Cannabis, cannabinoids, and health
Genevieve Lafaye, MD; Laurent Karila, MD, PhD; Lisa Blecha, MD;
Amine Benyamina, MD, PhD
annabis (also known as marijuana) is a psycho-
active plant that contains more than 500 components, of
which 104 cannabinoids have presently been identiﬁed.1
Two of these have been the subject of scientiﬁc investi-
gation into their pharmacological properties: ∆9-tetra-
hydrocannabinol (∆9-THC) and cannabidiol (CBD).
Cannabis potency is primarily evaluated according to
a sample’s THC concentration. This is the primary psy-
choactive cannabinoid in cannabis. The adverse effects
after acute or regular cannabis use are in direct relation
to THC concentrations in the product.2
Over the last few years, many studies have shown
that CBD levels may also have an important impact.
CBD may have a protective effect against certain nega-
tive psychological effects from THC. It may also be ca-
pable of antagonizing at least some of the adverse ef-
fects related to THC.3
Various cannabis preparations are available on the
illicit drug market: hashish, herbal cannabis (leaves and
ﬂowers), and oils. Real-time monitoring of conﬁscated
cannabis preparations has enabled scientists to mea-
sure the potency of currently used products. Changes
can then be compared with the prevalence of negative
health consequences in users. Certain authors speculate
that an increase in cannabis potency and in the ratio of
Copyright © 2017 AICH – Servier Research Group. All rights reserved 309 www.dialogues-cns.org
Keywords: cannabis; cannabidiol; medical cannabis; psychosis; synthetic can-
Author afﬁliations: AP-HP, GH Paris-Sud, Hôpital Paul Brousse, Dpt Ad-
dictologie, F94800 Villejuif, France; INSERM U1178, F94800 Villejuif,
Address for correspondence: Dr Genevieve Lafaye, Hôpital Paul Brousse,
Dpt Addictologie, F94800 Villejuif, France
Cannabis (also known as marijuana) is the most fre-
quently used illicit psychoactive substance in the world.
Though it was long considered to be a “soft” drug, stud-
ies have proven the harmful psychiatric and addictive ef-
fects associated with its use. A number of elements are
responsible for the increased complications of cannabis
use, including the increase in the potency of cannabis
and an evolution in the ratio between the two primary
components, ∆9-tetrahydrocannabinol (∆9-THC) and can-
nabidiol (toward a higher proportion of ∆9-THC). Syn-
thetic cannabinoid (SC) use has rapidly progressed over
the last few years, primarily among frequent cannabis
users, because SCs provide similar psychoactive effects
to cannabis. However, their composition and pharma-
cological properties make them dangerous substances.
Cannabis does have therapeutic properties for certain
indications. These therapeutic applications pertain only
to certain cannabinoids and their synthetic derivatives.
The objective of this article is to summarize current de-
velopments concerning cannabis and the spread of SCs.
Future studies must further explore the beneﬁt-risk pro-
ﬁle of medical cannabis use.
© 2017, AICH – Servier Research Group Dialogues Clin Neurosci. 2017;19:309-316.
the psychoactive component (9-THC) to CBD may be
the reason behind increases in harmful effects associ-
ated with cannabis use.
Furthermore, the last few years have seen a sub-
stantial rise in the use of synthetic cannabinoids (SCs),
especially in frequent cannabis users. The attraction of
SCs may be that whereas they provide psychoactive
effects that are similar to cannabis and are also easily
obtained, they are undetected through usual screenings.
However, their composition and pharmacological prop-
erties make them potentially dangerous substances.
Here, we summarize current developments concern-
ing cannabis and the spread of SCs. Despite increasing
detrimental issues arising from cannabis use, studies
have shown that this drug and some SCs may have a
number of therapeutic effects, depending on the spe-
Evolution of THC:CBD ratios
Recent reports indicate that cannabis production is in-
creasing and that cannabinoid formulations have been
changing over the last two decades, especially with re-
gard to their THC and CBD concentrations. This trend
has been observed not only in the United States, but
also in several European countries, such as the Neth-
erlands and Italy.4-6 Results are comparable since they
use a similar validated methodology: samples seized by
law enforcement ofﬁcials are analyzed using gas chro-
matography with a ﬂame ionization detector.
In a study by ElSohly et al,4 38 681 samples seized
in the United States between January 1, 1995 and De-
cember 31, 2014 were analyzed. The results showed an
8% increase in average THC levels during that period.
In parallel, CBD concentration decreased from 0.5%
to less than 0.2%. The resulting THC:CBD ratios in-
creased from 14 in 1995 to 80 in 2014.4 Elsewhere, Za-
mengo et al5 analyzed 4962 cannabis products seized
in the Venice area (Italy) from 2010 to 2013. Median
THC content showed a signiﬁcant increasing trend
from about 6.0% to 9.5%, especially between 2012 and
2013, with the total median THC content showing an
increase of about 16.7%. This increase pertained partic-
ularly to herbal materials (+25%), whereas resin mate-
rials increased by about +9.7%. Interestingly, the aver-
age and median THC content of handmade cigarettes,
which was determined by calculating the percentage of
THC in the whole tobacco-cannabis mixture, and which
can be a relevant indicator when studying patterns of
cannabis use, also showed signiﬁcant increases in 2013:
+28% and +45%, respectively.
Another study performed in the Netherlands in
2015 conﬁrmed these results with a different trend.6
Indeed, from 1999 to 2004, the THC content increased
from 8.5% to 20%. In the years 2005 to 2015, they found
a small but statistically signiﬁcant decline in THC con-
centration: a 0.22% decrease per year. Thus, in the
Netherlands, the THC content has remained stable dur-
ing the last 10 years. This study emphasized the fact that
global increases in THC levels and decreases in CBD
levels are largely linked to the spread of indoor cultiva-
tion practices. On average, cultivars from the Nether-
lands are twice as potent as imported products. The high
THC concentrations obtained from the various canna-
bis varieties result from technical advances in produc-
tion, such as genetic manipulations, cross-breeding, and
improvements in indoor hydroponic cultivation. As
advanced techniques and more potent seeds have be-
come more widely available, this has contributed to the
steadily increasing THC concentrations in cannabis.4
These changes may have signiﬁcant real-world clini-
cal consequences because the chances of detrimental
psychological effects seem to increase when canna-
bis with high concentrations of THC is consumed.7,8
CBD:THC ratio also appears to be an important fac-
tor.7,9 Epidemiological studies have shown that canna-
bis use during adolescence is an important risk factor
in the development of schizophrenia later in life.4 These
studies seem to show a risk of psychotic effects that is
proportional to THC concentrations and inversely pro-
portional to CBD concentrations. Some data also sug-
gest that the CBD:THC ratio may play a role in the risk
Emerging market of synthetic drugs: synthetic
Synthetic cannabinoids (SCs) emerged in the 1970s
when researchers were ﬁrst exploring the endocannabi-
noid system and attempting to develop new treatments
for cancer pain. Around the year 2000, SC appeared on
the illicit drug market, where their prevalence had long
been underestimated. Since then, their place in the mar-
ket has steadily increased. More than 560 synthetic psy-
Cannabis, cannabinoids, and health - Lafaye et al Dialogues in Clinical Neuroscience - Vol 19 . No. 3 . 2017
choactive substances have been identiﬁed on the illicit
market. There has been a steep rise over the last 5 years
with the appearance of 380 new synthetic drugs. Since
2008, more than 160 SCs have been identiﬁed in various
products, 24 of which appeared in 2015.10 Most SCs are
manufactured by chemical companies located in Asia
(China, South Korea). Today, intra-European produc-
tion is closely monitored.10,11 Current legislation is fre-
quently defeated and outwitted by manufacturers who
regularly modify their chemical formulations, resulting
in rapid turnover of SCs. Indeed, each SC is replaced by
newer analogs within a year or two.12
SC use varies a great deal between different coun-
tries and populations.13 For example, in Spain in 2012,
there was a low percentage (1.4%) of use of “Spice”
and its derivatives among youth between 14 and 18
years of age. In 2013 in Germany, a survey conducted
with students between 15 and 18 years of age showed
that 5% of them had used herbal blends. In 2016, the
European Monitoring Center for Drugs and Drug Ad-
diction’s (EMCDDA’s) 2015 European School Survey
Project on Alcohol and Other Drugs (ESPAD) report
showed that approximately 4% of all youths between
15 and 16 years of age had used an SC at least once in
their lifetime; few differences were noted between boys
Compared with other new drugs on the market,
the increase in consumption of SCs was particularly
remarkable.13 Generally, these products are offered as
herbal blends. They may also be sold as tablets, capsules,
or powders.14 Frequently, they are smoked by pipe or as
a joint.15 Recently, newer liquid formulations have ap-
peared that can be vaped via electronic cigarette.16
SCs have different pharmacological properties than
cannabis. These molecules are particularly lipophilic15
and are full agonists of CBD receptor 1 (CB1) and
CBD receptor 2 (CB2).17 Their potential binding afﬁn-
ity for these receptors is also much stronger than that of
THC, thus causing much more pronounced psychoac-
tive effects. They also do not contain any CBD whatso-
ever, contrary to cannabis, where it is present in varying
Products of the same brand and sold under the
same name have highly variable product compositions
and concentrations.19,20 SC effects depend on the type
of product used and its dose. Similarly, the pharmaco-
kinetics depends on the administration route. In some
cases, the onset of psychoactive effects and physical
symptoms begins a few minutes after smoking.15 The ef-
fects are comparable to those observed after high doses
of THC, and the high efﬁcacy—as well as differences
from batch to batch—results in the risk of accidental
overdosing.21 Anxiety is frequently reported. Some us-
ers have described feeling limited in their movements,
whereas no motor deﬁcits are objectively observed. On
average, the effects last for about 6 hours, steadily de-
creasing until the next day.15,21,22
Herbal formulations containing SC that are smoked,
known as Spice, imitate the psychoactive effects of
THC.19 Several studies have shown that a large majority
of SC users are also frequent cannabis consumers,23,24
especially among adolescents.25 It is possible such use is
inﬂuenced by the fact that whereas SCs provide similar
psychoactive effects to cannabis, they are not detected
during routine screening.26 Some consumers may also
use SC in order to decrease their cannabis use or to di-
minish symptoms of cannabis withdrawal.26
Certain serious complications
Evolution of THC:CBD ratios and psychosis risk
Almost 30 years ago, Andréasson et al showed an asso-
ciation between cannabis use and the later emergence
of schizophrenia.27 Since then, numerous prospective,
longitudinal studies have been published. Despite con-
founding factors, sufﬁcient proof currently exists show-
ing that cannabis use increases the risk of psychotic dis-
Over the last 5 decades, increasing THC concentra-
tions have been observed in products available in many
countries. In the 1970s, the THC concentration in can-
nabis found in England and in the Netherlands was less
than 3%. Current varieties contain on average 16% in
England and 20% in the Netherlands. New cannabis
preparation techniques have led to products contain-
ing THC levels of up to 40%. Traditional hashish (resin)
contains THC and CBD in similar proportions. How-
ever, newer varieties and forms, such as sinsemilla, have
high THC levels but contain almost no CBD.29
Some studies have indicated that CBD may have
antipsychotic properties.30,31 One recent case-control
study revealed that the use of cannabis with high lev-
els of THC may be associated with an increased risk
of psychosis, especially when its CBD levels are low.32
Certain recent epidemiological studies have shown an
increased incidence of schizophrenia in countries such
as England and the Netherlands where highly THC-
concentrated cannabis is regularly used versus in Italy
where more traditional cannabis varieties with lower
concentrations of THC are used.29 High THC cannabis
may increase the risk of earlier psychosis onset. One
study has suggested an association between dose and
response, showing that daily users of high-dose canna-
bis begin their ﬁrst psychotic episode an average of 6
months earlier than those who had never used canna-
bis.7 A recent meta-analysis has also shown that contin-
ued use may have a negative impact on schizophrenia
outcome. Psychotic patients who continue to use canna-
bis had a signiﬁcantly greater number of relapses than
patients who had stopped using cannabis or had never
Based on studies examining the evolution of THC
levels in cannabis over the last few decades, one hypoth-
esis is that previous studies may have underestimated
the impact of cannabis on existing psychosis. In fact,
ecological proof seems to argue in favor of greater psy-
chosis risk among youths who have recently been ex-
posed to high-dose cannabis than in former generations
exposed to lower THC doses. Such an analysis, however,
has yet to be performed.34 Future research would need
to show that different cannabis varieties are associated
with different psychosis risks.
It is too soon to conﬁrm this hypothesis. Current
clinical data are insufﬁcient to justify prevention mea-
sures concerning cannabis use or restriction of highly
concentrated varieties. Estimates that integrate data
from different countries have shown that between 8%
and 24% of all psychotic disorders could be avoided if
use of highly concentrated cannabis were prevented.32
Psychiatric, addictive, and physical consequences of
Numerous complications have been observed in SC us-
ers.35 Because of its pharmacological characteristics, SC
may be the source of more serious adverse effects than
those seen with cannabis.15,17,18
Anxious symptoms, such as ruminations, anxiety,
and panic attacks, are often seen following SC use.
Sleep disorders, hyperactivity, agitation, and irritabil-
ity have also been reported. Acute intoxication may be
associated with cognitive disorders such as short-term
memory loss. There have also been cases of paranoia,
ﬂashbacks, and suicidal ideation.36,37 In one case report,
manic symptoms were noted to have followed a single
use of SC.38
Although SCs have a similar mechanism of action
to THC, the different pharmacological properties, such
as higher afﬁnity for CB1 and CB2 receptors, higher
efﬁcacy, as well as the absence of CBD, result in dif-
ferent physiological and toxicological effects, especially
concerning its pro-psychotic effects. The psychotogenic
effects of SC are increasingly alarming, with numerous
reports of individuals who become psychotic after SC
Delirious symptoms, acoustico-verbal hallucina-
tions, and dissociative elements have all been described
in individuals without a history of psychosis.41,42 Two
cases of catatonia after SC use have also been reported
in patients with no history of psychosis.43SC may also
worsen psychotic symptoms in patients who were previ-
ously stabilized or cause transitory psychotic episodes
in healthy, but vulnerable individuals.15
SCs are potentially addictogenic because these sub-
stances can increase dopamine secretion within the nu-
cleus accumbens and the ventral tegmental area.18,19,44-46
Symptoms of tolerance and of withdrawal resulting
from long-term use have also been described.36,47,48 The
symptoms associated with ceasing SC use are similar to
cannabis-withdrawal syndrome: sleep disturbances, in-
tense dreams, severe anxiety, nausea, restlessness or leg
cramps, sweating, shaking, and loss of appetite.49 Nacca
et al observed that withdrawal symptoms lasted an av-
erage of 6 days after quitting. Intense and severe crav-
ings have also been reported.50
An increasing number of nonfatal intoxications,
as well as deaths, after presentation to the emergency
room or in consultation have been reported, especially
in young people.51 SC use has been associated with the
following physical complications: cardiac, pulmonary,
neurological, digestive, renal, and even dermatologi-
cal.13 These consequences may be severe and potentially
fatal, as reported in a number of cases in the literature.52
Therapeutic applications of cannabis and cannabinoids
THC is the psychoactive principle of cannabis, induc-
ing the cannabis inebriation sought by many users. Its
addictive potential and negative consequences are now
well known.53 The effects of CBD are distinct and, in
many cases, the opposite of THC’s effects. CBD seems
Cannabis, cannabinoids, and health - Lafaye et al Dialogues in Clinical Neuroscience - Vol 19 . No. 3 . 2017
not to induce euphoria and seems to have antipsychotic,
anxiolytic, antiepileptic, and anti-inﬂammatory proper-
According to an evaluation (in 1999) by the Insti-
tute of Medicine in the United States on cannabis as
a medication, the future of medical cannabis resides in
isolating its cannabinoid components and their synthet-
ic derivatives. The variable composition within the raw
cannabis plant and especially the differing THC/CBD
ratios make therapeutic applications of these products
Various forms of cannabis have been studied to
ascertain the therapeutic properties of cannabis. Cur-
rently, three molecules have been approved by the US
Food and Drug Administration (FDA); a single mol-
ecule in Canada and Europe.56 Dronabinol, a synthetic
THC, has been approved by the FDA in the treatment
of anorexia in patients suffering from AIDS and as a
second-line treatment in nausea and vomiting induced
by cancer chemotherapies. Nabiximols, a combination
of synthetic THC and CBD in equal proportions, is
delivered in spray form. It has been approved in sev-
eral countries (Canada, Europe), but not in the United
States, as an adjunctive therapy in the treatment of
spastic pain in patients with neurological disorders.56
A 2015 meta-analysis reviewed randomized clini-
cal trials worldwide of medical cannabis and cannabi-
noids from 1974 through 2014.57 This study analyzed
the results from 79 clinical trials performed in various
domains: chronic pain, nausea and vomiting induced
by chemotherapy, spasticity in multiple sclerosis or in
paraplegics, orexigenic effects in patients with human
immunodeﬁciency virus (HIV) or AIDS, sleep disor-
ders, Tourette syndrome, psychosis, anxiety disorders,
intraocular pressure from glaucoma, and depression.
The most frequently studied cannabinoid forms were
medications produced by pharmaceutical companies:
nabilone, nabiximols, and dronabinol. The other evalu-
ated cannabinoids included THC, CBD, and a combi-
nation THC/CBD. This study included only two trials
using plant-based cannabis (smoked and vaped).
The results of this meta-analysis revealed moderate-
quality proofs in favor of nabiximols, nabilone, dronabi-
nol, or THC/CBD in treating spasticity from multiple
sclerosis. The same level of proof was shown for nabixi-
mols or smoked THC in the treatment of chronic cancer
pain and neuropathic pain. Proofs of lesser quality were
found in favor of dronabinol or nabiximols in treating
nausea and vomiting induced by chemotherapy and in
weight gain in HIV/AIDS patients; for nabilone and
nabiximols in treating sleep disorders; and for THC cap-
sules in treating Tourette syndrome. This meta-analysis
showed that CBD was not signiﬁcantly more efﬁcient
in treating psychosis than a usual antipsychotic, such as
amisulpiride, or depression compared with nabiximols.
Finally, one very small crossover trial with six patients
was not able to detect an effect of cannabinoids on in-
A systematic review by the American Academy of
Neurology examined publications from 1948 through
November 2013 concerning the use of cannabinoids in
the treatment of multiple sclerosis, movement disor-
ders, and epilepsy.58 Only oral cannabis extracts (com-
bined THC/CBD or CBD alone) had a sufﬁcient level
of proof in treating spasticity from multiple sclerosis
and central pain. The other formulations seemed to be
effective in these indications, but with lower levels of
proof. Proof was insufﬁcient to conclude as to the ef-
ﬁcacy of smoked cannabis. In other neurological indi-
cations, such as Huntington disease and Tourette syn-
drome, proofs were judged insufﬁcient.
Cannabinoids would seem to have some therapeu-
tic interest in the following indications: epilepsy, addic-
tions, psychotic disorders, anxiety, and sleep disorders.
However, there are currently insufﬁcient levels of proof.
Indeed, a Cochrane review from 2014, for example, con-
cluded that there were insufﬁcient levels of proof for
cannabinoids in the treatment of epilepsy.59 Neverthe-
less, cannabis-based treatments continue to elicit great
interest. They remain the subject of preclinical and hu-
man research. In animal studies, CBD has shown sig-
niﬁcant antiepileptic activity, reducing seizure severity.
Recent studies in young patients suffering from severe,
treatment-resistant epilepsy have shown that CBD may
have a speciﬁc indication in these forms.60,61
Due to its implications in the reward system, en-
docannabinoid signaling represents a potential thera-
peutic target in treating addictions. The results from
randomized, controlled trials suggest that CB1 recep-
tor agonists such as dronabinol and nabiximols may
be effective in treating cannabis withdrawal. Dronabi-
nol may also decrease opioid withdrawal symptoms.
Rimonabant, an inverse agonist of CB1 receptors, has
shown promising effects in tobacco cessation; it also
causes adverse psychiatric effects. Few clinical trials
have examined the effect of cannabinoids in treat-
ing alcohol-use disorder; those examining rimonabant
have shown negative results.62 A systematic review has
examined the preclinical and clinical data on the im-
pact of CBD on addictive behaviors. Fourteen studies
were found, nine in animals and ﬁve in humans. Some
preclinical studies suggest that CBD may have some
therapeutic properties in treating opioid-, cocaine-, and
psychostimulant-use disorders. Some preliminary data
suggest that it could be advantageous in treating can-
nabis- and tobacco-use disorder in humans.63,64
One randomized, double-blind clinical trial com-
pared the use of CBD versus amisulpride for 4 weeks
in, respectively, 20 and 19 patients with psychosis. This
study showed comparable efﬁcacy between amisul-
pride and CBD (Positive and Negative Syndrome Scale
[PANSS], Brief Psychiatric Rating Scale [BPRS]). A
potential advantage for CBD is its milder side effects:
fewer extrapyramidal symptoms, less weight gain, and
Contrary to the effects of THC, several preclinical
studies have shown that CBD may have anxiolytic ef-
fects.66,67 In individuals with social anxiety, CBD 400 mg
considerably decreases anxiety measures versus pla-
cebo; measures were correlated with decreased activ-
ity within the limbic and paralimbic areas on functional
magnetic resonance imaging (fMRI).67 One clinical trial
in healthy volunteers has shown that acute CBD admin-
istration (300-600 mg) seems to decrease experimental-
ly induced anxiety without modifying baseline anxiety
levels; it would also seem to decrease social phobias.68
The understanding of the relationship between
sleep and cannabinoids has been obscured by signiﬁ-
cant methodological differences resulting in mitigated
results. The results from the literature seem to favor a
beneﬁcial effect of acute cannabis intoxication on sleep.
On the other hand, regular cannabis use seems to have
a negative impact on sleep quality. Different cannabi-
noids seem to have a differential impact on sleep. One
study has suggested a therapeutic potential for dronabi-
nol and nabilone on sleep disorders and nightmares.69
Studies speciﬁcally examining CBD have shown that
when used at small doses, it may have some stimulant
effects.70 At medium-to-high doses, it seems to have a
more sedative effect and thus may improve sleep qual-
ity.71 When CBD is associated with THC, it seems to re-
duce slow-wave sleep.72
Thus, there is preclinical evidence and some clinical
evidence for therapeutic properties regarding a number
of diseases. However, larger controlled clinical trials are
needed to show efﬁcacy and safety for each disorder.
Cannabis use and its negative consequences have in-
creased over the last several years in parallel with in-
creasing cannabis potencies. SCs seem to be particular-
ly popular among cannabis users. This emerging market
represents a speciﬁc public health problem in light of
the severe complications in relation to their use. What
the risks are of developing a psychotic disorder after SC
administration remains a fundamental question.
This is an emerging area of research in which more
robust epidemiological studies must be developed.
These must provide detailed information concerning
not only the quantity and the frequency of cannabis
use, but also, and more importantly, the type of canna-
bis used. Longitudinal studies including precise THC
and CBD measurements must be established in order
to clarify the impact of THC/CBD ratios on psychosis
risk. The use of SCs must also be more largely examined
in light of the severe consequences associated with their
The legislative policies that have been established
to reduce the risks in relation to cannabis have long
represented an obstacle to research concerning medi-
cal cannabis use. Improved knowledge of the endocan-
nabinoid system and of exocannabinoids has proven
that cannabis may have signiﬁcant therapeutic effects.
Despite sparse research, certain countries, such as the
United States, have authorized the use of plant-based
medical cannabis.73 Future studies must further explore
the beneﬁt-risk proﬁle of medical cannabis use. o
Acknowledgments/Conﬂict of Interest: The authors have no conﬂicts of
interest to declare.
Cannabis, cannabinoids, and health - Lafaye et al Dialogues in Clinical Neuroscience - Vol 19 . No. 3 . 2017
1. Pertwee R, ed. Handbook of Cannabis. Oxford University Press; 2014.
Available at: http://www.oxfordscholarship.com/view/10.1093/acprof:o
so/9780199662685.001.0001/acprof-9780199662685. Published online
January 2015. Accessed May 21, 2017.
2. Volkow N, Compton W, Weiss S. Adverse health effects of marijuana
use. N Engl J Med. 2014;371(9):879.
3. Niesink R, van Laar M. Does cannabidiol protect against adverse psy-
chological effects of THC? Front Psychiatry. 2013;4:130.
4. ElSohly M, Mehmedic Z, Foster S, Gon C, Chandra S, Church J. Chang-
es in cannabis potency over the last 2 decades (1995–2014): analysis of
current data in the United States. Biol Psychiatry. 2016;79(7):613-619.
5. Zamengo L, Frison G, Bettin C, Sciarrone R. Cannabis potency in the
Venice area (Italy): update 2013. Drug Test Anal. 2015;7(3):255-258.
6. Niesink R, Rigter S, Koeter M, Brunt T. Potency trends of κ9-
tetrahydrocannabinol, cannabidiol and cannabinol in cannabis in the
Netherlands: 2005-15: potency trends of Dutch cannabis. Addiction.
7. Di Forti M, Sallis H, Allegri F, et al. Daily use, especially of high-po-
tency cannabis, drives the earlier onset of psychosis in cannabis users.
Schizophr Bull. 2014;40(6):1509-1517.
8. Hall W, Degenhardt L. High potency cannabis: a risk factor for depen-
dence, poor psychosocial outcomes, and psychosis. BMJ. 2015;350:h1205.
9. Schubart C, Sommer I, van Gastel W, Goetgebuer R, Kahn R, Boks
M. Cannabis with high cannabidiol content is associated with fewer psy-
chotic experiences. Schizophr Res. 2011;130(1-3):216-221.
10. Johnson L, Johnson R, Portier R. Current “legal highs.” J Emerg Med.
11. Mills B, Yepes A, Nugent K. Synthetic cannabinoids. Am J Med Sci.
12. Sarpong I, Jones F. A critical analysis of national policy relating to
legal highs. Nurs Stand. 2014;28(52):35-41.
13. Scocard A, Benyamina A, Coscas S, Karila L. Cannabinoïdes de syn-
thèse : une nouvelle matrice des addictions. Presse Med. 2017;46(1):11-
14. Seely K, Patton A, Moran C, et al. Forensic investigation of K2, Spice,
and “bath salt” commercial preparations: a three-year study of new de-
signer drug products containing synthetic cannabinoid, stimulant, and
hallucinogenic compounds. Forensic Sci Int. 2013;233(1-3):416-422.
15. Fattore L. Synthetic cannabinoids—further evidence supporting
the relationship between cannabinoids and psychosis. Biol Psychiatry.
16. Castellanos D, Gralnik L. Synthetic cannabinoids 2015: an update for
pediatricians in clinical practice. World J Clin Pediatr. 2016;5(1):16-24.
17. Fantegrossi W, Moran J, Radominska-Pandya A, Prather P. Distinct
pharmacology and metabolism of K2 synthetic cannabinoids compared
to κ9-THC: mechanism underlying greater toxicity? Life Sci. 2014;97(1):45-
18. De Luca M, Castelli M, Loi B, et al. Native CB1 receptor afﬁnity, intrin-
sic activity and accumbens shell dopamine stimulant properties of third
generation SPICE/K2 cannabinoids: BB-22, 5F-PB-22, 5F-AKB-48 and STS-
135. Neuropharmacology. 2016;105:630-638.
19. Cottencin O, Rolland B, Karila L. New designer drugs (synthetic can-
nabinoids and synthetic cathinones): review of literature. Curr Pharm Des.
20. Debruyne D, Le Boisselier R. Emerging drugs of abuse: current per-
spectives on synthetic cannabinoids. Subst Abuse Rehabil. 2015;6:113-129.
21. Auwärter V, Dresen S, Weinmann W, Müller M, Pütz M, Ferreirós N.
“Spice” and other herbal blends: harmless incense or cannabinoid design-
er drugs? J Mass Spectrom. 2009;44(5):832-837.
22. Gurney S, Scott K, Kacinko S, Presley B, Logan B. Pharmacology, toxi-
cology, and adverse effects of synthetic cannabinoid drugs. Forensic Sci
23. Mounteney J, Grifﬁths P, Sedefov R, Noor A, Vicente J, Simon R. The
drug situation in Europe: an overview of data available on illicit drugs and
new psychoactive substances from European monitoring in 2015. Addic-
24. Archer J, Dargan P, Lee H, Hudson S, Wood D. Trend analysis of ano-
nymised pooled urine from portable street urinals in central London iden-
tiﬁes variation in the use of novel psychoactive substances. Clin Toxicol.
25. Nelson M, Bryant S, Aks S. Emerging drugs of abuse. Emerg Med Clin
North Am. 2014;32(1):1-28.
26. Gunderson E, Haughey H, Ait-Daoud N, Joshi A, Hart C. A survey
of synthetic cannabinoid consumption by current cannabis users. Subst
27. Andréasson S, Allebeck P, Engström A, Rydberg U. Cannabis and
schizophrenia. A longitudinal study of Swedish conscripts. Lancet Lond
28. Gage S, Hickman M, Zammit S. Association between cannabis and
psychosis: epidemiologic evidence. Biol Psychiatry. 2016;79(7):549-556.
29. Murray R, Di Forti M. Cannabis and psychosis: what degree of proof
do we require? Biol Psychiatry. 2016;79(7):514-515.
30. Iseger T, Bossong M. A systematic review of the antipsychotic proper-
ties of cannabidiol in humans. Schizophr Res. 2015;162(1-3):153-161.
31. Englund A, Morrison P, Nottage J, et al. Cannabidiol inhibits THC-
elicited paranoid symptoms and hippocampal-dependent memory im-
pairment. J Psychopharmacol Oxf Engl. 2013;27(1):19-27.
32. Di Forti M, Marconi A, Carra E, et al. Proportion of patients in south
London with ﬁrst-episode psychosis attributable to use of high potency
cannabis: a case-control study. Lancet Psychiatry. 2015;2(3):233-238.
33. Schoeler T, Monk A, Sami M, et al. Continued versus discontinued
cannabis use in patients with psychosis: a systematic review and meta-
analysis. Lancet Psychiatry. 2016;3(3):215-225.
34. Frisher M, Crome I, Macleod J, Millson D, Croft P. Substance misuse
and psychiatric illness: prospective observational study using the general
practice research database. J Epidemiol Community Health. 2005;59(10):847-
35. Aoun E, Christopher P, Ingraham J. Emerging drugs of abuse: clinical
and legal considerations. R I Med J (2013). 2014;97(6):41-45.
36. Tait R, Caldicott D, Mountain D, Hill S, Lenton S. A systematic review
of adverse events arising from the use of synthetic cannabinoids and their
associated treatment. Clin Toxicol (Phila). 2016;54(1):1-13.
37. Müller H, Kornhuber J, Sperling W. The behavioral proﬁle of spice
and synthetic cannabinoids in humans. Brain Res Bull. 2016;126(pt 1):3-
38. Ustundag M, Ozhan Ibis E, Yucel A, Ozcan H. Synthetic cannabis-in-
duced mania. Case Rep Psychiatry. 2015;2015:310930.
39. van Amsterdam J, Brunt T, van den Brink W. The adverse health ef-
fects of synthetic cannabinoids with emphasis on psychosis-like effects. J
Psychopharmacol (Oxf). 2015;29(3):254-263.
40. Zaurova M, Hoffman R, Vlahov D, Manini A. Clinical effects of syn-
thetic cannabinoid receptor agonists compared with marijuana in emer-
gency department patients with acute drug overdose. J Med Toxicol.
41. Tyndall J, Gerona R, De Portu G, et al. An outbreak of acute delirium
from exposure to the synthetic cannabinoid AB-CHMINACA. Clin Toxicol
42. Mörkl S, Blesl C, Wurm W, Tmava A. Acute psychosis after consump-
tion of synthetic cannabinoids. [in German]. Fortschr Neurol Psychiatr.
43. Khan M, Pace L, Truong A, Gordon M, Moukaddam N. Catatonia sec-
ondary to synthetic cannabinoid use in two patients with no previous psy-
chosis. Am J Addict. 2016;25(1):25-27.
44. Spaderna M, Addy P, D’Souza D. Spicing things up: synthetic cannabi-
noids. Psychopharmacology (Berl). 2013;228(4):525-540.
45. Chavant F, Boucher A, Le Boisselier R, Deheul S, Debruyne D. New
synthetic drugs in addictovigilance. Therapie. 2015;70(2):167-189.
46. Miliano C, Serpelloni G, Rimondo C, Mereu M, Marti M, De Luca M.
Neuropharmacology of new psychoactive substances (NPS): focus on the
rewarding and reinforcing properties of cannabimimetics and amphet-
amine-like stimulants. Front Neurosci. 2016;10:153.
47. Wells D, Ott C. The “new” marijuana. Ann Pharmacother.
48. Sampson C, Bedy S, Carlisle T. Withdrawal seizures seen in the setting
of synthetic cannabinoid abuse. Am J Emerg Med. 2015;33(11):1712.e3.
49. Andrabi S, Greene S, Moukaddam N, Moukkadam N, Li B. New
drugs of abuse and withdrawal syndromes. Emerg Med Clin North Am.
50. Nacca N, Vatti D, Sullivan R, Sud P, Su M, Marraffa J. The synthetic
cannabinoid withdrawal syndrome. J Addict Med. 2013;7(4):296-298.
51. Bush DM, Woodwell DA. Update: drug-related emergency department
visits involving synthetic cannabinoids. Rockville, MD: US Substance Abuse
and Mental Health Services Administration; 2013. The CBHSQ Report. Avail-
able at: http://www.ncbi.nlm.nih.gov/books/NBK350768/. Published Octo-
ber 16, 2014. Accessed June 1, 2017.
52. Labay L, Caruso JL, Gilson T, et al. Synthetic cannabinoid drug use as
a cause or contributory cause of death. Forensic Sci Int. 2016;260:31-39.
53. Murray R, Quigley H, Quattrone D, Englund A, Di Forti M. Traditional
marijuana, high-potency cannabis and synthetic cannabinoids: increasing
risk for psychosis. World Psychiatr Assoc. 2016;15(3):195-204.
54. Rong C, Lee Y, Carmona N, et al. Cannabidiol in medical marijuana: re-
search vistas and potential opportunities. Pharmacol Res. 2017;121:213-218.
55. Watson S, Benson J, Joy JE. Marijuana and medicine: assessing the sci-
ence base: a summary of the 1999 Institute of Medicine report. Arch Gen
56. Schrot R, Hubbard J. Cannabinoids: medical implications. Ann Med.
57. Whiting P, Wolff R, Deshpande S, et al. Cannabinoids for medical use:
a systematic review and meta-analysis. JAMA. 2015;313(24):2456-2473.
58. Koppel B, Brust J, Fife T, et al. Systematic review: efﬁcacy and safe-
ty of medical marijuana in selected neurologic disorders: report of the
Guideline Development Subcommittee of the American Academy of Neu-
rology. Neurology. 2014;82(17):1556-1563.
59. Gloss D, Vickrey B. Cannabinoids for epilepsy. Cochrane Database Syst
60. Devinsky O, Marsh E, Friedman D, et al. Cannabidiol in patients with
treatment-resistant epilepsy: an open-label interventional trial. Lancet
61. O’Connell B, Gloss D, Devinsky O. Cannabinoids in treatment-resis-
tant epilepsy: a review. Epilepsy Behav. 2017;70(pt B):341-348.
62. Sloan M, Gowin J, Ramchandani V, Hurd Y, Le Foll B. The endocannab-
inoid system as a target for addiction treatment: trials and tribulations.
Neuropharmacology. 2017 May 28. Epub ahead of print. doi:10.1016/j.neu-
ropharm.2017.05.031. Accessed June 4, 2017.
63. Hurd Y, Yoon M, Manini A, et al. Early phase in the development of
cannabidiol as a treatment for addiction: opioid relapse takes initial cen-
ter stage. Neurother J Am Soc Exp Neurother. 2015;12(4):807-815.
64. Prud’homme M, Cata R, Jutras-Aswad D. Cannabidiol as an interven-
tion for addictive behaviors: a systematic review of the evidence. Subst
65. Leweke F, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anan-
damide signaling and alleviates psychotic symptoms of schizophrenia.
Transl Psychiatry. 2012;2(3):e94.
66. Bergamaschi M, Queiroz R, Chagas M, et al. Cannabidiol reduces the
anxiety induced by simulated public speaking in treatment-naïve social
phobia patients. Neuropsychopharmacol. 2011;36(6):1219-1226.
67. Crippa J, Derenusson G, Ferrari T, et al. Neural basis of anxiolytic ef-
fects of cannabidiol (CBD) in generalized social anxiety disorder: a pre-
liminary report. J Psychopharmacol. 2011;25(1):121-130.
68. Blessing E, Steenkamp M, Manzanares J, Marmar C. Cannabidiol as
a potential treatment for anxiety disorders. Neurother J Am Soc Exp Neu-
69. Babson K, Sottile J, Morabito D. Cannabis, cannabinoids, and sleep: a
review of the literature. Curr Psychiatry Rep. 2017;19:23.
70. Zuardi A. Cannabidiol: from an inactive cannabinoid to a drug
with wide spectrum of action. Rev Bras Psiquiatr Sao Paulo Braz 1999.
71. Chagas M, Crippa J, Zuardi A, et al. Effects of acute systemic admin-
istration of cannabidiol on sleep-wake cycle in rats. J Psychopharmacol Oxf
72. Nicholson A, Turner C, Stone B, Robson P. Effect of ∆9-tetrahydrocan-
nabinol and cannabidiol on nocturnal sleep and early-morning behavior
in young adults. J Clin Psychopharmacol. 2004;24(3):305-313.
73. D’Souza D, Ranganathan M. Medical marijuana: is the cart before the
horse? JAMA. 2015;313(24):2431-2432.
La cannabis, los cannabinoides y la salud
La sustancia psicoactiva ilícita que se emplea con mayor
frecuencia en el mundo es la cannabis. Aunque se consi-
deró por largo tiempo una droga “suave”, los estudios
han probado los efectos dañinos asociados con su em-
pleo. Hay algunos elementos que son responsables del
aumento de las complicaciones del empleo de cannabis,
como el incremento en la potencia de ella y una evo-
lución en la relación entre los dos componentes princi-
pales, el delta-9-tetrahidrocannabinol y el cannabidiol
(con un porcentaje más importante de delta-9-tetrahi-
drocannabinol). El empleo de cannabinoides sintéticos
(CS) ha tenido un rápido aumento en los últimos años,
especialmente entre los usuarios frecuentes de canna-
bis, ya que tienen la ventaja de producir efectos psicoac-
tivos similares a esta droga. La composición y las pro-
piedades farmacológicas de los CS los hacen sustancias
peligrosas. Para ciertas indicaciones la cannabis también
tiene propiedades terapéuticas, pero esto se aplica sólo
para ciertos cannabinoides y sus derivados sintéticos. El
objetivo de este artículo es resumir el progreso actual
relacionado con la cannabis y la difusión de los CS. Se
requieren futuros estudios que promuevan la explora-
ción del perﬁl de riesgo-beneﬁcio del empleo medicinal
de la marihuana.
Cannabis, cannabinoïdes et santé
Le cannabis (connu aussi sous le nom de marijuana) est
la substance psychoactive la plus fréquemment utili-
sée dans le monde. Longtemps considérée comme une
drogue « douce », des études ont prouvé les effets ad-
dictifs et psychiatriques nocifs associés à son utilisation.
Un certain nombre d’éléments sont responsables de
l’augmentation des complications liées à l’utilisation du
cannabis, comme l’augmentation de sa puissance et une
évolution du rapport entre les deux principaux compo-
sants, le ∆9-tétrahydrocannabinol (∆9-THC) et le canna-
bidiol (avec une proportion plus importante de ∆9-THC).
L’utilisation des cannabinoïdes synthétiques (CS) a rapi-
dement progressé ces dernières années, principalement
parmi les utilisateurs fréquents de cannabis, les CS ap-
portant des effets psychoactifs similaires à ceux du can-
nabis. Cependant, leur composition et leurs propriétés
pharmacologiques en font des substances dangereuses.
Le cannabis a bien des propriétés thérapeutiques pour
certaines indications. Ces applications thérapeutiques
concernent seulement certains cannabinoïdes et leurs
dérivés synthétiques. L’objectif de cet article est de résu-
mer les développements actuels concernant le cannabis
et la progression de l’utilisation des CS. Il faut entre-
prendre de nouvelles études pour mieux étudier le pro-
ﬁl bénéﬁce-risque de l’usage médical du cannabis.