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Conversion of Cannabidiol (CBD) into Psychotropic Cannabinoids Including Tetrahydrocannabinol (THC): A Controversy in the Scientific Literature


Abstract and Figures

Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp plant Cannabis sativa L. and has been known to induce several physiological and pharmacological effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids. However, regulatory difficulties arise from its origin being a narcotic plant or its status as an unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This feature review aims to summarize the current knowledge of CBD degradation processes, specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of commercial formulations requires more attention in the future.
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Toxics 2020, 8, 41; doi:10.3390/toxics8020041
Conversion of Cannabidiol (CBD) into Psychotropic
Cannabinoids Including Tetrahydrocannabinol
(THC): A Controversy in the Scientific Literature
Patricia Golombek , Marco Müller , Ines Barthlott, Constanze Sproll
and Dirk W. Lachenmeier *
Chemisches und Veterinäruntersuchungsamt (CVUA) Karlsruhe, Weissenburger Straße 3, 76187 Karlsruhe,
Germany; (P.G.); (M.M.); (I.B.); (C.S.)
* Correspondence:; Tel.: +49-721-926-5434
These two authors contributed equally to the manuscript.
Received: 27 April 2020; Accepted: 29 May 2020; Published: 3 June 2020
Abstract: Cannabidiol (CBD) is a naturally occurring, non-psychotropic cannabinoid of the hemp
plant Cannabis sativa L. and has been known to induce several physiological and pharmacological
effects. While CBD is approved as a medicinal product subject to prescription, it is also widely sold
over the counter (OTC) in the form of food supplements, cosmetics and electronic cigarette liquids.
However, regulatory difficulties arise from its origin being a narcotic plant or its status as an
unapproved novel food ingredient. Regarding the consumer safety of these OTC products, the
question whether or not CBD might be degraded into psychotropic cannabinoids, most prominently
tetrahydrocannabinol (THC), under in vivo conditions initiated an ongoing scientific debate. This
feature review aims to summarize the current knowledge of CBD degradation processes,
specifically the results of in vitro and in vivo studies. Additionally, the literature on psychotropic
effects of cannabinoids was carefully studied with a focus on the degradants and metabolites of
CBD, but data were found to be sparse. While the literature is contradictory, most studies suggest
that CBD is not converted to psychotropic THC under in vivo conditions. Nevertheless, it is certain
that CBD degrades to psychotropic products in acidic environments. Hence, the storage stability of
commercial formulations requires more attention in the future.
Keywords: cannabidiol; tetrahydrocannabinol; degradation; psychotropic effects; Cannabis sativa
1. Introduction
The hemp plant Cannabis sativa L. naturally contains a number of different cannabinoids that are
related to the elementary chemical structure of cannabinol (CBN, Figure 1a) [1]. The most prominent
representative among the class of these compounds is Δ9-tetrahydrocannabinol 9-THC, Figure 1b),
which is hydrogenated in positions 6a and 7 [1]. Due to the well-known psychotropic properties of
Δ9-THC, only the cultivation of plant varieties with low contents of Δ9-THC is authorized in the
European Union (EU) at the moment [2,3]. There is a discrepancy in terms of the legality of products
derived from the hemp plant. In general, cannabis products (including flowering or fruiting tops of
Cannabis sativa) are listed in the United Nations (UN) single convention on narcotic drugs from 1961
[4] and are therefore prohibited regardless of their Δ9-THC content. However, processed products,
which contain hemp leaves are often regarded as safe and therefore legal, if the Δ9-THC content does
not exceed certain levels and an abuse as a narcotic drug can be ruled out. As explicitly excluded by
the definition of cannabis in the UN single convention [4], seed products (e.g., hemp seed oil), without
the cannabinoid-rich resin, are generally regarded as safe and may be marketed in the EU [5,6].
Toxics 2020, 8, 41 2 of 21
Figure 1. Chemical structures of (a) cannabinol (CBN) including the numbering system, (b) Δ9-
tetrahydrocannabinol (Δ9-THC) and (c) cannabidiol (CBD).
Besides Δ9-THC, the non-psychotropic cannabidiol (CBD, Figure 1c) gained increasing
popularity due to a broad spectrum of health-promoting effects ascribed to it with several reviews
on safety and efficacy available [718]. In recent years, this culminated in extensive consumer interest
with heavily increasing numbers starting in 2018 (Figure 2). Since then, so-called CBD extracts used
as a food constituent, in cosmetic products or in the liquids for electronic cigarettes are found with a
large variety in drug stores or in online shops [1921]. According to the Novel Food Regulation (EU)
2015/2283, an approval of CBD extracts for the use in food requires a history of food consumption
prior to May 1997 [3,22]. Thus, as such a history has not been demonstrated so far, CBD extracts are
classified as Novel Food and are therefore not authorized in the EU.
Figure 2. Google trends analysis for cannabidiol (CBD) (Data source: Google Trends [23]).
In addition to the discrepancy between the excessive product availability and the doubtful
compliance with legislation (EU and worldwide) for many of those products [24,25], questions also
arise in regard to the safety of these products. Regarding this, a major topic, which is discussed
controversially in the recent scientific literature, is the potential conversion of CBD into psychotropic
cannabinoids, including Δ9-THC. The observation that CBD products may still induce some
psychotropic effects, with various discussed mechanisms including direct action, degradation during
storage or under in vivo conditions, as well as contamination, recently highlighted the importance of
this question again [19].
This review aims to provide an overview of contemporary and older publications dealing with
the conversion of CBD to other (psychotropic) cannabinoids. After a detailed summary on the
psychotropicity of cannabinoids (Section 3.1), a comprehensive overview of the conversion of CBD
in different conditions is presented (Section 3.2). To provide a better understanding of the pitfalls of
cannabinoid research that may possibly account for some controversial results, some major analytical
challenges are presented in Section 3.2.1 before the conversion of CBD under acidic conditions
(Section 3.2.2) and in vitro conditions (using artificial or simulated gastric juice) is carefully discussed
(Section 3.2.3). The current debate about whether results of these studies and some in vivo studies in
13 (5)
2013 2014 2015 2016 2017 2018 2019 2020
Google searches on „CBD“ [%]
Toxics 2020, 8, 41 3 of 21
animals may be transferred to in vivo conditions in humans is elucidated in Section 3.2.4. Finally, the
debate about the in vivo conversion of CBD is expanded by the question of whether CBD may convert
to other (potentially psychotropic) cannabinoids under storage conditions (Section 3.2.5), and
conclusions regarding the risk assessment of CBD products upon oral consumption are provided.
2. Materials and Methods
A database research in April 2020 was conducted in Google Scholar and PubMed using the
keywords “conversion and/or degradation and/or isomerization of cannabidiol” as well as
“structure-activity relationship cannabinoids”, “receptor binding cannabinoids” and
psychoactivity/psychotropicity cannabinoids”. Other aspects of pharmacological effects of CBD not
relevant to the aim of the study were excluded.
3. Results and Discussion
3.1. Psychotropicity of Cannabinoids
The consumption of distinct parts of Cannabis sativa L., leading to psychotropic effects, has been
known for thousands of years [26]. There are two prominent products mainly used as a drug to
willingly induce states of intoxication, which are called marihuana (dried leaves and flowering tops
of the Cannabis sativa plant) and hashish (resin extracted from the Cannabis sativa plant) [27]. The UN
suggested prohibition of cannabis and extracts of cannabis in the single convention on narcotic drugs
in 1961 [4].
Pharmacological experiments with mixtures and/or single cannabinoids can be traced back to
the 1940s and 1950s, when a number of studies regarding THC, CBN and CBD were published
regardless of the fact that chemical structures were only elucidated in the mid-1960s [26,2830]. The
known psychotropic effects of cannabis were mainly attributed to Δ9-THC as a consequence to
substantial research during the mid-1960s and early 1970s [30]. The detailed understanding of the
biochemical processes induced by cannabinoids (predominantly Δ9-THC) was mainly achieved by
the discovery of cannabinoid receptors by Howlett et al. [31,32], which ultimately prompted the
discovery of endogenous cannabinoids, among which anandamide is the most prominent one [33].
To discuss their psychotropic effects, the most common cannabinoids may be divided into two
major groups according to the number of rings in the molecule. The first group is composed of
tricyclic cannabinols including CBN, and all THC and hexahydrocannabinol (HHC, Figure 3a)
isomers. The second groupwhich will be discussed later in this sectionconsists of bicyclic
cannabinoids with CBD, cannabigerol (CBG, Figure 3b) and cannabichromene (CBC, Figure 3c) being
the most prominent representatives.
In 1971, the UN released a convention listing psychotropic substances in four schedules ranging
from Schedule I (most restrictive) to Schedule IV (least restrictive) [34]. This convention classifies five
THC derivatives (i.e., Δ6a-THC, Δ7-THC, Δ8-THC, Δ10-THC and Δ10a-THC) and HHC in Schedule I,
while Δ9-THC is listed in Schedule II. However, scientific data on the psychotropic effects of these
substances are rather limited. Only recently the Expert Committee on Drug Dependence of the World
Health Organization (WHO) released a critical review on isomers of THC, stating that Δ8-THC and
Δ9(11)-THC were found to exhibit Δ9-THC like effects when administrated to different animals,
whereas Δ10-THC lacked a comparable effect [35]. Moreover, Δ8-THC and Δ6a(10a)-THC were found to
have psychotropic effects on humans while data regarding the effect of other THC derivatives on
humans are still missing [35].
Toxics 2020, 8, 41 4 of 21
Figure 3. Chemical structures of (a) hexahydrocannabinol (HHC), (b) cannabigerol (CBG) and (c)
cannabichromene (CBC).
The well-established fact that THC derivatives are metabolized by means of hydroxylation at
C11 prompted Lemberger et al. [36] to investigate 11-hydroxy-Δ9-THC and Watanabe et al. [37] to
study the psychotropic effects of 11-hydroxy-Δ8-THC. Both studies revealed that these substances
show even more enhanced effects than their respective non-hydroxylated forms when administrated
to humans. The same effect was also found for 11-oxo-Δ8-THC [37]. In another study by Järbe et al.
[38], two stereoisomers of 7-hydroxy-HHC showed psychotropic effects on rats and pigeons.
According to Watanabe et al. [39], 8-hydroxy-iso-HHC (9 mg/kg i.v.) produced a significant
hypothermia in mice at 15 to 90 min after administration, while-hydroxy-HHC failed to induce
this effect. Both caused a significantly prolonged pentobarbital-induced sleeping (1.8 to 8 times). In
summary, both hydroxy-HHCs showed THC-like effects in mice but they were less active than Δ9-
THC [39].
In contrast to that, the acid forms Δ8-tetrahydrocannabinolic acid (Δ8-THCA) and Δ9-THCA as
well as the metabolite 11-COOH-THC failed to cause any observable physiological effect or
psychotropic effect, even though detailed studies are missing [40]. However, as mentioned by
Moreno-Sanz et al. [41], Δ9-THCA slowly decarboxylates to form THC during storage and
fermentation but also during the baking of edibles, smoking or vaporizing and may thus exhibit
psychotropic effects upon respective consumption.
Despite some early uncertainty regarding the psychotropic effect of CBN as described by
Yamamoto et al. [42], Järbe et al. [43] reported on the psychotropic effects of CBN in rats and pigeons.
But high doses of up to 14 mg/kg were required, whereas Δ9-THC induced similar effects with doses
of 3 mg/kg. As also found for other cannabinoids, the hydroxylated form 11-hydroxy-CBN showed
more pronounced effects than the non-hydroxylated form [42].
Some general observations were reported by Compton et al. [44], who investigated the
correlation of binding affinity with psychotropic effects in humans for various different cannabinoids
in a detailed study and found a strong correlation. Interestingly, this study revealed that
cannabinoids with long (branched) side chains at C3 do have larger binding affinities compared with
ones with short (unbranched) side chains. Besides that, hydroxy groups or halogens located at the
terminal end of the side chain (i.e., at C5’ position) induced good binding affinities. Carboxylic acid
metabolites of either Δ9-THC or Δ8-THC, though, were not found to bind to the receptor at all. This is
well in agreement with findings of their non-psychotropic effects. The authors additionally reported
on different binding characteristics for CBD and Δ9-THC and used this as a hypothesis for their
different physiological effects [44].
In fact, CBD is described as “non-psychotropic” [45] or even “anti-psychotropic” [11,12] as it
does not show effects comparable to Δ9-THC, neither in studies on animals as already reported by
Mechoulam et al. [46] in 1970 nor in humans as reviewed by Iseger et al. [12]. However, a multitude
of psychological and physiological effects (some examples are anti-inflammatory, antiemetic,
antipsychotic, anticarcinogenic, anxiolytic and analgesic effects, effects on appetite, positive effects
nnabichromene (CBC)
Toxics 2020, 8, 41 5 of 21
on multiple sclerosis and spinal cord, as well as on Gilles de la Tourette’s syndrome, epilepsy,
glaucoma, diabetes, Parkinson disease and dystonia) were associated with CBD and reviewed in a
number of articles [7–18]. In agreement with the hypothesis by Compton et al. [44], a physiological
explanation for the different pharmacology was presented by Pertwee et al. [47], when they reported
on the unexpectedly high potency of CBD to act as the antagonist of CB1/CB2 receptors in cells or
tissues expressing these receptors. This is in contrast to Δ9-THC, which was described as an agonist
of the respective receptors [47].
Similar to THC- and HHC-type cannabinoids, the acid form (either methylated or not) of CBD
which is most likely also a product formed during the metabolism of CBDwas found to show some
effects on, e.g., cancer and hyperalgesia [48,49], neither of which, though, may be termed
psychotropic. Similarly, CBD monomethyl ether (CBD-ME) was found to lack psychotropic activity
in a study conducted on rats and pigeons [38].
In line with structural prerequisites, also CBG was termed “non-psychotropic” and, according
to binding studies on the cannabinoid receptors CB1 and CB2, may show some beneficial actions and
thus exert therapeutic potential such as protection against oxidative stress in macrophages [50]. Even
though data on metabolites of CBG is sparse, 5-acetyl-4-hydroxy-CBG was found to have
antileishmanial effects [51].
In an excellent review about the chemistry, synthesis and bioactivity of CBC, Pollastro et al. [52]
summarized recent studies on the psychotropicity of CBC. Even though no narcotic effect was found
in in vivo experiments, high doses of CBC may indeed exhibit responses typical for Δ9-THC (e.g.,
hypomotility, catalepsy, hypothermia and analgesia). The authors claim that the reason for this effect
most likely derives from another than the typical mechanism, as CBC was found to show only
marginal affinity for the cannabinoid receptors CB1 and CB2 [52]. Besides that, multiple other effects
are related to CBC, among which the antibacterial and antifungal activity is the most noteworthy one
as CBC outperforms other cannabinoids in this category. According to the authors, little information
exists regarding the biological profile of naturally occurring analogs of CBC [52].
Even though research on physiological, psychoactive and psychotropic effects on various
cannabinoids has been highly productive in the last 50 years, detailed clinical data of many isomers
and metabolites of cannabinoids are still missing. This gets even more relevant in the light of the
ongoing debate about the conversion of CBD to several of these compounds (Section 3.2). Further
studies on the psychotropicity of the respective conversion products may contribute and help to
further clarify the scientific debate about the in vivo activities of CBD.
3.2. Conversion of Cannabidiol
Various conversion routes for CBD are reported in the literature. An overview of the broad range
of conditions of these reactions and the resulting conversion products is presented in Figure 4 and
further discussed in the subsequent chapters. In brief, most of the reactions require acidic conditions,
high temperatures or are observed in vitro. Under these conditions, CBD is converted to ∆9-THC as
well as ∆7-THC, ∆8-THC, ∆10-THC, 11-THC and iso-THC [53,54]. A formation of the hydroxy
derivatives 11-hydroxy-CBD, 11-hydroxy-THC, 5′-hydroxy-CBD, 11, 5′-dihydroxy-CBD and 11,5′-
dihydroxy-THC was previously reported [54]. Furthermore, a formation of the two HHC derivatives
-hydroxy-HHC and 8-hydroxy-iso-HHC has been reported [39,54]. In the presence of methanol or
ethanol, the methoxy or ethoxy derivatives 9-methoxy-HHC and 10-methoxy-HHC or 9-ethoxy-HHC
and 10-ethoxy-HHC are formed [5355]. Besides that, CBN was reported to be formed under in vitro
conditions [39]. However, only one of the reported reactions (i.e., the conversion of CBD to Δ9-THC)
was observed in vivo in rats [56]. A detailed summary of all conversion reactions is also presented in
Table A1 (Appendix A).
Toxics 2020, 8, 41 6 of 21
Figure 4. Overview of various chemical conversions of cannabidiol (CBD) to different conversion
products and the respective conditions, which are reported in the literature.
3.2.1. Analytical Challenges in Detecting CBD, its Degradation Products and other Cannabinoids
By the time of their first detection, cannabinoids were mainly analyzed by color reactions such
as the DuquénoisNegm test and the Beam test as summarized by Vollner et al. [57]. Some of these
tests were highly sensitive and enabled the differentiation between various cannabinoids [57].
Besides that, thin layer chromatography (TLC), photometric and spectroscopic methods were
reported as well [57]. The development of gas chromatography (GC) by Martin and Synge in the early
1950s and its immediate success in analytical chemistry [58] soon also reached the field of cannabis
research when Farmillo and Davis developed the first GC method to separate a number of different
cannabinoids in 1960 [59,60]. Similar to GC, the invention and rise of the high-performance liquid
chromatography (HPLC) technique in the late 1960s [61] quite immediately paved its way to the field
of cannabis research. First reports on the use of HPLC to detect and quantify several cannabinoids
1) R: Methyl: 10-methoxy-HHC
2) R: Ethyl: 10-ethoxy-HHC
1) R: Methyl: 9-methoxy-HHC
2) R: Ethyl: 9-ethoxy-HHC
p-TSA (N2),
O, 0 °C (N
EtOH, HCl/H2SO4/Ac
/Ac, (N
, BF
(EtOH, H
, )
EtOH, HCl/Ac
EtOH, HCl/
EtOH, HCl/
in vitro SGJ
in vitro SGJ
in vitro SGJ
in vivo in rats
in vitro SGJ
EtOH, Ac,
Toxics 2020, 8, 41 7 of 21
can be ascribed to the working group of R.N. Smith, according to a series of publications starting in
1975 [6264]. Both GC and HPLC are still used as major tools in the analysis of cannabinoids
nowadays, yet in more sophisticated versions. Countless reports on MS and MS/MS hyphenation
techniques as well as two dimensional approaches (e.g., GC × GC) were reported and reviewed
carefully [65,66].
The most important drawback of GC was already reported by Farmillo and Davis in one of their
first publications [60]. Due to high temperatures in the injector port and the column oven, acidic forms
of cannabinoids are decarboxylated and are thus not detected in the resulting chromatogram. While
this causes an underestimation of such compounds, it may also lead to a substantial overestimation
of the decarboxylated forms [66]. However, according to Dussy et al. [67], thermal conversion
reactions under typical GC conditions are not limited to decarboxylation processes and expressing
the calculated amount of the decarboxylated form as a sum of the acidic and decarboxylated form
leads to a certain underestimation.
Moreover, thermal reactions possibly also occur for other derivatives of cannabinoids, such as
hydroxylated or methoxylated forms, which complicates the use of GC in this field. Notably, first
hints for thermal conversion of CBC to Δ9-THC (both with their pentyl side chain substituted by
hydrogen atoms) were reported by Garcia et al. [68]. This could most likely also apply to CBD and
Δ9-THC. In regard to this, an interesting observation was that all in vivo studies, which detected Δ9-
THC after the administration of CBD [56,69,70], applied GC/MS methods, while other studies were
conducted using liquid chromatography (LC)/MS or LC-MS/MS methods. Hence, the question arises
whether Δ9-THC may not be formed in vivo but rather artifactually based on thermal reactions in the
GC/MS system. Notably, efforts by applying derivatization, mainly by using trimethylsilylation with
N,O-Bis(trimethylsilyl)trifluoroacetamide (BSTFA) and chlorotrimethylsilane (TMCS) [65]
tremendously improved GC separations and even enabled the detection of acidic forms. However,
the derivatization process was sometimes found to be not quantitative [66,71]. Hence, it cannot be
excluded that even small amounts of CBD which evaded derivatization may account for positive
findings of Δ9-THC due to thermal reactions in the GC system.
However, not only results obtained by GC/MS need to be considered with a certain amount of
scrutiny. As multiple cannabinoids (e.g., Δ9-THC, CBD and CBC) are isobaric isomers, they form
identical signals and mass spectra even with LC-MS/MS measurements [19]. Hence,
chromatographical methods with high separation performance are required for an unambiguous
peak assignment and avoidance of false positive results. Interestingly, Broecker et al. [72] also
reported on the acid-catalyzed in-source equilibration of Δ9-THC and CBD after positive electrospray
ionization (ESI) in flow-injection experiments. Careful studies with H/D exchange experiments
proved that CBD and Δ9-THC may not be distinguishable by mass spectra alone. The authors thus
highlighted the great importance of using the retention time in LC-MS/MS measurements to
distinguish different cannabinoids. Problems arise for small abundant compounds, such as isomers
or degradation products, which could very likely exhibit similar retention times to other more
abundant compounds. For example, Kiselak et al. [54] claim in their manuscript that “LC/MS analysis
was able to separate all of the psychotropic cannabinoids”. However, according to the
chromatograms shown in Figures 25 of the respective manuscript, the LC separation shows multiple
peaks and shoulder peaks under the best separation conditions and may therefore not be complete
for some isobaric isomers besides Δ8- and Δ9-THC and coelutions cannot be excluded.
This is further complicated by the fact that not all isomers are distinguishable due to similar
MS/MS fragmentation patterns. Such problems were recently reported by Lachenmeier et al. [19], as
they identified minor compounds with MS/MS fragmentation patterns similar to CBN and Δ9-THC
but were unable to structurally assign them. In the discussion of their results, the authors draw
attention to the problem that data obtained with less selective and specific chromatographical
methods might easily lead to a mix-up of certain CBD degradation products with THC isomers,
besides Δ8- and Δ9-THC, due to structural similarities accompanied with nearly identical retention
times. According to the authors, this can account as a possible explanation for the (potentially false
positive) detection of Δ9-THC in some previous studies.
Toxics 2020, 8, 41 8 of 21
Despite the various problems arising from analytical challenges in the field of cannabis research,
only 2% of all publications on cannabis deal with analytics, as stated by Gertsch et al. [73] in the
editorial of a recently published special issue on cannabis. Hence, when comparing results of in vitro
(Section 3.2.3) or in vivo (Section 3.2.4) studies on the conversion of CBD, analytical challenges need
to be considered and all claims should be critically assessed.
3.2.2. Conversion of CBD under Acidic Conditions
The acid-catalyzed conversion of CBD has been studied since the early 1940s, when Adams et
al. [74] reported on the treatment of CBD with various acids. While adding trichloroacetic acid,
anhydrous oxalic acid, picric acid, 3,5-dinitrobenzoic acid, 87% formic acid, glacial acetic acid and
malic acid to a solution of CBD in benzene did not result in conversion even after boiling for 1020 h,
good results were achieved with the addition of dilute ethanolic hydrochloric acid, p-toluenesulfonic
acid or a drop of sulfuric acid (100%) in cyclohexane. The conversion product was described to be a
psychotropic cannabinoid, which the authors assumed to be either Δ9-THC or Δ8-THC (Figure 4). This
observation was later confirmed by Gaoni and Mechoulam [55], who described the correct structures
of CBD, Δ
9-THC and Δ8-THC based on careful spectroscopic studies (i.e., UV, IR and NMR
measurements). They were further able to verify the hypothesis of Adams et al. [75] that Δ9-THC was
the main product if CBD was subjected to treatment with hydrochloric acid. The addition of p-
toluenesulfonic acid, though, rather resulted in the formation of Δ8-THC.
Higher product yields of either Δ8-THC or Δ9-THC can be gained by means of the improved
conditions presented by Webster et al. [76]. The conversion of CBD to Δ8-THC is enhanced, if a CBD
solution in toluene is boiled in the presence of a Lewis acid (p-toluenesulfonic acid or boron
trifluoride, BF3), while Δ9-THC is preferably formed when CBD is dissolved in dichloromethane
(DCM) and stirred at 0 °C in the presence of boron trifluoride etherate (BF3Et2O). To avoid the
formation of oxidized side products, Webster et al. [76] further recommended conducting the
conversion of CBD to Δ8-THC or Δ9-THC under nitrogen atmosphere. This leads to the question
which additional products are formed in the presence of oxygen or oxidative agents. In a series of
publications, Gaoni and Mechoulam [53,55,77] reported on the formation of methoxy/ethoxy HHCs
(Figure 4) upon boiling a CBD solution in methanol/ethanol for 18 h in the presence of diluted sulfuric
acid or hydrochloric acid (HCl). A methoxy or ethoxy group was introduced either in the 9- or 10-
position, resulting in two distinct isomers, which were 9-ethoxy/methoxy-HHC and 10-
ethoxy/methoxy-HHC, respectively (Figure 4). Besides the above-mentioned products, the reaction
mixture also contained Δ9-THC, Δ8-THC and iso-THC (structure in Figure 4). The latter was also
found with a yield of 13% when a solution of CBD in DCM/chloroform was boiled in the presence of
BF3Et2O (Figure 4).
Layton et al. [78] investigated possible formation products when crystalline CBD was treated
with 3% hydrogen peroxide, 0.1 M sodium hydroxide (NaOH) or 0.1 M HCl. While oxidative and
basic conditions produced little to no conversion products, acidic conditions resulted in the formation
of Δ9-THC and Δ8-THC besides another cannabinoid, which showed the same ultra-performance
liquid chromatography (UPLC)-MS retention time as CBG. However, according to a high signal at
m/z 333 in the mass spectrum of the third compound, CBG (typical fragment m/z 317) was ruled out
as a possible formation product. In the light of recent studies by Kiselak et al. [54], the unknown
compound may tentatively be assigned to a hydroxy form of either CBD or THC.
In this study, Kiselak et al. [54] also reported on the conversion of CBD dissolved in ethanol and
refluxed for 24 h in the presence of battery acid (sulfuric acid), muriatic acid (HCl) or vinegar (acetic
acid). While sulfuric acid resulted in a full turnover of CBD after 4 h, the other two acids did not lead
to a complete isomerization of CBD even after 24 h. Careful studies by means of ion mobility-coupled
LC-MS/MS measurements enabled the detection of various formation products. Besides Δ9-THC, the
products 8-hydroxy-iso-HHC, 11-hydroxy-THC, 11,5′-dihydroxy-CBD, 11,5′-dihydroxy-Δ9-THC, 11-
hydroxy-CBD, 9α-hydroxy-HHC, 5′-hydroxy-CBD, Δ7-THC, Δ8-THC, Δ10-THC, Δ11-THC, 9-methoxy-
THC and 10-methoxy-THC were identified (Figure 4). Peak identification was accomplished by
comparison with the retention times of the reference standards and structures of unknown peaks
Toxics 2020, 8, 41 9 of 21
were assigned using data from the MS/MS fragmentation and ion mobility. Yet, the only available
reference substances were Δ8-THC, Δ9-THC, CBD, CBG, CBN, THCA (Figure 5a), cannabidiolic acid
(CBDA, Figure 5b) and CBC. The product pattern varied depending on the reaction conditions. HCl
yielded the largest number of products and exclusively led to the formation of 11,5′-dihydroxy-Δ9-
THC. The reaction with sulfuric acid was the only one to produce 10-methoxy-THC and the addition
of acetic acid was the only method to produce 5′-hydroxy-CBD. Interestingly, 11-hydroxy-CBD was
formed in all reactions [54].
Figure 5. Chemical structures of (a) cannabidiolic acid (CBDA) and (b) Δ9-tetrahydrocannabinolic acid
In the light of the reported results on the broad spectrum of products from the acid-catalyzed
conversions of CBD, the question arises if similar reactions are also found in the acidic conditions of
(artificial) gastric juice (Section 3.2.3).
3.2.3. In Vitro Studies: Conversion of CBD in Artificial Gastric Juice and Other Model Systems
Despite the importance to understand the conversion reactions of CBD in the presence of animal
or human cells or enzymes, the number of published studies reporting on in vitro studies of CBD is
rather small. The first report on the biotransformation of CBD to a derivative of the psychotropic Δ9-
THC was presented by Nagai et al. in 1993 [79]. In their experiments, the authors incubated a CBD
solution with hepatic microsomes of guinea pigs, rats and mice, extracted the mixture with ethyl
acetate, analyzed the resulting extract with GC/MS and identified 6β-hydroxymethyl-Δ9-THC.
Fourteen years later, the studies were continued by Watanabe et al. [39], who found that CBD
was converted to 9α-hydroxy-HHC, 8-hydroxy-iso-HHC, Δ9-THC and CBN when subjected with
artificial gastric juice (without pepsin) and incubated at 37 °C for 20 h. The analysis of the ethyl acetate
extracts was carried out by GC/MS and structures were assigned by mass spectral data and retention
times as compared to the self-synthesized (or isolated) reference standards (Δ9-THC, CBD, CBN, 8-
hydroxy-iso-HHC and -hydroxy-HHC).
More recently, Merrick et al. [80] investigated conversion products of CBD, which were formed
upon subjection with simulated gastric juice and a physiological buffer solution of 4-(2-
hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). Both solutions additionally contained 1%
sodium dodecyl sulfate (SDS) to improve solubility, as recommended by United States Pharmacopeia
(USP). Based on UPLC/UV and UPLC-MS/MS analyses, Δ9-THC and Δ8-THC were detected in
simulated gastric juice and HEPES buffer after one to three hours of incubation. This led the authors
to the conclusion that relevant levels of Δ9-THC and Δ8-THC may be formed in humans after oral
consumption of CBD. This statement was criticized by other scientists as animal and human clinical
studies did not provide evidence for the conversion of CBD to THC in vivo (see Section 3.2.4) [81].
In contradiction to the above-mentioned results, another recent study conducted by
Lachenmeier et al. [19] reported no observation of the formation of THC (neither the Δ9- nor the Δ8-
form) when CBD dissolved in methanol was incubated with artificial gastric juice or stored under
stress factors such as heat or light under moderate conditions. Only if a solution of CBD in methanol
was acidified with 0.5 mol/L HCl and stored for up to two weeks, a complete degradation of CBD
and formation of 27% THC were reported. This study attached great importance to the physiological
study design, especially in regard to incubation times, temperatures during incubation and
concentrations of solvents and analytes. In the controversial debate about whether or not Δ9-THC is
cannabidiolic acid (CBDA)
tetrahydrocannabinolic acid (THCA)
Toxics 2020, 8, 41 10 of 21
formed under in vitro conditions (i.e., with simulated gastric juice) and—based on thatalso in in
vivo conditions (reviewed in Section 3.2.4), the authors thus positioned themselves on the opposing
3.2.4. In Vivo Studies: Conversion of CBD in Animals and Humans
Even though the metabolism of CBD was studied in several animal species (e.g., dogs and rats)
[8285] before, Harvey and Mechoulam were the first to report on the human CBD metabolism in the
early 1990s [69,70]. As they measured human urine samples with a GC/MS method after the patients
were orally administrated with CBD, they found over 30 metabolites, which were mainly
hydroxylated in various positions. Interestingly, Harvey and Mechoulam also reported on the
detection of two cyclized cannabinoids, which they termed “delta-6-THC” and “delta-1-THC” (the
latter one most likely corresponds to Δ9-THC as termed by present nomenclature) [69]. They
concluded that these analytes rather emerged artifactually in the urine sample than being metabolites
formed in humans, as this would have caused “psychoactivity with obvious adverse effects for the
patient” [69].
This hypothesis was supported by findings of Consroe et al. [86], who treated 14 patients with
Huntington disease with a CBD dose of 10 mg/kg/day and compared plasma CBD levels with a group
treated with a placebo. Over the course of six weeks, Δ9-THC was not detected in the plasma. Similar
results were also reported by Martin-Santos et al. [87] while conducting a double-blinded study with
16 healthy volunteers treated with either Δ9-THC (10 mg), CBD (600 mg) or a placebo. Neither Δ9-
THC, 11-hydroxy-THC or 11-nor-9-carboxy-tetrahydrocannabinol (11-COOH-THC) were detected in
significant amounts in the blood of patients treated with CBD, while the oral administration of Δ9-
THC itself had both effects on the plasma concentration and measurable psychotropicity. In a recent
review article, Ujváry et al. [88] further summarized literature data on CBD metabolites and human
metabolic pathways of CBD.
More recently, the question whether or not CBD may be converted to Δ9-THC or to other
(potentially) psychotropic cannabinoids under in vivo conditions after oral administration
culminated in a scientific debate, which was mainly initiated by an article published by Merrick et al.
[80], who studied the in vitro conversion of CBD to Δ9-THC and concluded that this can be applied
to in vivo situations as well. In a direct rebuttal to this publication, Grotenhermen et al. [81] cited
multiple clinical studies on CBD administration to human volunteers, which rule out psychotropic
effects of CBD and thus a conversion to Δ9-THC. In reply to Grotenhermen’s rebuttal letter, Bonn-
Miller et al. [89] stressed the multiple recent studies that proved the conversion of CBD to Δ9-THC in
an acidic environment (such as simulated gastric juice) and indicated the lack of data and the need
for further human clinical studies. These studies should also monitor the formation of other
cannabinoids, such as -hydroxy-HHC or 8-hydroxy-iso-HHC. In an immediate response, Nahler et
al. [90] argued that a conversion of CBD to Δ9-THC does not occur in humans and stated that
simulated gastric juice might not sufficiently reflect conditions in the human body. According to the
authors, if Δ9-THC was formed upon oral administration of CBD in the human stomach, Δ9-THC and
its metabolites 11-hydroxy-THC and 11-COOH-THC should be detectable in the serum as well.
However, Nahler et al. [90] found no evidence for that when analyzing previously published results.
In the timeframe of only one year following this debate, several articles were published that
either support one or the other side. For example, Palazzoli et al. [91] did neither detect Δ9-THC nor
the metabolites 11-hydroxy-THC or 11-COOH-THC (or its glucuronides) in the whole blood of male
rats 3 or 6 h after an oral CBD dose of 50 mg/kg in olive oil. Notably, this study was conducted with
an LC–MS/MS method. A similar method was also used when Wrey et al. [92] examined
blood/plasma samples of minipigs after they were given a dose of 15 mg/kg CBD in sesame oil (twice
a day, for four days with a single final dose at day five). Similar to Palazzoli et al. [91], Wrey et al.
[92] did not detect Δ9-THC or one of its metabolites 1, 2, 4 or 6 h after oral administration of CBD to
the minipigs.
In contradiction to this, Hložek et al. [56] were able to detect Δ9-THC in the serum and in the
brain of rats after they were administrated with doses of 60 mg/kg CBD. Even lower doses of 10
Toxics 2020, 8, 41 11 of 21
mg/kg CBD caused Δ9-THC to be detected in the serum, while it was not detectable in the brain.
According to the authors, Δ9-THC levels in the brain may have been below the limit of detection of
their GC/MS method. The authors further stated that these findings remain to be demonstrated in
humans. Only recently, Crippa et al. [93] published an article about a pharmacokinetic study in 120
healthy human subjects. They found that orally administered CBD (300 mg as corn oil formulation)
was not converted to Δ8-THC or Δ9-THC in humans. None of the different THC forms were detected
in the whole blood 3 and 6 h after intake by means of an LC-MS/MS method.
As a side note to the ongoing debate, it should be mentioned that using highly pure CBD is of
utmost importance. Crude extracts, which contain other cannabinoids, such as Δ9-THC, may not only
cause false results but may also lead to psychotropic effects in humans [19,94]. The use of a non-pure
CBD reference material (e.g., due to conversion during storage (Section 3.2.5) or an insufficient
isolation process) may explain the controversial findings by Hložek et al. [56] on the one side and
Palazzoli et al. [91] or Wrey et al. [92] on the other side. Different studies may also be distinguished
by the analytical method (GC/MS or LC-MS/MS) used for the detection and/or quantification of
cannabinoids. Especially with regard to the problems related with either of these techniques, it seems
to be useful to critically asses this aspect (Section 3.2.1).
Finally, recent studies mainly focused on the conversion of CBD to Δ9-THC and its metabolites.
While this isbeyond doubtcurrently the most important psychotropic cannabinoid, the
conversion of CBD may potentially also lead to other products that can cause psychotropic effects
(Section 3.1), which were not examined by most of the studies so far. Despite the increasing number
of publications driven by the ongoing scientific controversy, the question if conversion processes of
CBD may lead to psychotropic effects in the human body is still not answered conclusively.
3.2.5. Conversion of CBD during the Storage of CBD Products
Due to the heavily increasing trend of CBD products on the market (Figure 2), the consumer
safety in regard to these products is of great interest. In a recent publication by Lachenmeier et al.
[21], the authors listed multiple CBD products, which contained significant amounts of Δ9-THC and
were thus reported in the Rapid Alert System for Food and Feed (RASFF) of the EU. In another
publication, Lachenmeier et al. [19] reported on consumer complaints noting “THC-like effects” after
consumption of CBD products. The authors discussed three hypotheses for this effect, of which the
first one that CBD may have a psychotropic action itself, was immediately ruled out due to missing
scientific evidence that CBD exhibits psychotropic effects as compared to Δ9-THC. Another reason
for the psychotropic effects may be explained by the transformation of CBD to Δ9-THC under in vivo
conditions. Even though the authors rather neglected that option due to the results of their own
conversion studies, the scientific debate about this hypothesis is still ongoing (Section 3.2.4). A third
reason discussed by the authors is that Δ9-THC may already be present in the CBD products as
contamination, e.g., due to the use of crude hemp extracts instead of purified CBD. This point was
also highlighted in a recent investigation of Liebling et al. [95], as they found multiple cannabinoids
(including psychotropic forms) in over-the-counter CBD products in the UK.
A further hypothesis, which was not discussed in the mentioned article by Lachenmeier et al.
[19], is that other psychotropic cannabinoids (e.g., Δ9-THC) are not present in the original CBD extract
or CBD product, but potentially result from chemical reactions under storage conditions. The most
obvious and indisputable case is the storage of CBD products under acidic conditions, which
facilitates the conversion of CBD into Δ9-THC, as proven by many studies (Section 3.2.2). Such
conditions are sometimes found in liquids for electronic cigarettes resulting in the need of special
attention for these products. Besides the well-studied effects of acidic conditions, also basic
conditions were found to lead to conversion products of CBD. As reported by Srebnik et al. [96], CBD
isomerizes in a high yield to Δ6-CBD upon heating with t-pentyl potassium in toluene-hexamethyl-
phosphoric triamide (6:1, v/v). This is especially interesting as Δ6-CBD exhibits THC-like effects in
rhesus monkeys according to Mechoulam et al. [97]. Additionally, several recent investigations
[20,24,98–100] demonstrated that CBD products often contain much less CBD than declared. This
Toxics 2020, 8, 41 12 of 21
leads to the question if other than acidic (or basic) conditions may contribute to the conversion of
CBD into further (potentially psychotropic) cannabinoids as well.
During the 1970s, the decomposition of CBD in various solvents was controversially discussed
between Turner et al. [101], who reported no decomposition, and Fairbairn et al. [102] as well as
Parker et al. [103], who indeed found CBD to be decomposed in different solvents under storage
conditions. When Smith et al. [104] stored different cannabinoids at -18 °C in darkness, they only
found small decomposition rates, which slightly increased at room temperature (20 °C), depending
on the cannabinoid (decomposition rate of Δ9-THC higher than that of CBD). However, light seemed
to spark the decomposition as the rates were significantly higher in daylight conditions.
Unfortunately though, no conversion products were measured in this study [104]. Another study was
conducted by Lyndon et al. [105], who found that CBD is decomposed by 11% upon UV irradiation
for seven days. As this decay was not associated with an increase in Δ9-THC, the authors concluded
that photochemical conversions of CBD to Δ9-THC “probably do not occur”. As Δ9-THC is
decomposed itself, a closer look into the decomposition rates appears necessary.
The mechanism of the main decomposition route for Δ9-THC, which ultimately leads to the
formation of CBN, was reported by Turner et al. [106]. This was proved by Harvey et al. [107], when
they found low levels of Δ9-THC but increased levels of CBN in marihuana samples stored for nearly
100 years. Further, Lindholst et al. [108] identified CBN as the resulting product from Δ9-THC
decomposition in a study on cannabis resin stored over the course of four years. Another long-term
study by Trofin et al. [109,110] reported on the decomposition of Δ9-THC but also CBD to the final
product CBN in samples stored for four years in different conditions. As the decay of CBD was half
the difference between the decay of Δ9-THC and the formation of CBN, the authors postulated the
degradation route of CBD to start with a cyclization to Δ9-THC, which is followed by the
decomposition to CBN. Notably, room temperature and daylight were found to increase the
decomposition rates in the studies of Trofin et al. [109,110] and Lindholst et al. [108]. An interesting
finding was reported by Skopp et al. [111], who claimed that CBN might not be the final conversion
product in keratinized hair samples, as it could be further degraded by a light-induced radical
A recent report by Grafström et al. [112] also highlights the role of oxygen in the decomposition
process, as samples stored in contact with air showed higher decomposition rates of Δ9-THC and
CBD both in daylight and dark conditions. The authors additionally reported on a greater stability of
CBD as compared with Δ9-THC, regardless of the applied conditions. However, Δ8-iso-THC detected
in the samples was reported to arise from a ring closure between the phenolic OH group and the
endo double bond within the CBD molecule. Acidic forms of cannabinoids (e.g., Δ9-THCA and
CBDA) are more prone to degradation than their respective non-acid forms and notable decay was
also found in dark conditions with higher rates at room temperature than at 4 °C or −20 °C [108].
Hence, next to the effects in acidic conditions, first hints on the effects in basic conditions as well
as the reported decomposition processes and their dependence on temperature, light and available
oxygen need to be considered when storing CBD products. The described cyclization of CBD to Δ9-
THC may lead to psychotropic effects and to potential harm for the consumer of the respective
product. It has to be mentioned, though, that most of the findings were reported for long-term storage
tests with time frames considerably exceeding typical storage times of CBD products. Moreover, as
the decomposition rate of Δ9-THC was reported to be higher than the one of CBD, large amounts of
Δ9-THC resulting from decomposition processes are not to be expected in stored products. Regardless
of that, the accumulation of CBN formed in decomposition processes during long-term storage
should be avoided due to potential psychotropic effects related to CBN. Thus, the storage of CBD
products needs to be carefully monitored.
Toxics 2020, 8, 41 13 of 21
4. Conclusions
The increasing number of publications related to the pharmacological effects of CBD has
stimulated marketers of CBD products to advertise their goods with specific health claims, despite a
lack of clinical evidence in most cases [113]. Along with the increasing number of such products on
the market, this opens up concerns regarding consumer safety and consumer deception related to the
efficacy of these articles. One of these questions is the potential conversion of CBD to psychotropic
cannabinoids under in vitro and in vivo conditions, which is currently the topic of an ongoing
scientific debate. A conversion of CBD to the psychotropic forms Δ9-THC and Δ8-THC upon treatment
with strong acids, such as hydrochloric acid, sulfuric acid or p-toluenesulfonic acid, was doubtlessly
proved by many publications. Some of these findings were demonstrated to also occur under in vitro
conditions, e.g., by using artificial gastric juice for incubation.
The transfer of these results to in vivo conditions seems to be the major point of the ongoing
controversy as the in vivo conversion of CBD to Δ9-THC was not supported by the majority of the
animal studies, where neither Δ9-THC nor one of its metabolites 11-hydroxy-THC and 11-COOH-
THCA were detected in blood or in brain tissues. Adding to this, neither Δ9-THC nor any of its
metabolites were detected after oral CBD administration in any of the human studies. Difficulties
arising from detection methods such as GC/MS and LC-MS/MS may help to explain some of the
contradictory results, contributing to the ongoing debate. Nevertheless, most of the published data
support the conclusion that upon oral consumption of CBD products, a conversion of CBD to an
amount of Δ9-THC that exceeds the threshold of pharmacological action is not very likely in the
human organism.
A comprehensive risk assessment of CBD products, however, not only requires the monitoring
of an in vivo formation of Δ9-THC (or other psychotropic cannabinoids) but also the pre-consumption
reactions occurring in the product itself. The strongest and the most clinically relevant piece of
evidence determined in this review in favor of CBD’s conversion to psychotropic metabolites is
during improper storage. For example, CBD may cyclize to Δ9-THC under storage conditions, even
though both compounds are further degraded to CBN, which in turn may exhibit psychotropic effects
itself. Hence, there is a special need for manufacturers to include shelf-life studies dedicated to the
long-term stability of CBD in the finished products, considering the formation of psychotropic
compounds by the degradation of CBD. Accordingly, an interesting possibility would also be testing
for compounds or conditions that help to prevent or slow down CBD degradation, comparable to
antioxidants used to protect lipid compounds in food from oxidation.
Author Contributions: Conceptualization, C.S. and D.W.L.; methodology, D.W.L.; investigation, P.G., M.M. and
I.B.; writingoriginal draft preparation, P.G. and M.M.; writingreview and editing, I.B., C.S. and D.W.L.;
visualization, P.G.; supervision, D.W.L. All authors have read and agreed to the published version of the
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Toxics 2020, 8, 41 14 of 21
cannabidiol monomethyl ether
cannabidiolic acid
electrospray ionization
European Union
gas chromatography
4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
high performance liquid chromatography
hydrochloric acid
liquid chromatography
mass spectrometry
nuclear magnetic resonance
over the counter
Rapid Alert System for Food and Feed
sodium dodecyl sulfate
sodium hydroxide
-tetrahydrocannabinolic acid
thin layer chromatography
ultra-performance liquid chromatography
ultra violet
United Nations
United States Pharmacopeia
World Health Organization
Toxics 2020, 8, 41 15 of 21
Appendix A
Table A1. Overview of products formed upon acid-catalyzed degradation of CBD.
Compound Abbreviation Conditions Reported in Literature
in vitro (SGJ
) [39]
yes [43]
HCl/acetic acid in ethanol [54] (conversion was not complete)
no [45]
9-Tetrahydrocannabinol 9-THC
/HCl/acetic acid in ethanol/methanol, refluxing (N
) [54,55,76];
BF3Et2O (N2), 0 °C [76]; acidic conditions (HCl) [74,75,78]; in vitro
) [39,80]; in vivo (rats) [56]
4 yes [30]
HCl/acetic acid in ethanol [54]
8-Tetrahydrocannabinol 8-THC
/HCl/acetic acid in ethanol [54]; p-TSA
in benzene/toluene,
refluxing (N2) [53,55,76]; acidic conditions (H2SO4, p-TSAb) [74,75,78];
in vitro (SGJa) [80]
4 yes [35]
HCl/acetic acid in ethanol [54]
no [35]
HCl/acetic acid in ethanol [54]
yes [35]
11- hydroxy-CBD
/HCl/acetic acid in ethanol [54]
Acetic acid in ethanol [54]
/HCl/acetic acid in ethanol [54]
11- hydroxy-THC
HCl in ethanol [54]
yes [36]
HCl in ethanol [54]
/HCl/acetic acid in ethanol [54]; in vitro (SGJ
) [39]
yes [39]
/HCl/acetic acid in ethanol [54]; in vitro (SGJ
) [39]
yes [39]
/HCl/acetic acid in ethanol [54]; H
in methanol [53]
[10]; H
in methanol [53]
in ethanol [53,55]
in ethanol [53,55]
in DCM/CCl
or HCl/H
in ethanol [53]
a SGJ: simulated gastric juice; b p-TSA: p-toluenesulfonic acid
Toxics 2020, 8, 41 16 of 21
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... Two major phytocannabinoids that receive the most attention are ∆9-THC and CBD-both are in medical use and, despite their similar chemical structure, differ in the effects they exert. ∆9-THC is known for its psychoactive properties, which CBD does not have [3]. This last one is rapidly absorbed by adipose tissue and other organs and passes through the blood-brain barrier into the central nervous system (CNS). ...
... 7 , GPR55, GPR18, GPR3, GPR6, GPR12, Kv2.1, TRPM8, Cav 3 . 1-3 .3 , α7nACh, δ-OR, and µ-OR. ...
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Cannabis-derived therapies are gaining popularity in the medical world. More and more perfect forms of cannabinoids are sought, which could be used in the treatment of many common diseases, including metabolic syndrome, whose occurrence is also increasing. The purpose of this review was to investigate the usefulness of cannabinoids, mainly cannabidiol (CBD), in individuals with obesity, impaired glucose and lipid metabolism, high blood pressure, and non-alcoholic fatty liver disease (NAFLD). We summarised the most recent research on the broad topic of cannabis-derived influence on metabolic syndrome components. Since there is a lot of work on the effects of Δ9-THC (Δ9-tetrahydrocannabinol) on metabolism and far less on cannabidiol, we felt it needed to be sorted out and summarised in this review. The research results on the use of cannabidiol in obesity are contraindicatory. When it comes to glucose homeostasis, it appears that CBD maintains it, sensitises adipose tissue to insulin, and reduces fasting glucose levels, so it seems to be a potential target in this kind of metabolic disorder, but some research results are inconclusive. CBD shows some promising results in the treatment of various lipid disorders. Some studies have proven its positive effect by decreasing LDL and increasing HDL as well. Despite their probable efficacy, CBD and its derivatives will likely remain an adjunctive treatment rather than a mainstay of therapy. Studies have also shown that CBD in patients with hypertension has positive effects, even though the hypotensive properties of cannabidiol are small. However, CBD can be used to prevent blood pressure surges, stabilise them, and have a protective effect on blood vessels. Results from preclinical studies have shown that the effect of cannabidiol on NAFLD may be potentially beneficial in the treatment of the metabolic syndrome and its components. Nevertheless, there is limited data on CBD and NAFLD in human studies. Because of the numerous confounding factors, the conclusions are unclear, and more research in this field is required.
... 3,4 Different semisynthetic approaches and stereoselective pathways are reported in literature. 2,[5][6][7][8][9][10][11][12] As a non-fully synthetic cannabinoid, the legal status in Germany is not clearly specified at the moment, because the "Narcotics Act" (Betäubungsmittelgesetz, BtMG) 13 and "New Psychoactive Substances Act" (Neue-psychoaktive-Stoffe-Gesetz, NpSG) 14 do not explicitly include it. Various HHC products such as oils, THC-free flowers, and liquids available for use in vaporizers can currently be bought on the Internet and in local stores. ...
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The semisynthetic cannabinoid hexahydrocannabinol (HHC) is currently getting a lot of media attention because the legal status in many countries is not clearly specified. In this study, a GC–MS method for the quantification of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Δ9-tetrahydrocannabinol (THC-COOH) was extended to (9R)- and (9S)-HHC. The applicability was proven by serum/plasma samples from drivers suspected of cannabis consumption. Limit of detection (LOD) and lower limit of quantification (LLOQ) were 0.15 and 0.25 ng/mL, respectively. Within-run imprecision was <6.5% and between-run imprecision was <10.0%. Inter-injection stability, processed sample stability (3 days), freeze–thaw stability (three cycles), and storage stability (1 week room temperature; 1 month 4°C, −20°C) could be proven. Both HHC diastereomers could be detected in 17 (5.3%) out of 321 analyzed samples from traffic controls in Western Saxony. The mean ratio between (9R)- and (9S)-HHC was 1.99 (CV = 14.6%). Quantification resulted in concentrations between <LLOQ and 35.35 ng/mL for (9R)-HHC and <LLOQ and 21.76 ng/mL for (9S)-HHC. Additionally, cross-reactivities of HHC, 11-hydroxy-hexahydrocannabinol (11-OH-HHC), 11-nor-9-carboxy-hexahydrocannabinol (HHC-COOH), hexahydrocannabiphorol (HHC-P), hexahydrocannabinol acetate (HHC-O), and tetrahydrocannabidiol (H4-CBD) were evaluated in five immunological screening tests for serum, urine, and saliva. Urine test strips and ELISA tests for the detection in serum seem to be beneficial to detect HHC consumption in comparison with saliva tests. HHC analogs and H4-CBD showed no cross-reactivity with any of the tests.
... The Internet is a fast-moving market and "legal" alternatives are rapidly replacing prohibited molecules. We can cite the recent case of hexahydrocannabinol (HHC) that has entered the European cannabis market and was banned one year later, in June 2023 (1) HHC is a mixture of 9(R)-HHC and 9(S)-HHC diastereoisomers manufactured from CBD hemp extract (2). HHCs have gained increasing popularity thanks to its forms of consumption: sprayed on a THC joint, vaped with vaping device or eaten (appetizing and flavoured products). ...
... The properties and effects of THC-Oacetate are not well understood, as there has been limited research on this compound. 7 Currently, information on THC-O-acetate is scarce, and its use as a recreational or medicinal substance is not widely reported. The legality of THC-O-acetate, like other forms of THC, can vary depending on the jurisdiction, and it may be illegal in some countries (Table 1). ...
Introduction: In the wake of continued consumer demand despite increasing regulatory scrutiny, there is a need to develop systematic methods for identifying the harm profile of new psychoactive substances derived from hemp. Tetrahydrocannabinol-O (THC-O)-acetate, colloquially known as THCO, is the acetate ester of the principal psychoactive compound in cannabis. The heating of THCO can create ketene gas, which is harmful to the lungs. Materials and Methods: The research team used a multidisciplinary, iterative process to develop a survey to incorporate consumers' perspectives of semisynthetic cannabinoids. The survey was then distributed across the social media platform Reddit to learn about delivery device preferences and associated use styles when consuming THCO. Results: Most participants (74.9%) vaped THCO and one-quarter of participants (24.3%) dabbed THCO and tended to report higher temperatures for dabbing than vaping THCO. A small portion (12.0%) of participants reported concerns regarding ketene risk. Conclusion: As there are multiple variables associated with the formation of ketene, and consumer responses indicate temperatures use that might enable ketene formation, more research is needed to understand the risk profile of hemp-derived substances like THCO. Further studies are needed to understand the how various routes of administration and delivery devices used with THCO may exacerbate the risk of ketene formation and other potential harms.
... Δ8-THC production is fueled by an excess supply of CBD extracted from hemp. This CBD is used as the starting material to produce Δ8-THC and several other THC isomers (10). Interest has grown in producing and selling Δ8-THC, resulting in a proliferation of Δ8-THC vape liquids, tinctures and edibles, which are now available at thousands of retail outlets around the USA. ...
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Because of structural similarities, the presence of 11-Nor-9-carboxy-Δ8-tetrahydrocannabinol (Δ8-THC-COOH) in a urine specimen might interfere with testing for 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (Δ9-THC-COOH). A set of samples containing Δ8-THC-COOH with concentrations ranging from 10 to 120 ng/mL were tested at cut-offs of 20, 50 and 100 ng/mL using cannabinoid immunoassay reagents from three different manufacturers. Cross-reactivities ranged from 87% to 112% for Δ8-THC-COOH at the cut-off of 50 ng/mL for the three different platforms. Additionally, samples containing both Δ8-THC-COOH and Δ9-THC-COOH were fortified by the National Laboratory Certification Program (NLCP). U.S. Department of Health and Human Services (HHS)-Certified Laboratories tested the samples to determine the interference of Δ8-THC-COOH on confirmatory tests commonly used in workplace drug testing laboratories for the confirmation and quantification of Δ9-THC-COOH. When evaluating confirmation and quantification of Δ9-THC-COOH in the presence of Δ8-THC-COOH, unreportable results for Δ9-THC-COOH were observed because of chromatographic interference or mass ratio failures. However, there were no false-positive Δ9-THC-COOH reports from any HHS-certified laboratory.
Confirmation of cannabinoid use by forensic toxicology testing in urine has been traditionally focused on ∆9-tetrahydrocannabinol (∆9-THC) with analysis of its major metabolite, 11-nor-9-carboxy-∆9-THC (∆9-cTHC), in free and conjugated forms. Legalization of hemp, however, has led to the widespread production and sale of cannabidiol (CBD) derivatives with psycho-activity, including ∆8-THC and ∆10-THC isomers. The increasing availability and growing use of isomer derivatives necessitate an expanded scope of cannabinoid confirmation test protocols. We report a quantitative, isomer-selective method of cannabinoid confirmation by liquid chromatography-tandem mass spectrometry determination of parent drug isomers (∆8-THC, ∆9-THC, ∆10-THC and CBD) as well as isomeric metabolites (∆8-cTHC and ∆9-cTHC). An efficient C18 phase chromatography on 1.6-µm solid core particles was used with a step gradient for near isocratic separation of both early-eluting THC metabolite isomers and later-eluting CBD and THC isomers. A rapid method of hydrolysis, dilution and analysis was employed for the quantitative co-determination of free and conjugated analytes, using stable isotope internal standardization. Method validation is reported, along with interference assessment from a prior confirmation method. Casework experience with the isomer-selective method revealed a 14% prevalence of ∆8-cTHC positive cases with a pattern of concomitant ∆8-THC and ∆9-THC use. A comparison of ∆8-cTHC and ∆9-cTHC phase two metabolism is also reported.
Background: The concept of an "entourage" effect in the cannabis and cannabinoids' field was first introduced in the late 1990s, during a period when most research on medical cannabinoids focused on the effects of isolated cannabinoids, such as cannabidiol and Δ9-tetrahydrocannabinol. Over the past decade, however, with the increased understanding of the endocannabinoid system, the discovery of other phytocannabinoids and their potential therapeutic uses, the term has gained widespread use in scientific reviews and marketing campaigns. Objective: Critically review the application of the term "entourage effect (EE)" in the literature and its endorsement by certain sectors of the cannabis market. Also, explore the perspectives for further interpretation and elaboration of the term based on current evidence, aiming to contribute to a more nuanced understanding of the concept and its implications for cannabinoid-based medicine. Methods: A comprehensive review of the literature was conducted to evaluate the current state of knowledge regarding the entourage effect. Relevant studies and scientific reviews were analyzed to assess the evidence of clinical efficacy and safety, as well as the regulation of cannabinoid-containing product production. Results: The EE is now recognized as a synergistic phenomenon in which multiple components of cannabis interact to modulate the therapeutic actions of the plant. However, the literature provides limited evidence to support it as a stable and predictable phenomenon. Hence, there is also limited evidence to support clinical efficacy, safety, and appropriate regulation for cannabinoid-containing products based on a "entourage" hypothesis. Conclusion: The EE has significant implications for the medical use of cannabinoid-containing products and their prescription. Nevertheless, a critical evaluation of the term's application is necessary. Further research and evidence are needed to establish the clinical efficacy, safety, and regulatory framework for these products. It's crucial that regulators, the pharmaceutical industry, the media, and health care providers exercise caution and avoid prematurely promoting the entourage effect hypothesis as a scientific proven phenomenon for cannabinoids and other cannabis-derived compound combinations.
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Background Hemp-derived delta-9 tetrahydrocannabinol (∆ ⁹ THC) products are freely available for sale across much of the USA, but the federal legislation allowing their sale places only minimal requirements on companies. Products must contain no more than 0.3% ∆ ⁹ THC by dry weight, but no limit is placed on overall dosage and there is no requirement that products are tested. However, some states—such as Colorado—specifically prohibit products created by “chemically modifying” a natural hemp component. Methods Fifty-three ∆ ⁹ THC products were ordered and submitted to InfiniteCAL laboratory for analysis. The lab analysis considered potency, the presence of impurities, and whether the ∆ ⁹ THC present was natural or converted from CBD. The presence of age verification, company-conducted testing, and warning labels was also considered. Results While 96.2% of products were under the legal ∆9 THC limit, 66.0% differed from their stated dosage by more than 10%, and although 84.9% provided a lab report to customers, 71.1% of these did not check for impurities. Additionally, 49% of products converted CBD to THC to achieve their levels, and only 15.1% performed age verification at checkout. Conclusions Despite some positive findings, the results show that hemp ∆ ⁹ THC companies offer inaccurately labeled products that contain more THC than would be allowed in adult-use states. This raises serious issues around consumer safety, and consent when consuming intoxicating products. Steps to boost accountability for companies must be considered by either the industry or lawmakers if intoxicating hemp products are to remain on the market safely.
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Background There is increasing interest in the use of purified cannabidiol (CBD) as a treatment for a wide range of conditions due to its reported anti-inflammatory, anxiolytic, antiemetic and anticonvulsant properties.Objective The objective of this study was to assess the safety, tolerability and pharmacokinetics of a single ascending dose of a new lipid-based oral formulation of CBD in healthy volunteers after a high-fat meal.MethodsA total of 24 eligible healthy volunteers (aged 18–48 years) were randomised to one of three sequential cohorts (each with six active and two placebo subjects). Cohort 1 received 5 mg/kg CBD or placebo, cohort 2 received 10 mg/kg CBD or placebo (cohort 2), and cohort 3 received 20 mg/kg CBD or placebo. Data relating to adverse events, vital signs, clinical laboratory assessments, 12-lead ECGs, physical examinations and concomitant medications were collected to assess safety and tolerability. Blood samples were collected up to 8 days postdose and plasma was analysed by liquid chromatography and mass spectrometry to assess the pharmacokinetics of the CBD formulation.ResultsCBD was well tolerated in the healthy volunteers (mean age: 24.0 years) treated with a single oral dose of CBD. There were no safety concerns with increasing the dose and the safety profiles of the CBD-treated and placebo-treated subjects were similar. The most frequently reported treatment emergent adverse events (TEAEs) were headache (17%) and diarrhoea (8%). There were no reported serious adverse events (SAEs) and no clinical laboratory findings, vital signs, ECGs or physical examination findings that were reported as TEAEs or were of clinical significance during the study. After a high-fat meal, CBD was detected in plasma samples at 15 min postdose; the median time to maximum plasma concentration (Tmax) was 4 h across all three CBD dose cohorts. The CBD plasma exposure [maximum observed plasma concentration (Cmax) and the area under the concentration–time curve (AUC)] increased in a dose-proportional manner and declined to levels approaching the lower level of quantification by day 8. The terminal elimination half-life was approximately 70 h, suggesting that 2–3 weeks are needed to fully eliminate CBD.Conclusions This new CBD formulation demonstrated a favourable safety and tolerability profile in healthy volunteers that was consistent with the profiles reported for other purified CBD products. No severe or serious AEs were observed in this study and there were no safety concerns.Trial RegistrationACTRN12618001424291. Registered August 2018.
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Cannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB1 and CB2. None of the cannabinoid receptor ligands is entirely CB1- or CB2-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB1 and non-CB2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ9-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.
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The case of cannabidiol (CBD) makes the deficits in the current regulatory approach for food supplements clearly evident. Therefore, we strongly urge for a paradigm shift towards pre-marketing approval.
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Cannabidiol (CBD) is being investigated as a treatment for several medical disorders but there is uncertainty about its safety. We conducted the first systematic review and meta-analysis of the adverse effects of CBD across all medical indications. Double-blind randomized placebo-controlled clinical trials lasting ≥7 days were included. Twelve trials contributed data from 803 participants to the meta-analysis. Compared with placebo, CBD was associated with an increased likelihood of withdrawal for any reason (OR 2.61, 95% CI: 1.38-4.96) or due to adverse events (OR 2.65, 95% CI: 1.04-6.80), any serious adverse event (OR 2.30, 95% CI: 1.18-4.48), serious adverse events related to abnormal liver function tests (OR 11.19, 95% CI: 2.09-60.02) or pneumonia (OR 5.37, 95% CI: 1.17-24.65), any adverse event (OR 1.55, 95% CI: 1.03-2.33), adverse events due to decreased appetite (OR 3.56, 95% CI: 1.94-6.53), diarrhoea (OR 2.61, 95% CI: 1.46-4.67), somnolence (OR 2.23, 95% CI: 1.07-4.64) and sedation (OR 4.21, 95% CI: 1.18-15.01). Associations with abnormal liver function tests, somnolence, sedation and pneumonia were limited to childhood epilepsy studies, where CBD may have interacted with other medications such as clobazam and/or sodium valproate. After excluding studies in childhood epilepsy, the only adverse outcome associated with CBD treatment was diarrhoea (OR 5.03, 95% CI: 1.44-17.61). In summary, the available data from clinical trials suggest that CBD is well tolerated and has relatively few serious adverse effects, however interactions with other medications should be monitored carefully. Additional safety data from clinical trials outside of childhood epilepsy syndromes and from studies of over-the-counter CBD products are needed to assess whether the conclusions drawn from clinical trials can be applied more broadly.
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Zusammenfassung Im Novel-Food-Katalog der Europäischen Kommission sind Cannabidiol (CBD) und Hanfextraktprodukte als neuartig eingestuft und benötigen somit vor dem ersten Inverkehrbringen eine Zulassung. Vonseiten der Lebensmittelunternehmen wird aber eine Vielzahl derartiger Produkte ohne Zulassung in den Verkehr gebracht und von der amtlichen Überwachung beanstandet. Sieben Gerichtsurteile haben mittlerweile einheitlich die Einstufung als Novel Food untermauert und die amtlichen Maßnahmen bestätigt. Es ist zu hoffen, dass sich die Lebensmittelunternehmen der Problematik bewusst werden und ihrer Sorgfaltspflicht nachkommen, indem sie die Sicherheit der Produkte im Rahmen eines Zulassungsverfahrens belegen. Eine große Rechtsunsicherheit besteht allerdings weiterhin vor dem Hintergrund einer möglichen Betäubungsmitteleinstufung von Hanflebensmitteln, insbesondere solchen aus Blättern (beispielsweise als Tee). Summary In the Novel Food catalogue of the European Commission, cannabidiol (CBD) and hemp extract products are classified as novel and therefore require a marketing authorisation before being placed on the market for the first time. Contrary to this, a large number of such products has been placed on the market by food companies without approval and has been objected by the official control authorities. Seven court rulings meanwhile have uniformly supported the classification as Novel Food and have confirmed the official measures. It is to be hoped that the food business operators will become aware of the problem and fulfil their duty of care by proving the safety of products within the framework of approval procedures. However, a great deal of legal uncertainty still exists within the framework of a possible narcotic classification of hemp foods, especially those made from leaves (e.g. as tea).
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Cannabidiol (CBD) has become a buzzword in many products that have bloomed on the market. The scientific community and some authorities have recently raised concerns on the quality of these products. In particular, the discrepancy between the labelled and the real content of cannabidiol in liquids for e-cigarettes seems to be emerging as a major issue. Furthermore, to-date no studies have been carried out on the chemical stability upon storage of these type of products. The aim of this work was to investigate the accuracy in labelling of thirteen commercially e-liquids containing CBD and the effects of different storage conditions on their quality. The results showed that only 38% of samples were labelled within a ±10% variance from their labels. Stability tests showed a maximum degradation of CBD when samples were stored at 37 °C for 30 days with average values up to 20%. The effect of light was lower but still significant with averages values up to 15% degradation after 30 days. In conclusion, we believe that health authorities should regulate and control this market more stringently to protect customers and their health. Furthermore, our stability tests have shown that if clear indications are provided on the best storage conditions, the quality of these products can be mostly preserved.
Cannabidiol (CBD) is the major non-psychotropic phytocannabinoid present in Cannabis sativa. In 2018, Congress designated certain C. sativa plant material as “hemp,” thus removing it from the DEA’s list of controlled substances. As a result, CBD-containing hemp extracts and other CBD products are now widely available and heavily marketed, yet their FDA regulatory status is still hotly debated. The goal of this study was to investigate the effects of a cannabidiol-rich cannabis extract (CRCE) on the gut microbiome and associated histomorphological and molecular changes in the mouse gut mucosa. Male C57BL6/J mice were gavaged with either 0, 61.5, 184.5, or 615 mg/kg/bw of CRCE in sesame oil for 2 weeks (Mon–Fri). Substantial CRCE-induced increases in the relative abundance of A. muciniphila, a bacterial species currently accepted as probiotic, was observed in fecal samples at all doses. This was paralleled by decreases in the relative abundance of other gut bacterial species. Coincident with the observed changes in gut ecology were multiple pro-inflammatory responses, including increased expression of cytokines and chemokines—Il1ß, Cxcl1, and Cxcl2 in the colon tissue. Furthermore, dramatic increases in the relative abundance of A. muciniphila significantly decreased expression of Muc2—a gene intimately associated with gut integrity. Taken together, these findings raise concerns about the safety of long-term CBD usage and underline the need for additional well-designed studies into its tolerability and efficacy.
Introduction: Over-the-counter cannabidiol (CBD) products have seen unprecedented recent growth in the United Kingdom. However, analysis of these predominantly unregulated products from other countries tells us that they are often mislabeled or contain unlabeled and potentially dangerous chemicals. Thus, the aim of the present study was to analyze CBD oils available in the United Kingdom. Materials and Methods: Phytocannabinoids, residual solvent, and heavy metals were measured blinded in 29 widely available CBD products by an independent testing facility using high-performance liquid chromatography with diode-array detection for cannabinoids, Headspace-gas chromatography-flame ionization detector and gas chromatography-mass spectrometry for residual solvents, and inductively coupled plasma-mass spectrometry for heavy metals. Results: The mean advertised CBD content was 4.5%, and the actual mean measured CBD content of products was 3.2% (p=0.053, Mann-Whitney test). Only 11/29 (38%) products were within 10% of the advertised CBD content. Fifty five percent of products had measurable levels of the controlled substances Δ9-tetrahydrocannabinol (mean content 0.04%) or cannabinol (mean content 0.01%), as well as most other phytocannabinoid compounds including cannabidiolic acid (CBDA), cannabidivarin (CBDV), and cannabidivarin acid (CBDVA). Detectable levels of N-pentane, ethanol, isopropanol, heptane, lead, and arsenic were found in many of the CBD products, but these were within acceptable levels. Conclusions: As demonstrated in other countries, the quality of over-the-counter CBD products in the United Kingdom can be substandard, particularly with regard to CBD content, and often contains levels of controlled substances. We recommend that these products be more strictly regulated for consumer welfare.
Introduction The use and availability of oral and inhalable products containing cannabidiol (CBD) as the principal constituent has increased with expanded cannabis/hemp legalization. However, few controlled clinical laboratory studies have evaluated the pharmacodynamic effects of oral or vaporized CBD or CBD-dominant cannabis. Methods Eighteen healthy adults (9 men; 9 women) completed four, double-blind, double-dummy, drug administration sessions. Sessions were separated by ≥1 week and included self-administration of 100 mg oral CBD, 100 mg vaporized CBD, vaporized CBD-dominant cannabis (100 mg CBD; 3.7 mg THC), and placebo. Study outcomes included: subjective drug effects, vital signs, cognitive/psychomotor performance, and whole blood THC and CBD concentrations. Results Vaporized CBD and CBD-dominant cannabis increased ratings on several subjective items (e.g., Like Drug Effect) relative to placebo. Subjective effects did not differ between oral CBD and placebo and were generally higher for CBD-dominant cannabis compared to vaporized CBD. CBD did not increase ratings for several items typically associated with acute cannabis/THC exposure (e.g., Paranoid). Women reported qualitatively higher ratings for Pleasant Drug Effect than men after vaporized CBD and CBD-dominant cannabis use. CBD-dominant cannabis increased heart rate compared to placebo. Cognitive/psychomotor impairment was not observed in any drug condition. Conclusions Vaporized CBD and CBD-dominant cannabis produced discriminable subjective drug effects, which were sometimes stronger in women, but did not produce cognitive/psychomotor impairment. Subjective effects of oral CBD did not differ from placebo. Future research should further elucidate the subjective effects of various types of CBD products (e.g., inhaled, oral, topical), which appear to be distinct from THC-dominant products.