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Cannabis (also known as marijuana) is the most frequently used illicit psychoactive substance in the world. Though it was long considered to be a “soft” drug, studies have proven the harmful psychiatric and addictive effects 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, Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (toward a higher proportion of Δ⁹-THC), Synthetic 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 pharmacological 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 developments concerning cannabis and the spread of SCs. Future studies must further explore the benefit-risk profile of medical cannabis use.
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Pharmacological aspects
Cannabis, cannabinoids, and health
Genevieve Lafaye, MD; Laurent Karila, MD, PhD; Lisa Blecha, MD;
Amine Benyamina, MD, PhD
Introduction
C
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-
nabinoid; tetrahydrocannabinol
Author affiliations: AP-HP, GH Paris-Sud, Hôpital Paul Brousse, Dpt Ad-
dictologie, F94800 Villejuif, France; INSERM U1178, F94800 Villejuif,
France
Address for correspondence: Dr Genevieve Lafaye, Hôpital Paul Brousse,
Dpt Addictologie, F94800 Villejuif, France
(email: genevieve.lafaye@aphp.fr)
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.
Pharmacological aspects
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-
cific posology.
Cannabis today
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
of addiction.2,7-9
Emerging market of synthetic drugs: synthetic
cannabinoids
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-
310
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
and girls.
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
concentrations.18
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-
orders.28
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
311
Pharmacological aspects
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
used.33
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
SC use
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
use.39,40
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
312
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-
ties.54
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
quite complex.55
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-
traocular pressure.57
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-
313
Pharmacological aspects
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
no hyperprolactinemia.65
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.
Conclusion
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
use.
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.
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315
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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.
... Cannabis use may lead to addiction, particularly when usage starts early in adolescence [73,74]. Cannabis abuse and dependence have been combined in the DSM-5 into a single entity termed ''cannabis use disorder.'' ...
... Of all these mentioned administration methods, smoking is the most common form [93]. Over the past few years, synthetic cannabinoids (SCs) have had a growing presence in the market, and more recently, liquid formulations can now be vaped through electronic cigarettes [73]. ...
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IntroductionPain is a global phenomenon encompassing many subtypes that include neuropathic, musculoskeletal, acute postoperative, cancer, and geriatric pain. Traditionally, opioids have been a mainstay pharmacological agent for managing many types of pain. However, opioids have been a subject of controversy with increased addiction, fatality rates, and cost burden on the US healthcare system. Cannabinoids have emerged as a potentially favorable alternative or adjunctive treatment for various types of acute and chronic pain. This narrative review seeks to describe the efficacy, risks, and benefits of cannabinoids as an adjunct or even potential replacement for opioids in the treatment of various subtypes of pain.Methods In June of 2022, we performed a comprehensive search across multiple databases for English-language studies related to the use of cannabinoids in the treatment of various types pain: neuropathic pain, musculoskeletal pain, acute postoperative pain, cancer pain, and geriatric pain. Data from meta-analyses, systematic reviews, and randomized control trials (RCTs) were prioritized for reporting. We sought to focus our reported analysis on more recent literature as well as include older relevant studies with particularly notable findings.ResultsThere is conflicting evidence for the use of cannabinoids in the management of pain. While cannabinoids have shown efficacy in treating specific chronic pain subtypes such as neuropathic pain, fibromyalgia pain, and geriatric pain, they do not show as clear benefit in acute postoperative and the majority of musculoskeletal pain syndromes. Data trends towards cannabinoids having a positive effect in treating cancer pain, but results are not as conclusive. To date, there is a paucity of data comparing cannabinoids directly to opioids for pain relief. Overall, the side effects of cannabinoids appear to be relatively mild. However, there is still potential for addiction, altered brain development, psychiatric comorbidities, and drug–drug interactions.Conclusion Cannabinoids may be effective in specific subtypes of pain, but current evidence and guidelines do not yet support its use as the first-line treatment for any type of acute or chronic pain. Rather, it may be considered a good adjunct or alternative for patients who have failed more typical or conservative measures. Additional studies are needed with standardized forms of cannabinoids, route of delivery, and dosing for greater-powered analysis. Providers must weigh the individualized patient risks, benefits, and concurrent medication list in order to determine whether cannabinoids are appropriate for a patient’s pain treatment plan.
... Given the cumulative effects that could result from the lipophilicity of several substances found in this plant, this could pose a serious threat to one's health [14,15]. It is Known that CBD has therapeutic properties and no psychoactive effect therapeutic properties and no psychoactive effect [9,14]. However, its adverse effects are not fully understood [9,16]. ...
... It is Known that CBD has therapeutic properties and no psychoactive effect therapeutic properties and no psychoactive effect [9,14]. However, its adverse effects are not fully understood [9,16]. Given the potential therapeutic benefits that some cannabinoids may offer, searches have been made for substances that can neutralize their potential acute side effects (hypothermia, tachycardia, etc.) [17,18]. ...
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Several studies show that chronic marijuana use opens doors to several disorders, especially neuropsychiatric disorders. Others consider cannabinoids to be promising in therapeutic practice. Here, we present a literature review, based on selected publications on the Medline and Scielo databases, on health and cannabis use. This review aims to assist health professionals and students in understanding the growing number of marijuana users who look for help in outpatient clinics and offices. Therefore, there is an increase in the frequency of hospital admissions for psychotic disorders in clinics and specific treatment institutions. Research over the past 35 years has shown that marijuana use promotes only momentary anxiolysis. This drug alone or in combination with cigarette, when consumed for a long term, can deteriorate the user’s intellectual capacity, academic performance, and professional achievements and finally results in social isolation. The current situation demonstrates that cannabis usage is a public health issue that needs to be addressed in health policy because the majority of users get sick and lose their ability to work.
... Very interestingly, several works have indicated that people who abuse cannabis tend to adjust the number, frequency, and intensity of puffs from the cannabis cigarette that they smoke to selfadminister a relatively low amount of THC at each session, regardless of cannabis potency (Korf et al., 2007;van der Pol et al., 2014). This seems to suggest that it is the THC/CBD ratio, and not the absolute concentration of THC, that is the most important factor to be taken into account in order to consider cannabis potency (Lafaye et al., 2017). Cannabis abuse causes several adverse effects. ...
Thesis
Cannabis sativa is among the most abused drugs worldwide. THC, its main psychoactive component, represents a risk factor of several mental pathologies, such as cannabis use disorder, addiction, and psychosis. Being a biphasic drug, high doses of THC cause hypoactivity and aversion, whereas low doses of THC cause hyperactivity and reward. THC acts on the type-1 cannabinoid receptor (CB1), one of the most abundant G-protein coupled-receptors (GPCRs) in the brain, whose signaling is biased, meaning that different transducers can carry specific pathway following different conditions. Biased signaling was proven to be extremely relevant in drug discovery and understanding CB1 signaling in pathologic conditions is essential for cannabinoid-based drug development. It is known that different doses of THC bring along different behavioral, cellular, and molecular outcomes. However, the link between those phenomena has never been investigated.Thus, for a therapeutic purpose PREG-like CB1-SSi compounds have been synthetized that share the same PREG therapeutic potential, but cannot be metabolized in downstream steroids. The CB1-SSi studied in the current work is the CB1-SSi lead compound, AEF0117.The first aim of the current work was to understand the intracellular signaling pathways following low, medium, and high doses of THC, leading to three distinct known behavioral outputs in mice, hyperlocomotion, asociability, and hypolocomotion, respectively.The second aim of the thesis was to understand the mechanism of action of AEF0117, and its capability to block the behavioral and molecular effects of THC at low, medium, and high doses.The doctoral dissertation is divided into five main parts. The introduction serves to preface the concepts of the endocannabinoid system, as well as cannabis abuse in humans and the counterpart behavioral outcomes of THC in mice, including hyperlocomotion, asociability, and hypolocomotion. The state of the art of CB1 signaling involving the biased CB1 system is described with particular emphasis on CB1 Signaling Specific Inhibitors (CB1-SSi), in particular the endogenous pregnenolone (PREG), and its synthetic analogue, the lead CB1-SSi compound, AEF0117.The article Zanese*, Tomaselli* et al., 2020 (published in J. Neurosci. Methods) oversees the validation of the high throughput analytical technique (AlphaLISA) of choice in this study for detection of protein phosphorylation in brain tissue lysates.The article Tomaselli et al. (to be submitted), is devoted to the studies of the low dose of THC that causes hyperlocomotion, with the discovering of its related intracellular CB1 signaling pathway, along with the signaling transducer involved in the CB1-rich brain areas relevant for locomotor activity (NAc, Str, CB). The main data revealed that THC via CB1 recruits the β-Arrestin1-PI3K-Akt-GSK3β signaling pathway that lead to hyperlocomotion. Furthermore, both PREG and AEF0117 were able to block the THC-induced hyperlocomotion and altered signaling in mice.The third part of the data represent studies on the effects of THC at medium and high doses that induce asocial behavior and hypolocomotion, respectively. Each dose of THC induced specific alterations in the CB1intracellular signaling pathways in the most CB1-rich brain areas, and the treatment with AEF0117 rescued both behaviors.The general discussion then addresses conclusions and perspectives, highlighting the role of specific CB1 pathways in THC-induced addiction and psychosis, and proposes a mechanism of action for CB1-SSi compounds, including AEF0117.
... Exogenous cannabinoids can be both synthetic and natural [8]. Of approximately 500 components contained in Cannabis sativa L., cannabidiol (CBD) and ∆9-tetrahydrocannabinol (THC) are the two predominant and most studied phytocannabinoids [7,10,11]. THC, a partial agonist of CB1 and CB2 receptors, is best known for the psychotropic effects associated with cannabis usage [10,12]. CBD exhibits a very low affinity to the endocannabinoid receptors, especially CB1, which explains its lack of psychoactive properties [10,12]. ...
... 11,12 The success of such treatments will depend on the dose, the individual, the tumor stage, and many other circumstances. 13,14 The use of cannabis in health care and pharmacy puts strict demands on growers raising plants with optimal production of the required compounds. 15 Cultivation can be done either by growing in soil or hydroponically. ...
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Introduction: The use of Cannabis sativa L. in health care requires stringent care for the optimal production of the bioactive compounds. However, plant phenotypes and the content of secondary metabolites, such as phytocannabinoids, are strongly influenced by external factors, such as nutrient availability. It has been shown that phytocannabinoids can exhibit selective cytotoxicity against various cancer cell lines while protecting healthy tissue from apoptosis. Research Aim: This study aimed to clarify the cytotoxic effect of cannabis extracts on colorectal cell lines by identifying the main active compounds and determining their abundance and activity across all developmental stages of medical cannabis plants cultivated under hydroponic conditions. Materials and Methods: Dimethyl sulfoxide extracts of medical cannabis plants bearing the genotype classified as chemotype I were analyzed by high-performance liquid chromatography, and their cytotoxic activity was determined by measuring cell viability by methylthiazolyldiphenyl-tetrazolium bromide assay on the human colon cancer cell lines, Caco-2 and HT-29, and the normal human epithelial cell line, CCD 841 CoN. Results: The most abundant phytocannabinoid in cannabis extracts was tetrahydrocannabinolic acid (THCA). Its maximum concentrations were reached from the 7th to the 13th plant vegetation week, depending on the nutritional cycle and treatment. Almost all extracts were cytotoxic to the human colorectal cancer (CRC) cell line HT-29 at lower concentrations than the other cell lines. The phytocannabinoids that most affected the cytotoxicity of individual extracts on HT-29 were cannabigerol, Δ9-tetrahydrocannabinol, cannabidiol, cannabigerolic acid, and THCA. The tested model showed almost 70% influence of these cannabinoids. However, THCA alone influenced the cytotoxicity of individual extracts by nearly 65%. Conclusions: Phytocannabinoid extracts from plants of the THCA-dominant chemotype interacted synergistically and showed selective cytotoxicity against the CRC cell line, HT-29. This positive extract response indicates possible therapeutic value.
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The development of Cannabis sativa strains with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) content is a growing field of research, both for medical and recreational use. However, the mechanisms behind clinical actions of cannabinoids are still under investigation, although there is growing evidence that mitochondria play an important role in many of them. Numerous studies have described that cannabinoids modulate mitochondrial activity both through activation of mitochondrial cannabinoid receptors and through direct action on other proteins such as mitochondrial complexes involved in cellular respiration. Thus, the aim of this study was to determine the actions of a panel of extracts, isolated from high-CBD varieties of Cannabis sativa, on the activity of the mitochondrial electron transport chain complex IV, cytochrome c oxidase (CCO), in order to select those with a safer profile. After demonstrating that Cannabis sativa strains could be identified by cannabinoids content, concentration-response curves were performed with a collection of extracts from strains with high-CBD and low-THC content using bovine CCO. The CCO rate was clearly modified by specific extracts of Cannabis sativa plants compared to others. Half maximal inhibitory concentrations (IC50) of extracts and the inhibitory effects evoked at 1 × 10-4 g/mL displayed a significant correlation with the THC. Therefore, the screening of extracts based on CCO activity provides a powerful and rapid methodology to identify those plants with higher mitochondrial toxicity or even mito-protective actions.
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Dietary supplements are widely available products used by millions of people around the world. Unfortunately, the procedure of adding pharmaceutical and psychoactive substances has recently been observed, in order to increase the effectiveness of supplements in the form of hemp oils. For this reason, it is extremely important to develop analytical methods for the detection of substances prohibited in dietary supplements and food products. In the present study, using the LC–MS/MS technique, an innovative method for the detection and quantification of 117 synthetic cannabinoids and 13 natural cannabinoids in dietary supplements and food products in the form of oils during one 13-min chromatographic run was developed. Each method was fully validated by characterization of the following parameters: The limit of detection was set to 0.1 ng/mL (100 µg/g, 0.01%). The limit of quantification ranged from 0.05 ng/mL to 50 ng/mL. The criteria assumed for systematic error caused by methodological bias (±20%) resulting from the recovery of analytes after the extraction process, as well as the coefficient of variation (CV) (≤20%), were met for all 130 tested compounds. The positive results of the validation confirmed that the developed methods met the requirements related to the adequacy of their application in a given scope. Additionally, methods developed using the LC–MS/MS technique were verified via proficiency tests. The developed analytical procedure was successfully used in the analysis of hemp oils and capsules containing them in the studied dietary supplements.
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Purpose of review: The current review aims to summarize the state of research on cannabis and sleep up to 2014 and to review in detail the literature on cannabis and specific sleep disorders from 2014 to the time of publication. Recent findings: Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications.
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New psychoactive substances (NPS) are a heterogeneous and rapidly evolving class of molecules available on the global illicit drug market (e.g smart shops, internet, "dark net") as a substitute for controlled substances. The use of NPS, mainly consumed along with other drugs of abuse and/or alcohol, has resulted in a significantly growing number of mortality and emergency admissions for overdoses, as reported by several poison centers from all over the world. The fact that the number of NPS have more than doubled over the last 10 years, is a critical challenge to governments, the scientific community, and civil society [EMCDDA (European Drug Report), 2014; UNODC, 2014b; Trends and developments]. The chemical structure (phenethylamines, piperazines, cathinones, tryptamines, synthetic cannabinoids) of NPS and their pharmacological and clinical effects (hallucinogenic, anesthetic, dissociative, depressant) help classify them into different categories. In the recent past, 50% of newly identified NPS have been classified as synthetic cannabinoids followed by new phenethylamines (17%) (UNODC, 2014b). Besides peripheral toxicological effects, many NPS seem to have addictive properties. Behavioral, neurochemical, and electrophysiological evidence can help in detecting them. This manuscript will review existing literature about the addictive and rewarding properties of the most popular NPS classes: cannabimimetics (JWH, HU, CP series) and amphetamine-like stimulants (amphetamine, methamphetamine, methcathinone, and MDMA analogs). Moreover, the review will include recent data from our lab which links JWH-018, a CB1 and CB2 agonist more potent than Δ(9)-THC, to other cannabinoids with known abuse potential, and to other classes of abused drugs that increase dopamine signaling in the Nucleus Accumbens (NAc) shell. Thus the neurochemical mechanisms that produce the rewarding properties of JWH-018, which most likely contributes to the greater incidence of dependence associated with "Spice" use, will be described (De Luca et al., 2015a). Considering the growing evidence of a widespread use of NPS, this review will be useful to understand the new trends in the field of drug reward and drug addiction by revealing the rewarding properties of NPS, and will be helpful to gather reliable data regarding the abuse potential of these compounds.
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The high and increasing prevalence of medical marijuana consumption in the general population invites the need for quality evidence regarding its safety and efficacy. Herein, we synthesize extant literature pertaining to the phytocannabinoid cannabidiol (CBD) and its brain effects. The principle phytocannabinoid Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and CBD are the major pharmacologically active cannabinoids. The effect of CBD on brain systems as well as on phenomenological measures (e.g. cognitive function) are distinct and in many cases opposite to that of Δ⁹-THC. Cannabidiol is without euphoriant properties, and exerts antipsychotic, anxiolytic, anti-seizure, as well as anti-inflammatory properties. It is essential to parcellate phytocannabinoids into their constituent moieties as the most abundant cannabinoid have differential effects on physiologic systems in psychopathology measures. Disparate findings and reports related to effects of cannabis consumption reflect differential relative concentration of Δ⁹-THC and CBD. Existing literature, notwithstanding its deficiencies, provides empirical support for the hypothesis that CBD may exert beneficial effects on brain effector systems/substrates subserving domain-based phenomenology. Interventional studies with purified CBD are warranted with a call to target-engagement proof-of-principle studies using the research domain criteria (RDoC) framework.
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Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100 mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled "Cannabinoids and Epilepsy".
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Synthetic cannabinoids (SC) belong to the emergent market of new psychoactive substances, sold on the Internet or specialized shops. Since the 1970s, more than 160 new SC have invaded the drug market. These substances imitate the psychoactive effects of cannabis. Underestimated for too long, SC's market growth and consequences are no longer to be ignored, first of all in terms of public health. SC were first synthesized during researches on the endocannabinoid system. Though they are agonists of the cannabinoid receptors 1 and 2, as Δ9-tetrahydrocannabinol in cannabis, they can also have a really high affinity with these receptors, rising up their potency. Each country in the world has chosen various ways how to deal with SC: scheduling, blanket ban, regulation… In order to contour the legal system, producers regularly modify the chemical formulas of those substances and hand out an attracting packaging looking harmless. However, the content of those small packets is extremely unstable and unreliable, including harmful compounds to health. Reports show an increasing number of non-fatal intoxications but also fatalities. Consequences on the body are numerous but there have been also reports of mental health imbalance and appearances of addiction-linked clinical signs. This review of literature aims at establishing a picture on SC in order to raise awareness among professionals in the health field on this new addiction matrix. Copyright © 2016 Elsevier Masson SAS. All rights reserved.
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Epidemiological evidence demonstrates that cannabis use is associated with an increased risk of psychotic outcomes, and confirms a dose-response relationship between the level of use and the risk of later psychosis. High-potency cannabis and synthetic cannabinoids carry the greatest risk. Experimental administration of tetrahydrocannabinol, the active ingredient of cannabis, induces transient psychosis in normal subjects, but this effect can be ameliorated by co-administration of cannabidiol. This latter is a constituent of traditional hashish, but is largely absent from modern high-potency forms of cannabis. Argument continues over the extent to which genetic predisposition is correlated to, or interacts with, cannabis use, and what proportion of psychosis could be prevented by minimizing heavy use. As yet, there is not convincing evidence that cannabis use increases risk of other psychiatric disorders, but there are no such doubts concerning its detrimental effect on cognitive function. All of the negative aspects are magnified if use starts in early adolescence. Irrespective of whether use of cannabis is decriminalized or legalized, the evidence that it is a component cause of psychosis is now sufficient for public health messages outlining the risk, especially of regular use of high-potency cannabis and synthetic cannabinoids.
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INTRODUCTION: Mocarz is a Legal high that consists of dried parts of plants mixed with synthetic cannabinoids. There is currently limited information on its acute toxicity. CASE REPORT: We describe a 35-year-old patient with no previous medical and psychiatric history who was admitted to the psychiatric clinic after developing agitation and paranoid psychotic symptoms following the use of Mocarz purchased over the internet. CONCLUSION: Legal highs are a challenge in psychiatric acute care, because they provoke unpredictable mental states endangering self and others. © Georg Thieme Verlag KG Stuttgart · New York.