Germany, the UK,
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Trends in Food Science & Technology 115 (2021) 31–41
France, Italy, the Netherlands, Portugal, Russia, China, Japan, Persia,
and Siam agreed to regulate and control opium and coca commerce and
use. The treaties were actually not extended to cannabis, but the nations
settled for a compromise to forbid the exportation of Cannabis indica to
those countries where it was explicitly outlawed (Pisanti & Bifulco,
2017).
In terms of legal aspects, cannabis cultivation, sale and recreational
use were prohibited by the majority of countries during the 20th cen­
tury. This scenario started to drastically change in the current century,
when several countries decriminalized cannabis possession, and legal­
ized its use in medical treatments. Moreover, some countries such as
Canada, South Africa, and Georgia, states and territories in the United
States of America and the Australian Capital Territory have legalized
recreational cannabis. In regards to medical use allowance, the list of
countries increases: Argentina, Australia, Barbados, Bermuda, Brazil,
Canada, Chile, Colombia, Ecuador, Estonia, Iceland, Israel, Jamaica,
Kuwait Lebanon, Liechtenstein, Malawi, Malta, Member States of EU
(exceptions are Bulgaria and Latvia), Macedonia, México, Norway, New
Zealand, North Macedonia, Norway, Peru, Saint Vincent and the Gren­
adines, Samoa, Sri Lanka, Switzerland, Thailand, The Philippines,
Puerto Rico, United Kingdom, United Arab Emirates, Vanuatu, Zambia
and Zimbabwe (Aguilar et al., 2018; Kilmer, 2017).
Fig. 1 summarizes the countries where cannabis possession is legal
for any kind of use, and where its use is allowed only if authorized by a
physician.
In terms of medical use, there is a clear trend in cannabinoid legal­
ization for medical treatments throughout western countries. Although
Asia remains at the forefront of repressive drug policies, several coun­
tries have seen positive developments; such as the Philippines, Thailand
and India (Aguilar et al., 2018). Considering industrial development,
Canada and the United States of America are at the forefront of tech­
nological progress; at the same time achieving specific tax collection
goals and offering a stable base for expanding recreational and industrial
systems (Lashley & Pollock, 2020). Recently, the inflated excitement
caused by the new cannabis market, and together with frustrations
about the growth of sales and profit, resulted in a cannabis stock bubble
that burst in Canada. However, in Canada more types of products will
soon be available in the market as well. The Canadian government is
legalizing alternative cannabis goods, such as edibles, and vapes;
keeping the investors optimistic about this new market share (Weis­
skopf, 2020).
3. Chemical composition of cannabis: a basic requirement to
evaluate its potential application
It is well known that the content of bioactive compounds in plant
material is highly variable for different strains, varieties, plant parts or
hybrid plants; in terms of composition and concentration. Also, envi­
ronmental parameters such as weather, age, storage conditions, and
Fig. 1. Map of cannabis legality considering medical and recreational use
(Aguilar et al., 2018; Kilmer, 2017).
G.B. Rasera et al.
method of extraction, affect the composition of those target compounds,
creating great variety. Additionally, the synergic effects between com­
pounds also needs to be considered, as well as their stability during
sample analysis (Atapattu & Johnson, 2020). For cannabis plant mate­
rial and analysis, these scenarios would not be different (Rashid et al.,
2021).
With more than 500 known constituents, including hydrocarbons,
nitrogenous compounds, flavonoids, fatty acids, non-cannabinoid phe­
nols, phytosterols, vitamin K, carotene and xanthophylls as pigments,
various simple alcohols, aldehydes, ketones, carboxylic acids, esters and
lactones; the cannabis compounds of current interest are the organic
compounds that become biochemically active after inhalation, digestion
or absorption through the skin, mostly, the cannabinoids (Atapattu &
Johnson, 2020; Knutson, 2020a; Rashid et al., 2021).
Cannabinoids, terpenoids and flavonoids comprise the most inter­
esting classes of biologically active compounds found in cannabis, due to
their health potential (see Topic 4) and already characterized biological
activity (Hazekamp et al., 2010). The peculiar and most studied com­
ponents in cannabis plant are shown in Fig. 2.
Cannabinoids are terpenophenols composed of 21 carbon atoms in
the form of carboxylic acid (Lynch & Campbell, 2011). They were
thought to be exclusive to Cannabis sativa, but they were recently found
in Rhododendron species, some legumes, the liverwort genus Radula, and
some fungi (Gülck & Møller, 2020). Hundreds of cannabinoids are
known and well described, such as cannabigerol, cannabinol, cannabi­
chromenel, and tetrahydrocannabivarin. However, tetrahy­
drocannabinolic acid (THCA) and cannabidiolic acid (CBDA); the acid
forms of Delta-9-Tetrahydrocannabinol (THC) and cannabidiol (CBD)
respectively, are the most discussed due to their biological effects. The
neutral forms (THC and CBD), that are more pharmacologically active,
are not produced by the metabolism of cannabis but formed during
thermal decarboxylation (Hazekamp et al., 2010; Knutson, 2020a).
THC is the major psychotropic cannabinoid found in cannabis. It is a
pharmacologically and toxicologically relevant constituent, exerting
several biological effects. The degradation of THC results in the forma­
tion of cannabinol (CBN) or delta-8-tetrahydrocannabinol (delta-8-THC,
with a similar pharmacological profile and slightly lower psychoactive
potency) and consequently changes the biological effects; which is what
must be considered (Hazekamp et al., 2010; Knutson, 2020a).
CBD is the major non psychotropic cannabinoid found in cannabis;
and it is found more abundantly in hemp (a fibrous-variety of C. sativa)
in its acid form. It has a variety of biological effects, such as antioxidant
and anti-inflammatory properties and immunomodulatory effects
(Hazekamp et al., 2010).
Different secondary metabolite groups that usually display biological
activity in animals are found in cannabis plant material, including al­
kaloids and nitrogenous compounds, non-cannabinoid phenols, stilbe­
noids, lignanamides and phenolic amides; however, terpenes and
Fig. 2. The exclusive and most important molecules identified in cannabis.
THCA is tetrahydrocannabinolic acid and CBDA is cannabidiolic acid.
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Trends in Food Science & Technology 115 (2021) 31–41
flavonoids are the most described (Hazekamp et al., 2010).
Terpenes are small volatile isoprenoid molecules, and more than 120
terpenoids have been identified in cannabis. Due to their volatility, they
are responsible for the distinct and unique smell and flavor of cannabis,
and are suitable for protection against possible predators (Knutson,
2020a; Lynch & Campbell, 2011).
The common terpenes naturally found in cannabis include; myrcene,
limonene, α and β pinene, linalool, β-caryophyllene, humulene, perillyl
alcohol, terpinolene, γ and α-terpinene, α- and γ-terpineols, geraniol,
nerolidol, borneol, α-bisabolol, α-, β- and γ-bisabolene, β-elemene, fen­
chone, pulegone, α-phellandrene, and β-eudesmol (Booth & Bohlmann,
2019; Nuutinen, 2018). Interestingly, only one terpene is exclusively
present in cannabis: the monoterpenoid-mentha-1,8(9)-dien-5-ol. All
the others can be found elsewhere in nature (Hazekamp et al., 2010).
Like cannabinoids and terpenes, flavonoids are ring structures but
are based on a 15-carbon phenolic structure instead. Twenty-three fla­
vonoids have been reported from cannabis and they have potential
antioxidative, anti-inflammatory, antimutagenic, and anticarcinogenic
properties. Between them, two are unique to the cannabis plant: can­
nflavin A and cannflavin B (Hazekamp et al., 2010; Knutson, 2020a).
4. Therapeutic effects of cannabis and its relationship to health
The therapeutic potential of cannabis and cannabinoids is immense.
Extensive reviews have already been made to elucidate the biological
effects of cannabis compounds and their therapeutic potential (O’Sh­
aughnessy, 1843; Hazekamp et al., 2010; Whiting et al., 2015; National
Academies of Sciences, Engineering, and Medicine, 2017).
In 2017, the National Academy of Sciences analyzed 10,700 research
articles to review and classify the associated therapeutic effects of
cannabis into: 1. Conclusive evidence or substantial evidence, 2. Mod­
erate evidence, 3. Limited evidence and 4. No or insufficient evidence to
support therapeutic association. The conclusive evidence that cannabis
or cannabinoids are effective were in the area of chronic pain treatment
in adults; as antiemetics in the treatment of chemotherapy-induced
nausea and vomiting; and for improving patient-reported multiple
sclerosis spasticity symptoms. The moderate evidence were in
improving short-term sleep outcomes in individuals with sleep distur­
bance, associated with obstructive sleep apnea syndrome; and in fibro­
myalgia, chronic pain, and multiple sclerosis (National Academies of
Sciences, Engineering, and Medicine, 2017). Limited and insufficient
evidence are discussed in topic 4.3.
Several studies were performed, however, few completely elucidated
the pharmacological effects of each compound in relation to its phar­
macokinetic properties (Vozella et al., 2019). Cannabis is still illegal in
most of countries and this is one of the biggest limitations for clinical
studies, which is crucial for cannabis use as a therapeutic compound.
4.1. The endocannabinoid system
Investigating why our own bodies would have “cannabis-like mole­
cules”, scientists started to examine the physiological relevance of those
bioactive lipids called endocannabinoids (DiPatrizio, 2016). Endo­
cannabinoids include a group of lipid mediators characterized by
N-acylethanolamines (NEAs) and 2-acyl glycerol derivatives. The most
studied are N-arachidonoylethanolamine (AEA), and anandamide and
2-arachidonoylglycerol (2AG). These molecules are an endogenous
signaling pathway in health and disease; and they vary across disease
states as an inherent response to physiologic stress and as a marker of
disease severity (Scharf & Ebbert, 2020).
The endocannabinoid system (ECS) is a biological system that is
comprised of these endogenous molecules, the cannabinoid receptors 1
(CB1) and 2 (CB2) and the enzymes that synthesize and degrade the
endocannabinoids; such as fatty acid amide hydroxylase (FAAH) and
monoacylglycerol lipase (MAGL) (DiPatrizio, 2016). The CB1 receptors
are found in the central nervous system including the brain and CB2
G.B. Rasera et al.
receptors are on immune cells circulating through the bloodstream; both
receptors are also present in the skin (Fig. 3) (Knutson, 2020a). THC
(Tetrahydrocannabinol) and CBD (Cannabidiol) compounds, as well as
exocannabinoids are all high-affinity agonists for both CB1 and CB2
receptors; one of the reasons that cannabis and their compounds or
products are gaining influence in scientific literature (Knutson, 2020b).
Studied since the early 1940s (Mechoulam et al., 2014), the ECS is
not an easy to understand system. Its complexity, species-specific
characteristics, contradictory findings in preclinical studies, and over­
lapping pharmacological targets are all interesting subjects researched
by scientists worldwide (Scharf & Ebbert, 2020). One of the major
functions of the ECS is the maintenance of homeostasis. It has a function
in multiple physiological roles; including caloric energy balance, im­
mune function, neurogenesis, pain, arousal, sleep, stress reactivity,
reward processing (Kayser et al., 2019); the regulation of gastrointes­
tinal function – enhanced food intake and inhibition of peristalsis and
gastric acid secretion (DiPatrizio, 2016); and also, as a possible line of
defense against bacteria (Friedman et al., 2019). Dysregulation of the
endocannabinoid system (for example, elevated AEA and 2AG) has been
observed in some health problems, such as obesity (Abdulnour et al.,
2014), insulin resistance (Fernández-Aranda et al., 2014), chronic in­
flammatory diseases (Chiurchiù, 2016) and intestinal disorders (DiPa­
trizio, 2016). However, the mechanisms and actions of the
endocannabinoid system involved with the exocannabinoid therapeutic
effects of cannabis are not completely elucidated and consequently, is
still the focus of much research.
4.2. THC and CBD health benefits
The National Academy of Sciences and other systematic reviews
(Lynch & Campbell, 2011; Whiting et al., 2015; Lynch & Ware, 2015;
Hill et al., 2017; Hutchison et al., 2019) support that there is substantial
evidence for cannabis as an effective treatment for chronic pain in
adults.
Due to its analgesic and antihyperalgesic effects, cannabis can be
safely used for diabetic neuropathic pain treatment (Williams et al.,
2008), fibromyalgia, rheumatoid arthritis, mixed chronic pain (Lynch &
Campbell, 2011) and spasticity (Whiting et al., 2015); all considered
chronic non-cancer pain. Medicinal cannabis use could potentially
decrease the utilization of opioids and other medications (Hutchison
Fig. 3. Endocannabinoids receptors (CB1 and CB2), their location and impor­
tance: CB1 at brain, central nervous system and skin; and CB2 at immune cells
circulating through the bloodstream.
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Trends in Food Science & Technology 115 (2021) 31–41
et al., 2019). Based on this assumption, Hutchison et al. (2019) sug­
gested ‘clinical guidelines based on existing evidence’ for patients who
have already decided to use cannabis products for pain and/or to reduce
opioid use; and to give health care providers the ability to discuss these
options with their patients.
Since THC was synthetized and evaluated for the first time in 1941
(Gaoni & Mechoulam, 1964), scientists have investigated the analgesic
properties of this compound and numerous other natural and synthetic
cannabinoids (Hill et al., 2017). It was identified that THC and CBD were
the main compounds responsible for this therapeutic effect (Harris et al.,
2019; Lim et al., 2003; Notcutt et al., 2004).
Moreover, exogenously administered cannabinoids, such as THC,
have the therapeutic potential to reduce chemotherapy-induced nausea;
an elusive and difficult to control symptom that current antiemetic
treatments cannot control, showing the unique ability of cannabinoids
to effectively manage nausea (Rock et al., 2016).
THC has been shown to be responsible for reducing chemotherapy-
induced vomiting and/or nausea when either smoked or orally admin­
istered. Also, Rock et al. (2016) indicated that combined subthreshold
doses of THC and cannabidiolic acid (CBDA), the acidic precursor of
CBD, effectively reduce acute nausea and anticipatory nausea in rats.
4.3. Other benefits
Despite the moderate and limited evidence reported by the National
Academies of Sciences, Engineering, and Medicine (2017), some other
therapeutic effects are the focus of many recent studies; some examples
are given in Table 1. Gallily et al. (2018) have encouraged the potential
use of cannabis terpenes for acute inflammation relief after an in vitro
and in vivo study. The alleviation of malaria symptoms was observed
after a 14 day diet based completely of cannabis in naive mice (Akinola
et al., 2018). Additionally, a review emphasized that cannabis will
emerge as a potential treatment for some headache sufferers (Lochte
et al., 2017).
CBD was considered as an immune suppressor and that the mecha­
nisms involve the direct suppression of the activation of various immune
cell types, induce apoptosis, and promote regulatory cells; which in turn,
control other immune cell targets (Nichols & Kaplan, 2020). In addition,
Alves et al. (2020) discussed the therapeutic potential of CBD for in­
flammatory conditions, Alzheimer’s and Parkinson’s diseases, multiple
sclerosis, epilepsy, autism, spectrum disorders, pain and cancer.
Medical cannabis and its role in relation to anxiety disorders has also
been reported. Oral CBD ingestion caused noticeable reductions in social
avoidance and anxiety, as well as improvements in sleep, feeding, motor
coordination, language skills, and sensory processing (Tartaglia et al.,
2019). Cannabis administration can reduce the need for benzodiazepine,
a medication normally prescribed for anxiety disorders, according to a
study published by Purcell et al. (2019).
Despite insufficient evidence, there are other biological effects that
encourage further studies, such as the possible future therapeutic value
for colorectal cancer (Nallathambi et al., 2017; Raup-Konsavage et al.,
2018); therapeutic effects of cannabinoids in sickle cell disease (Roberts
et al., 2018; Ballas, 2017); CBD as a therapeutic candidate for stroke
prevention (Scharf, 2017); cannabinoids for motor functions, mood and
cognition on Parkinson’s Disease (Bassi et al., 2017); and Δ8THC and
CBD as effective agents in the treatment of ocular pain and inflammation
resulting from corneal surface injuries (Thapa et al., 2018).
4.4. Side effects
Contradictory to the therapeutic effects reported above, cannabi­
noids including THC have also been reported to have adverse effects;
such as paranoia and anxiety in both medical patients and recreational
consumers (Blake & Nahtigal, 2019; McClements, 2020). Accordingly,
Canadian consumers carry doubts regarding the safe use of edible
cannabis, corroborating the need for future evaluation of food safety
G.B. Rasera et al. Trends in Food Science & Technology 115 (2021) 31–41

Table 1
Therapeutic effects of cannabis.
Compound Extraction process Objectives Results References

C. sativa extract with terpenes;
extract without terpenes; and Δ9-
THC extract
Δ9 Tetrahydrocannabinol (THC),
Cannabidiol (CBD) and a 1:1
mixture of them both (>95% of
purity)
Essential oils prepared from three
monoecious non-psychoactive
chemotypes of Cannabis
(Whole) Dried leaves, twigs, and
seeds of the C. sativa plant
Fresh and baked Cannabis sativa
flowers alcoholic extracts
THC, CBD and HU-308 (CBD
derivative) isolates
Extraction by maceration in
hexanes for 17 h
Medicinal standards
Steam distillation of female
flowers (upper third of the
plant)
Absolute ethanol extraction
(1:4; w:v) under stirring for
30 min followed by
methanol resuspension
Role of Cannabinoids and Terpenes
in Cannabis-Mediated Analgesia in
Rats
Medicinal extracts of cannabis for
chronic pain
Comparison of anti-inflammatory
properties of terpenoids with those of
cannabidiol (CBD).
Evaluation of the effects of whole
cannabis consumption on malaria-
infected host.
Anti-inflammatory activity in colon
models (inflammatory bowel
diseases are characterized by chronic
intestinal inflammation)
Antinociceptive and anti-
inflammatory effects of
cannabinoids in an experimental
model of corneal increased pain
response.
THC alone produced robust analgesia equivalent Harris et al.
to the full cannabis extract, whereas terpenes (2019)
alone did not produce analgesia. Isolated THC
appears to be all that is required to produce such
effects.
Extracts which contained THC were the most Notcutt et al.
effective in symptom control. Despite side-effects (2004)
were common, they were generally acceptable
and little different to those seen when other
psychoactive agents are used for chronic pain.
None of the essential oils was as effective as Gallily et al.
purified CBD. In contrast to CBD that exerts (2018)
prolonged immunosuppression and might be
used in chronic inflammation, the terpenoids
showed only a transient immunosuppression and
might thus be used to relieve acute
inflammation.
C. sativa displayed mild antimalarial activity in Akinola et al.
vivo as a result of the evident reduction in (2018)
symptomatic manifestation of malaria disease,
though unrelated to levels of parasitemia.
It is suggested that the anti-inflammatory Nallathambi
activity of Cannabis extracts on colon epithelial et al. (2017)
cells derives from a fraction of the extract that
contains THCA. THCA should be used rather than
CBD to treat Inflammatory bowel diseases.
Topical cannabinoids reduce corneal Thapa et al.
hyperalgesia and inflammation and could be a (2018)
novel clinical therapy for corneal pain and
inflammation resulting from ocular surface
injury.

measures and risk perception related to cannabis food products (Char­
lebois, 2020). Some examples of side effects are given in Table 2.
At first, the most pronounced distinction between cannabis extract
ingestion and inhalation, is the delayed start of drug activity through
ingestion. Thus, consumers often use more of the product than originally
intended, increasing the possibility of overdosing due to over­
consumption (Barrus et al., 2016).
A recent study (Schlienz et al., 2020) evaluated seventeen healthy
adults who had not used cannabis for at least three months, and had
them consume a cannabis-infused brownie with 0, 10, 25, or 50 mg of
THC. All THC doses resulted in increased heart rates. The 25 and 50 mg
doses caused prominent subjective effects, substantially reducing
cognitive and psychomotor functions. Considering the active doses,
pharmacodynamic effects occurred 30–60 min after ingestion, and peak
effects manifested 1.5–3 h after administration. In comparison, a study
using cannabis containing doses of 0, 10, and 25 mg, that was vaporized
and smoked by participants who previously abstained, reported peak
effects occurring within 10–30 min (Spindle et al., 2018).
This variation in activity start and duration is due to differences in
drug metabolism. When smoked, cannabinoids enter the circulatory
system through the lung alveoli. With ingestion, THC passes through the
stomach and then liver, where it is converted into several metabolites,
and finally passes through portal veins to reach the circulatory system.
Remarkably, one of the metabolites produced in the liver, 11-hydroxi-
THC, has its own psychoactive effects which are assumed to be stron­
ger than THC (Blake & Nahtigal, 2019) (Fig. 4).
In order to compare edible versus inhalable cannabis exposure,
Monte et al. (2019) studied the visits related to edible and inhaled
cannabis consumption at the emergency department of the University of
Colorado academic hospital. Visits due to cannabis inhalation were
more likely to be related to cannabinoid hyperemesis syndrome (char­
acterized by chronic cannabis use, cyclic episodes of nausea and vom­
iting, and frequent hot bathing); whereas visits due to edible cannabis
were more likely to be attributed to acute psychiatric symptoms,
intoxication, and cardiovascular symptoms. Intoxication reports are 1.7
times higher in edible consumers than in inhaled consumers, which can
be explained by the delayed effect of edibles; as well as the broad range
of edible preparations without standard cannabinoid concentrations,
leading to overconsumption (Allen, 2004).
Another explanation for increased intoxication cases in comparing
edibles and inhaled cannabis, are the frequent reports of accidently
intoxicated children through cannabis edibles. According to Cao et al.
(2016), from 381 reported calls to USA poison centers in states with
decriminalized medical/recreational marijuana, the most common age
group was children five years old or less; reporting symptoms such as
drowsiness/lethargy, ataxia, and red eye/conjunctivitis. This may be
related to the fact that edibles are usually sold as brownies, cakes,
cookies and candies, which can be indistinguishable from non-cannabis
foods; and lead to intoxication when consumers don’t understand what
they are eating.
The side effects of CBD are extensively reported by Iffland and
Grotenhermen (2017). In general, the majority of studies reviewed re­
ported that the most common side effects are tiredness, diarrhea and
changes of appetite/weight. Despite this, CBD has a better side effect
profile than most other drugs.
5. Applications of cannabis in food and beverage products: a
major challenge for the industry
5.1. Which part of the plant is used and how to extract?
Cannabinoids are produced in a thick sticky resin on gland-like
structures called trichomes. Trichomes are found on the plant
epidermal layer as glandular surface outgrowths; and are known to
contain a complex chemical secretion, including cannabinoids and ter­
penes (Blake & Nahtigal, 2019). Due to this morphology, the most
famous part are the flowers, which contain the majority of psychoactive
cannabinoids. Cannabis resin is also used to produce hashish, and
cannabis seeds to produce oil or eaten raw (Leghissa et al., 2018).
The use of cannabis in the food industry includes the extraction

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G.B. Rasera et al. Trends in Food Science & Technology 115 (2021) 31–41

Table 2
Cannabis side effects or risk factors.
Objectives Study information Results Reference

Use of alcohol FreeSurfer’s TRACULA Co-use was Wade

and cannabis was used to assess white associated with et al.
and its effects matter in emerging adults. lower white mass (2020)
in white integrity and
matter in neuronal integrity.
teenager Co-users also
appeared to be more
severe substance
users.
Chronic Rats were administered Chronic exposure to Ravula
exposure to THC intravenously (1 mg/ cannabis smoke et al.
cannabis kg) or exposed to smoke induces (2019)
smokes and from 5 or 10 sequentially dependence.
dependence smoked cannabis Withdrawal
in rats cigarettes (5.3% THC) in symptoms, which
an automated smoking include lack of
machine. Plasma samples motivation, appetite
were analyzed using loss, restlessness,
liquid and depressed
chromatography–mass mood, and can
spectrometry to THC contribute
identification. In a significantly to
separate study, three relapse.
groups of male Wistar rats
were trained in an Fig. 4. Different forms of cannabis consumption result in different metabolites.
intracranial self- 11-hydroxi-THC, formed in the liver after digestion process, have a stronger and
stimulation (ICSS) prolonged effect than smoked THC.
procedure, and exposed to
smoke from burning 5 or
10 cannabis cigarettes (or fluid extraction (SFE) and molecular weight cut-off-based cleanup op­
clean air control tions such as ultrafiltration (UF) and turbulent flow chromatography
conditions), 5 days/week
(TFC) (Leghissa et al., 2019; Marzorati et al., 2020).
for 4 weeks.
Body mass 401 adolescents ages Results reports a Ross et al. Classic extraction processes using different solvents (naphtha, pe­
index and 14–17 at baseline who negative association (2020) troleum ether, ethanol, or olive oil) can also be applied (Leghissa et al.,
cannabis use were at risk for escalation between cannabis 2018). It is crucial to understand that the extract quality, and conse­
relation in their use of cannabis. A use and body mass quently the need for downstream refinement, is totally related to the
parallel process latent index.
extraction method or the solvent used. The most common solvent-based
growth curve model to
examine associations extractions use ethanol, supercritical fluid extraction using carbon di­
between the cannabis use oxide (CO2) or are solvent-less (Dry-sieve extraction; water extraction;
and body mass index was rosin press extraction) (Blake & Nahtigal, 2019). Solvent free extraction
conducted.
techniques such as heat/pressure-based extractions are frequently
People with Sixteen people with Lower cognitive Kindred
multiple multiple sclerosis (eight function was not et al. applied (Knutson, 2020a).
sclerosis users), underwent clinical associated with (2018) Identification methods for THC and CBD from different sources and
using testing followed by [18F]- resting brain purposes have already been discussed and some are reported in Table 3.
cannabis and Fluorodeoxyglucose glucose uptake. Creating a CBD and THC concentrate requires extraction, phase
resting brain positron emission Cognitive
separation, decarboxylation, and distillation; with endless variables
glucose tomography/computed dysfunction may be
uptake and tomography imaging a contraindication (King, 2019; Knutson, 2020a). Thus, different strategies can be used for
clinical test or consequence of cannabinoid concentrate production. It is important to recognize that
relation cannabis use in the final application and the compound of interest are essential in
people with
deciding the most sufficient way to obtain the concentrated product. The
multiple sclerosis
most used steps for obtaining cannabis consumer products or extracts
are presented in Fig. 5.
process; isolation and purification of cannabinoids, and the analytical
methods to test concentration of cannabinoids in products (identifica­
tion and quantification of cannabinoids) (Knutson, 2020b). 5.2. How to incorporate this “ingredient” in the food matrix and what are
The extraction process constitutes the separation of cannabis plant the technological challenges?
material compounds into a concentrate with different applications,
either as a food ingredient or for vaping or topical use (Knutson, 2020b). The whole industry of cannabis edibles is a hybrid between food and
It is important for two main reasons: 1. To identify and quantify the pharma; and can be an option for a medical patient or recreational user
cannabinoids for a comprehensive therapeutic effect and also to accu­ who prefers not to smoke (Knutson, 2020c; Marangoni, 2019). Thus,
rately establish the concentration and composition of cannabinoids and edible cannabis can be regulated as a dietary ingredient or as a food
terpenes present; and 2. To elaborate consumer products or cannabis additive (Knutson, 2020b).
extracts. The lipophilic nature of cannabinoids requires the use of a lipid
Considering the lipophilic nature of cannabinoids, the most common carrier to solubilize these bioactives. Consequently, understanding the
techniques for extracting cannabis compounds include: pressurized type of matrix is the first step. Different incorporation possibilities are
liquid extraction (PLE), solid-phase extraction (SPE), matrix solid-phase possible; such as a cannabis oil-water-emulsions; lipid based self-
dispersion (MSPD), microwaved-assisted extraction (MAE), supercritical nanoemulsifying drug delivery systems; and lipid nanoparticles (Chen
& Rogers, 2019) all ensure cannabinoid solubility. In addition, an

36
G.B. Rasera et al. Trends in Food Science & Technology 115 (2021) 31–41

Table 3
THC, CBD and their metabolites identification in plasma and brain, whole blood
samples, cannabis concentrated, cannabis different parts (seeds, flowers,
leaves), food products and cannabis methanolic extracts.
Identification methods Reference
Compound and source

Quantification of THC and its Sample preparation (protein Vozella et al.

main oxidative metabolites precipitation and phospholipid (2019)
in plasma and brain of mice removal) followed by liquid
treated with a single chromatography/tandem mass
intraperitoneal dose of THC spectrometry (LC/MS-MS)
protocol (commercially available
C18 reversed-phase column and a
simple methanol/water gradient
system)
THC, 11-OH-THC and Solid-phase extraction, followed Castro et al.
THCCOOH in whole blood by gas chromatography/tandem (2018)
samples. mass spectrometry (GC–MS/MS) Fig. 5. The steps for obtaining cannabis-based products. The Cannabis har­
analysis in multiple reaction vesting is followed by drying process and trimming. The flower can be used for
monitoring mode, with a total run smoke or for extraction process. Laboratory tests are crucial at this point of the
time of 7.6 min. process. The most used green extraction process are super critical carbon di­
THCa and its analogs Dilution in methanol followed by Islam et al. oxide (CO2) extraction and Heat/pressure-based extraction. The winterization
(concentrates) surface enhanced Raman (2020)
is a purification steep that can be performed on an extract or after the extract
Scattering (SERS)
has gone through decarboxylation. It is a ‘dewaxing’ via precipitation in cold
THCa, THCAa, CBDa, CBDAa, Extracted with a mixture of Hädener
and CBNa (flowers, mixed methanol/hexane 9:1 (v/v) by et al. (2019) ethanol that is evaporated. The decarboxylation process removes the carboxyl
material consisting of ultrasonication for 20 min, group at a high temperature. To finish, distillation generates the isolates
leaves and stems without followed by HPLC-DAD products by temperature control. Vapors condense and different fractions are
flowers, hashish) identification and quantification collected at the beginning, middle, or the end of distillation. Based on King
analysis. (2019) and Knutson (2020d). THC is Tetrahydrocannabinol and CBD is Can­
CBDa; CBDAa, Δ9-THCa, Water and/or acetonitrile Christinat nabidiol. (For interpretation of the references to color in this figure legend, the
THCA-Aa, CBNa, CBCa, extraction followed by addiction et al. (2020) reader is referred to the Web version of this article.)
CBCAa, CBDVa, CBDVAa, of QuEChERS salt mixture to phase
CBGa, THCVa, THCVA, Δ8- separation followed by UPLC–MS/
THCa, THC-COOHa in MS quantification and water activity. Edibles should be packaged contrary to certain
twenty food products. identification. commercially available products; and be conducive to packaging indi­
THCa, CBDa, and CBNa in Methanol extraction followed by Jang et al.
vidual serving sizes (portion-evident or individually packaged) mainly
commercial hemp seeds and gas chromatography–mass (2020)
hempseed oil extracts spectrometry (GC/MS)
because of the dose. Also, packaging opacity is desirable to block light,
a
which degrades the compounds, and reduce product visibility from
THC or Δ9-THC is Tetrahydrocannabinol; 11-OH-THC is 11-hydroxy-THC children. Child-resistant packaging involves an opaque design, opening
(the main active metabolite of tetrahydrocannabinol); THCCOOH or THC-
mechanism, use of warning labels, and testing packaging for child
COOH is 11-nor-9-carboxy-THC (the main secondary metabolite of THC); THCA
resistance (Knutson, 2020b, 2020c).
or THCA-A is Tetrahydrocannabinolic acid (precursor of THC); CBD is Canna­
bidiol; CBDA is cannabidiolic acid (precursor of CBD); CBN is Cannabinol The presence of co-extract constituents such as pesticides, metals or
(degraded product of tetrahydrocannabinolic acid (THCA); CBC is Cannabi­ microbial toxins should also be carefully analyzed (Leghissa et al.,
chromene, CBCA is Cannabichromenic acid, CBDV is Cannabidivarin; CBDVA is 2019); despite more robust analytical methods required for
Cannabidivarinic acid; CBG is cannabigerol; THCV is tetrahydrocannabivarin; multi-residue pesticide analysis detection in cannabis plant material
THCVA is Tetrahydrocannabivarin acid; Δ8-THC is Δ8-tetrahydrocannabinol (Atapattu & Johnson, 2020). Additionally, increased analytical scrutiny
(THC isomer). of all components besides cannabinoids and terpenes used in formu­
lating cannabis-infused foods is necessary (King, 2019).
immense area of study is based on the encapsulation of cannabis oil, as it It is clear, after all considerations and challenges to the cannabis
is a possible guarantee to solve almost all challenges that will be dis­ industry, cannabis-infused edibles are gourmet, high-end and quite
cussed (Marangoni & Marangoni, 2019). expensive to make and purchase; because of this, the measures taken are
Despite the existing incorporation possibilities, the changes in vis­ to ensure production waste is reduced (Knutson, 2020c). The book, Food
cosity, consistency and flavor should also be considered since cannabis Safety Lessons for Cannabis-Infused Edibles (Food Safety Lessons for
oils are bitter and ‘tar-like’ in physical properties (King, 2019). Cannabis-Infused Edibles, 2020), provides information about the
The lipid properties could also possibly cause oxidation, interfering cannabis industry and excellent descriptions for operating and
with THC stability and shelf-life during storage; THC oxidation results in manufacturing of cannabis products.
a non-psychoactive form (CBN). Another important factor is the fact that In general, it is essential to understand exactly the composition of
heat is necessary to transform the non-psychoactive THC (acid form) cannabinoids and terpenes that are present in the food matrix; the sta­
into the psychoactive form (neutral). The THC decarboxylation by heat bility of compounds and the guaranteed dosage (Leghissa et al., 2019).
should be closely optimized during food processing. Consequently, in
regards to these points, THC dosage during storage should also be 5.3. What is the relationship between the addition of cannabinoids to food
carefully considered (Marangoni & Marangoni, 2019). matrices and their biological effects?
Cannabinoid homogeneity is extremely important for dosing and
potency; and is a critical control point. It can be monitored through the The concentration of cannabinoids added to food matrices are the
creation of a homogenized and partitioned batch and tested for CBD or main molecules responsible for the biological properties of the food
THC concentration. This again emphasizes the importance of validation, products. Considering that THC and fat metabolism are similar, many
identification and quantification analytical methods (Knutson, 2020b). variables can be shared; thus, the intake of THC will depend on body
Cannabis products must be shelf-stable and water activity control is weight, metabolism, gender, and eating habits. Consequently, every
one of the tools that can be used to maintain their stability. Thus, individual will vary in their reaction to cannabinoids. All of these factors
packaging characteristics should help the maintenance of a controlled changes bioavailability, affects the time to achieve intoxication, and the

37
G.B. Rasera et al.
duration of these effects (Beal, 2019). This is one of the reasons that the
pharmacokinetics of THC is necessary (Marangoni & Marangoni, 2019).
The ingestion of cannabinoids subsequently introduces them to the
body via the gastro intestinal tract, instead of the respiratory system.
Therefore, fat intake increases the bioavailability of THC and CBD, due
to their lipophilic nature. After CBD and THC solubilization in mixed
micelles following lipid digestion in the small intestine, the chylomicron
carries the THC and CBD for systemic circulation via the lymphatic
system (Chen & Rogers, 2019). Those exocannobinoids will then con­
nect to CB1 and CB2 receptors in the brain or immune system (Knutson,
2020a).
As mentioned before, oral ingestion causes a longer experience when
compared to smoking and inhalation (pulmonary absorption of THC);
because the most psychoactive form of THC is enzymatically created in
the liver after THC metabolization (Marangoni & Marangoni, 2019). In
addition, ingestion is more discreet than smoking, and it also prevents
the creation of toxins associated with plant material combustion
(Leghissa et al., 2019).
5.4. Products in the market
There are different types of products that can be produced from
cannabis plant material. In a medical context, a cannabis edible is a
product containing cannabis that is ingested as oils, tinctures, and oil-
filled capsules. In a recreational context, there is a wide variety of
cannabis-infused food products, including everyday commodities such
as teas or coffees, pizza, lollypops, chocolates, breakfast cereals, gummy
consistent products, chocolate cookies/brownies, beef jerky; and even
more recently, beer, wine, hemp-infused milks, barley-based sodas,
health beneficial-honeys, alcoholic beverages aromatized with cannabis
flowers and fortified sports products. The main ingredients used in the
preparation of cannabis edibles are oil and butter (Leghissa et al., 2019;
Blake & Nahtigal, 2019; King, 2019; Ascrizzi et al., 2020). Some
gourmet examples are given in Fig. 6.
Fig. 6. Examples of famous and gourmet Cannabis products.
38
Trends in Food Science & Technology 115 (2021) 31–41
An example is the production of chocolate incorporated with edible
cannabis oil. Different extraction procedures can be adopted, such as
soaking plant material in an edible oil or in melted cocoa butter to
produce a fat-based preparation; solvent extractions; rosin technique
(heat and pressure to remove essential oil) or separating the trichome
heads from the plant material. One of the critical steps is the ability to
temper the chocolate due to the changes in the melting point of cocoa
butter; resulting in a very soft chocolate bar, that melts on the fingers
and would not have the proper shine, snap and mouth feel of a well-
tempered bar. Other observations are the terpenes and the flavor
notes, the safety and standard tests and concerns about the production
(Beal, 2019).
The global cannabis market size was estimated to be valued at USD
20.5 billion in 2020, with a projected growth to USD 90.4 billion by
2026 (Markets and Markets, 2021). Additionally, it is projected that the
cannabis food and beverage market, specifically, will grow by USD
22.18 billion during 2020–2024, registering a compound annual growth
rate of 22% during this period (Business Wire, 2021); placing the
cannabis-based products into an extraordinary status.
6. Conclusion
There is abundant evidence showing that cannabis or cannabinoids
display a wide variety of biological effects; such as chronic pain treat­
ment in adults, antiemetics in the treatment of chemotherapy-induced
nausea and vomiting, and for improving patient-reported multiple
sclerosis spasticity symptoms. The findings from several studies support
their added benefits to human health, especially as therapeutic agents.
Based on the evidence, producing cannabis-based products has been
explored by the food and beverage industries as an emerging and
innovative market. The legal status of cannabis worldwide can be the
most challenging to its future applications as an ingredient in food and
beverages; since it requires a great deal of processing and manipulation
with extremely strict control. Aspects related to quality processing and
G.B. Rasera et al.
maintenance, such as the solubility, stability, dose, packaging, shelf-life
and oxidation of cannabis compounds emerge as industrial challenges.
However, the world scientific community in association with industries
has been making efforts to ensure that these products are widely pro­
duced and distributed; making this portion of the market ideal for
development and with great potential. Finally, aspects related to food
security cannot be overlooked and are extremely necessary to guarantee
a safe and reliable supply to the population.
Funding
This work was substantially supported by grants from National
Council for Scientific and Technological Development - Brazil (CNPq)
and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -
Brazil (CAPES) - Finance Code 001 (PROEX process number
23038.000795/2018–61).
CRediT authorship contribution statement
Gabriela Boscariol Rasera: Conceptualization, Writing – original
draft, preparation, Visualization, Investigation. Andre Ohara: Concep­
tualization, Writing – original draft, preparation, Visualization, Inves­
tigation. Ruann Janser Soares de Castro: Conceptualization, Writing –
review & editing, Supervision, Project administration, Funding
acquisition.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.tifs.2021.06.035.
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