1. Toxicol Appl Pharmacol. 2018 Dec

Multigenerational consequences of early-life cannabinoid exposure in zebrafish.

Carty DR(1), Miller ZS(2), Thornton C(2), Pandelides Z(2), Kutchma ML(2), Willett
KL(3).

Author information: 
(1)Department of BioMolecular Sciences, School of Pharmacy, University of
Mississippi, University, MS 38677, USA; Department of Molecular Biosciences,
School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
(2)Department of BioMolecular Sciences, School of Pharmacy, University of
Mississippi, University, MS 38677, USA.
(3)Department of BioMolecular Sciences, School of Pharmacy, University of
Mississippi, University, MS 38677, USA. Electronic address: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

While Δ9-tetrahydrocannabinol (THC) has been widely studied in the realm of
developmental and reproductive toxicology, few studies have investigated
potential toxicities from a second widely used cannabis constituent, cannabidiol 
(CBD). CBD is popularized for its therapeutic potential for reducing seizure
frequencies in epilepsy. This study investigated developmental origins of health 
and disease (DOHaD) via multigenerational gene expression patterns, behavior
phenotypes, and reproductive fitness of a subsequent F1 following an F0
developmental exposure of zebrafish (Danio rerio) to THC (0.024, 0.12, 0.6 mg/L; 
0.08, 0.4, 2 μM) or CBD (0.006, 0.03, 0.15 mg/L; 0.02, 0.1, 0.5 μM). Embryonic
exposure at these concentrations did not cause notable morphological
abnormalities in either F0 or F1 generations. However, during key developmental
stages (14, 24, 48, 72, and 96 h post fertilization) THC and CBD caused
differential expression of c-fos, brain-derived neurotrophic factor (bdnf), and
deleted-in-azoospermia like (dazl), while in F1 larvae only CBD differentially
expressed dazl. Larval photomotor behavior was reduced (F0) or increased (F1) by 
THC exposure, while CBD had no effect on F0 larvae, but decreased activity in the
unexposed F1 larvae. These results support our hypothesis of cannabinoid-related 
developmental neurotoxicity. As adults, F0 fecundity was reduced, but this was
not in F1 adults. Conversely, in the adult open field test there were no
significant effects in F0 fish, but a significant reduction in the time in
periphery was seen in F1 s from the highest THC exposure group. The results
highlight the need to consider long-term ramifications of early-life exposure to 
cannabinoids.

Copyright © 2018. Published by Elsevier Inc.



2. Epilepsia. 2018 Dec
Cannabidiol reduces seizures and associated behavioral comorbidities in a range
of animal seizure and epilepsy models.

Patra PH(1)(2), Barker-Haliski M(3), White HS(3), Whalley BJ(4), Glyn S(1)(2),
Sandhu H(1), Jones N(4), Bazelot M(1)(4), Williams CM(2), McNeish AJ(1).

Author information: 
(1)School of Pharmacy, University of Reading, Reading, United Kingdom.
(2)School of Psychology and Clinical Language Sciences, University of Reading,
Reading, United Kingdom.
(3)Department of Pharmacy, University of Washington, Seattle, Washington.
(4)GW Research, Cambridge, United Kingdom.

OBJECTIVE: Epilepsy is a progressive neurological disease characterized by
recurrent seizures and behavioral comorbidities. We investigated the antiseizure 
effect of cannabidiol (CBD) in a battery of acute seizure models. Additionally,
we defined the disease-modifying potential of chronic oral administration of CBD 
on associated comorbidities in the reduced intensity status
epilepticus-spontaneous recurrent seizures (RISE-SRS) model of temporal lobe
epilepsy (TLE).
METHODS: We evaluated the acute antiseizure effect of CBD in the maximal
electroshock seizure, 6-Hz psychomotor seizure, and pentylenetetrazol acute
seizure tests, as well as the corneal kindling model of chronic seizures in mice 
following intraperitoneal administration. Median effective or behavioral toxic
dose was determined in both mice and rats. Next, we tested an intravenous
preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine-induced
status epilepticus. We defined the effect of chronic CBD administration
(200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory
function in the rat RISE-SRS model of TLE.
RESULTS: CBD was effective in a battery of acute seizure models in both mice and 
rats following intraperitoneal administration. In the pilocarpine-induced status 
epilepticus rat model, CBD attenuated maximum seizure severity following
intravenous administration, further demonstrating CBD's acute antiseizure
efficacy in this rat model. We established that oral CBD attenuated the
time-dependent increase in seizure burden and improved TLE-associated motor
comorbidities of epileptic rats in the RISE-SRS model without affecting gait.
Chronic administration of CBD after the onset of SRS ameliorated reference memory
and working memory errors of epileptic animals in a spatial learning and memory
task.
SIGNIFICANCE: The present study illustrates that CBD is a well-tolerated and
effective antiseizure agent and illustrates a potential disease-modifying effect 
of CBD on reducing both seizure burden and associated comorbidities well after
the onset of symptomatic seizures in a model of TLE.

© 2018 The Authors Epilepsia published by Wiley Periodicals, Inc. on behalf of
International League Against Epilepsy.



3. Ther Drug Monit. 2018 Dec

Simultaneous quantification of thirteen cannabinoids and metabolites in human
plasma by liquid chromatography tandem mass spectrometry in adult epilepsy
patients.

Roslawski MJ(1), Remmel RP(2), Karanam A(1)(2), Leppik IE(1)(2)(3), Marino
SE(1)(2), Birnbaum AK(1)(2).

Author information: 
(1)Department of Experimental and Clinical Pharmacology and.
(2)Center for Clinical and Cognitive Neuropharmacology, College of Pharmacy,
University of Minnesota.
(3)MINCEP Epilepsy Care, University of Minnesota Physicians.

BACKGROUND: A sensitive, robust method was developed and validated to quantitate 
thirteen major natural cannabinoid parent and metabolite compounds in human
plasma at or below 0.5 ng/mL.
METHODS: A liquid chromatography-tandem mass spectrometry method was developed
and validated to measure thirteen cannabinoid compounds: cannabidiol (CBD),
cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol 
(CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), Δ-tetrahydocannabinol
(THC), Δ-tetrahydrocannabinolic acid A (THCA), Δ-tetrahydrocannabivarin (THCV),
11-hydroxy-Δ-tetrahydrocannbinol (11-OH-THC),
11-nor-9-carboxy-Δ-tetrahydrocannbinol (THC-COOH), and
11-nor-9-carboxy-Δ-tetrahydrocannabinol-glucuronide (THC-COOH-glu). Samples (200 
µL) were extracted via protein precipitation and separated with a Kinetex-EVO C18
column and a 65%-95% gradient of methanol and 0.2% ammonium hydroxide/H2O at a
flow rate of 0.4 mL/min. Samples were obtained from patients with epilepsy
receiving cannabis for the treatment of seizures.
RESULTS: The extracted lower limit of quantification was 0.05 ng/mL for CBD,
CBDV, CBN, and 11-OH-THC; 0.10 ng/mL for CBDA, CBG, CBC, CBGA, THC, THCA, and
THCV; 0.50 ng/mL for THC-COOH and THC-COOH-glu. Mean QC intra-day accuracy and
precision for all analytes ranged 96.5-104% and 2.7-4.9% respectively while
inter-day accuracy and precision ranged 98-103.3% and 0.2-3.6%, respectively. An 
absolute matrix effect was observed for some analytes, however, with minimal
relative matrix effect. Lack of nonspecific drug binding to extraction glass and 
plasticware was verified. Patient CBD levels ranged from 0.135-11.13 ng/mL.
CONCLUSIONS: The validated method met FDA guidelines for Bioanalytical Assays
precision and accuracy criteria. The assay reliably confirmed the use of
particular medical cannabis formulations in patient samples as well as reliably
measured low CBD concentrations from single dose CBD exposure.


4. Curr Opin Neurol. 2019 Feb

Cannabinoid drugs: will they relieve or exacerbate tinnitus?

Zheng Y(1)(2)(3), Smith PF(1)(2)(3).

Author information: 
(1)Department of Pharmacology and Toxicology, School of Biomedical Sciences,
University of Otago Medical School, and the Brain Health Research Centre,
Dunedin.
(2)Brain Research New Zealand.
(3)The Eisdell Moore Centre for Hearing and Balance Research, University of
Auckland, New Zealand.

PURPOSE OF REVIEW: Recent enthusiasm for cannabinoid drugs for the treatment of
chronic pain and some forms of epilepsy, raises the question of whether they
could be useful for other disorders associated with abnormal neuronal activity in
the brain, such as subjective tinnitus. Indeed, there is evidence to indicate
that some tinnitus sufferers self-medicate using Cannabis. The aim of this review
is to critically evaluate the available evidence relating to the effects of
cannabinoids on tinnitus.
RECENT FINDINGS: Despite the fact that cannabinoids have been shown to decrease
neuronal hyperactivity in many parts of the brain, the current evidence suggests 
that in auditory brain regions such as the dorsal cochlear nucleus, they have the
potential to facilitate neuronal hyperactivity and exacerbate tinnitus. All of
the available experimental evidence from animal studies suggests that cannabinoid
CB1 receptor agonists will either have no effect on tinnitus or will worsen it.
SUMMARY: In our opinion, the use of the available cannabinoid drugs to alleviate 
tinnitus, based on their alleged efficacy for neuropathic pain conditions and
some forms of epilepsy, is premature and not supported by the available evidence.



5. Expert Opin Investig Drugs. 2018 Dec

Investigational small molecules in phase II clinical trials for the treatment of 
epilepsy.

Greco M(1), Varriale G(1), Coppola G(2), Operto F(2), Verrotti A(1), Iezzi ML(1).

Author information: 
(1)a Department of Pediatrics , University of L'Aquila , L'Aquila , Italy.
(2)b Child and Adolescent Neuropsychiatry, Medical School , University of Salerno
, Salerno , Italy.

INTRODUCTION: Epilepsy is a neurological disorder that significantly impacts the 
quality of life of affected persons. Despite advances in research, nearly a third
of patients have refractory or pharmacoresistant epilepsy. Even though numerous
antiepileptic drugs (AEDs) have been approved over the past decade, there are no 
agents that halt the development of epilepsy. Thus, new and improved AEDs to
prevent these conditions are necessary. Areas covered: We highlight recent
advances in new and innovative drugs for epilepsy disorders. We review three
small molecule drugs in phase II clinical trials: Cannabidivarin, BGG492
(Selurampanel) and Ganaloxone. Expert opinion: The full potential of
Cannabidivarin will be realized by testing in other types of treatment-resistant 
seizures; if they are beneficial, larger phase III clinical trials would probably
be undertaken in the same patient population. About BGG492, the challenge will be
to find 'superselective' AMPAR antagonists targeting only calcium-permeable
receptors, with specific mechanisms, that may be attractive partners for drugs in
polytherapy. Moreover, there is anew interest surrounding Ganaloxone because of a
new submicron formulation that improves its absorption and pharmacokinetic
profile, but new studies are necessary before progressing. Further clinical
innovations will define the future for these small molecule-type drugs in
epilepsy therapeutics.