The Neurotoxic Effects of Cannabis on Brain: Review of Clinical and

Experimental Data

OMAR M.E. ABDEL-SALAM

Department of Toxicology and Narcotics, Medical Research and Clinical Studies Institute, National

Research Centre, Tahrir Street, Cairo,

EGYPT

Abstract: - Cannabis is the most widely used illicit drug worldwide. Evidence indicated negative impact for

cannabis on the brain. Animal research and in vitro studies using delta-9-THC (THC) or cannabis extracts with

high THC content provided evidence for a detrimental effect on neuronal integrity with DNA damage, cell

shrinkage, atrophy and apoptosis. The mechanisms by which herbal cannabis affects brain structure and

function are not clear but impaired mitochondrial functioning, reduced glucose availability and inhibition of

brain energetic metabolism by cannabis have been shown. Clinical studies investigating the effects of cannabis

in humans found raised serum levels of proinflammatory cytokines in chronic cannabis users. Human studies

also indicated increased oxidative stress biomarkers and reduced antioxidants in blood of chronic cannabis

users. Preclinical data on the effect of cannabis or THC on oxidative stress, however, were less conclusive in

that cannabis might increase or attenuate oxidative stress and neurotoxicity. The aim of this review is to

summarize the evidence from animal and clinical studies pertaining to the toxic effects of cannabis and its main

psychoactive ingredient THC on the brain and possible mechanisms involved.

Key-Words: - delta-9-tetrahydrocannabinol; brain; cannabis; oxidative stress; neuroinflammation

Received: May 13, 2021. Revised: February 14, 2022. Accepted: March 12, 2022. Published: April 13, 2022.

1 Introduction

The psychoactive plant Cannabis sativa is the most

widely used illicit drug worldwide, with an

estimated 192 million people having used cannabis

in 2018. Cannabis use is also on the rise with the

increasing legalisation for medicinal and

recreational use [1]. The term ‘marijuana’ or

‘marihuana’ refers to the flowering tops and leaves

of the female plant while the resin obtained from

these flowers is known as ‘hashish’ [2]. The

chemistry of Cannabis sativa plant is complex with

over 650 compounds and a group of a

terpenophenolic compounds, unique to cannabis and

known as cannabinoids [2,3]. To date, more than

120 cannabinoids have been described [4], the most

abundant of them is the Δ9-tetrahydrocannabinol

(THC) which is responsible for the psychomimetic

effects that occurs when cannabis is smoked such as

feelings of euphoria, distortion of time perception,

altered sensory experiences, motor incoordination

and impairments of memory [5,6]. Cannabidiol

(CBD) is another cannabinoid present in small

mounts in the cannabis plant, but is devoid of

psychotropic effects and appears to antagonize some

of the biological effects of THC. The latter exerts

its effects by acting on two types of G-protein

coupled receptors; cannabinoid CB1 and CB2

receptors [7]. CB1 receptors are abundant in brain

areas associated with cognition, memory, learning,

emotions, appetite, and motor coordination and

mediate most of the central actions of cannabis in

humans. CB2 receptors are mainly found on cells of

the immune system in the periphery. There are also

endogenous compounds, the endocannabinoids that

can act on cannabinoid receptors eg., anandamide

and 2-arachidonylglycerol [8].

The last decade has witnessed increasingly growing

interest in using cannabis for treating a variety of

medical conditions.. The inhalation of THC-

containing cannabis was reported by patients with

Parkinson’s disease [9], fibromyalgia [10], sickle

cell disease [11], inflammatory bowel disease [12],

neuropathic pain [13]. Formulations of whole plant

extract containing 1:1 THC/CBD in the form of an

oromucosal spray is used by patients with multiple

sclerosis for improving spasticity [14] and bladder

dysfunction [15].

There is evidence, however, that indicate a negative

impact for cannabis on the brain on the short- and

on the long-term [16,17]. Adolescents and young

adults are particularly prone to the health hazards of

cannabis with decline in IQ among cannabis users,

impaired cognitive performance, lower academic

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

achievement and educational outcome with longer

time to graduation [18,19]. Cannabis induces

impairment of driving performance increasing road

accidents [20]. Evidence links cannabis use to

development of psychotic events late in life

[21].Users of cannabis might also suffer ischaemic

stroke, more frequently in young men [22].

Neuroimaging studies of cannabis’s influence on

brain in humans have shown structural alterations

indicative of neurotoxic effects [23]. The present

review therefore aims to shed light on the

consequences of cannabis use and its main

psychoactive compound THC on brain neuronal

integrity and the underlying mechanisms involved in

neurotoxicity.

2 Evidence that Cannabis is Toxic to

Cells

Animal research and in vitro studies using cannabis

extracts rich in THC or its main psychotropic

ingredient THC provided strong evidence for a

detrimental effect for THC on neuronal integrity

[24-28]. Sarafian et al. [25] found that exposing

endothelial cells to smoke from marijuana cigarettes

for 30 min induced a time-dependent increase in

necrotic cell death that increased steadily reaching

reached 78% at 48 h. In vitro studies using A549

cells, a human lung cancer cell line, showed that

THC decreased in ATP levels with an IC50 value of

7.5 µg/ml, decreased mitochondrial membrane

potential (at concentrations of 2.5 or 10 µg/ml) as

early as 1 h after exposure and caused cell death

[26]. Zhu et al. [29] showed that treatment of

murine ConA-activated splenocytes and LPS-

activated peritoneal macrophages in culture with

THC (10 µg/ml) increased DNA fragmentation.

THC treatment decreased Bcl-2 mRNA and protein

in splenocytes. THC–induced apoptosis was blocked

by the caspase-1 inhibitor. Downer et al. [30,31]

reported that THC-induced apoptosis of primary rat

cortical neurons. The mechanism involved the

activation of c-jun N terminal kinase, release of

cytochrome c, activation of caspase-3, an increase in

Bax expression, and cleavage of the DNA repair

enzyme poly-ADP ribose polymerase. The THC-

induced apoptosis was blocked by the CB (1)

receptor antagonist AM-251. Gowran and Campbell

[32] showed in addition that in primary cortical

neurons, THC (5 µM) caused rapid, but transient,

increase in lysosomal membrane permeability. This

effect on lysosomal integrity occurred within 15 min

after exposure to THC and was maintained for 30

min. THC-induced caspase-3 activation and

apoptotic cell death by evoking the release of the

lysosomal cathepsin enzyme, cathepsin-D, into the

cytosol. These effects of THC were CB-mediated

and involved the tumour suppressor protein, p53.

Chan et al. [24] found that concentrations of THC as

low as 0.5 µM were toxic to rat hippocampal

neurons. Rat hippocampal slices were exposed to

THC. The CA1 pyramidal cell layer of hippocampal

slices exposed to THC exhibited condensed,

contracted and smaller nuclei, shrinkage of neuronal

cell bodies and genomic DNA breakage. Steel et al.

[27] reported impaired hippocampal neuroplastic

response, and new-born neurons induced by training

in rats after intraperitoneal (i.p) injection of THC (6

mg/kg).

Studies in rats treated with THC (10 or 20 mg/kg

orally) for 90 days revealed reduction in the

dendritic length of CA3 pyramidal neurons. The

higher dose of 60 mg/kg induced 44% reduction in

the number of synapses per unit volume [33].

Landfield et al. [34] found decreased neuronal

density and increased glial cell reactivity in the

hippocampus of rats treated chronically THC for 8

months. Other studies investigated the effect of

cannabis extracts containing 10%THC in vivo. Rats

received cannabis extracts at doses of 5, 10 or 20

mg/kg (expressed as THC), i.p., once a day for 30

days. Brain sections showed the presence of dark

neurons with small or undefined nuclei, cellular

infiltration, and gliosis. Immunohistochemical

staining with caspase 3 antibody, revealed increased

number of positively reactive cells, indicative of

apoptosis. Electron microscopy of a neuron from

rats treated with 20 mg/kg cannabis, showed an

elongated nucleus, discontinued nuclear envelope

and dispersed rough endoplasmic reticulum.

Cannabis caused DNA damage of

polymorphonuclear leucocytes (PNL) evaluated by

alkaline single cell gel electrophoresis (comet

assay). The above effects of cannabis were dose-

dependent [35]. Glial fibrillary acidic protein

(GFAP) is a marker of reactive gliosis, a process,

whereby, astrocytes became activated in response to

brain injury [36]. Studies showed increased GFAP

staining in the hippocampus and parietal cortex in

rats treated with THC during adolescence [37].

Moreover, rats given cannabis extracts also showed

significant increments in brain and serum levels of

GFAP [38] (Table 1).

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

Table 1. In vitro and in vivo cellular toxic effects of THC or cannabis extracts

Experimental model

Toxic effect

Suggested mechanisms

Study

Endothelial cells exposed to marijuana

smoke containing THC

 Necrotic cell death

 Cellular GSH

 ROS

[24]

A549 cells treated with THC (2.5 or

10 µg/ml)

 Cell death

 ATP

 Mitochondrial

membrane potential

[25]

Rat hippocampal slices exposed to

THC (0.5 µM)

 Size of neuronal cell bodies &

Genomic DNA breakage

[26]

Murine ConA-activated splenocytes

and LPS-activated peritoneal

macrophages exposed to THC (10

µg/ml)

 DNA fragmentation

Apoptosis

Caspase-1 mediated

 Bcl-2 mRNA and

protein

[29]

Primary rat cortical neurons treated

with THC

 Neuronal apoptosis

 Caspase-3

 Bax expression

 c-jun N terminal

kinase

 Cytochrome c

[30][31]

Primary rat cortical neurons treated

with THC (5 µM)

 Apoptotic cell death

 Lysosomal membrane

permeability

 Caspase-3

Release of the

lysosomal cathepsin-D

into the cytosol

[32]

Rats treated with THC (10 or 20

mg/kg orally) for 90 days

 Dendritic length of CA3

pyramidal neurons.

[33]

Rats treated with THC for 8 months

 Neuronal density in

hippocampus

 Glial cell reactivity

[34]

Rats treated with cannabis extracts

(10-20 mg/kg) THC for 4 weeks

 Dark neurons with small or

undefined nuclei

Cellular infiltration

Gliosis

 DNA damage of PNL (comet

assay).

 Caspase 3

[35]

Rats treated with THC during

adolescence

 Glial fibrillary acidic protein

(GFAP) staining in the

hippocampus and parietal cortex

[37]

Rats treated with cannabis extracts

(10-20 mg/kg) THC for 6 weeks

 Brain & serum GFAP

[38]

3 Cannabis in Animal Models of Brain

Neurotoxicity

In an in vivo model of excitotoxicity induced by

intracerebral injection of Na+/K+-ATPase inhibitor

ouabain in neonatal rats, co-injection of THC (1

mg/kg, i.p.) exerted neuroprotective effects.

Diffusion-weighted magnetic resonance imaging

showed that THC reduced the volume of cytotoxic

edema (neuronal swelling) 15 min after ouabain

injection and the volume of infarcted tissue after 7

days. THC reduced neuronal damage via a CBR1-

dependent mechanism [39].

Hayakawa et al. [40] suggested that acute but not

chronic administration of THC protects against

ischaemic brain injury. In this study, THC (3 and 10

mg/kg) and also cannabidiol significantly reduced

the infarct volume induced by middle cerebral artery

occlusion for 4h in mice. THC (3 and 10 mg/kg)

was injected i.p. immediately before and 3 h after

cerebral ischaemia. The neuroprotective effect of

acutely administered THC was inhibited by CBR1

antagonist and is likely to involve an increase in

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

cerebral blood flow and hypothermic effect. In

contrast to acute treatment, repeated i.p. injection of

THC (10 mg/kg) for 14-day prior to cerebral

ischaemia in mice significantly increased infarct

volume.

In another study, transient global cerebral ischaemia

was induced in rats by bilateral common carotid

artery (CCA) occlusion for 45 minutes followed by

4 h of reperfusion. Cannabis extract was i.p.

administered in a single dose of 20 mg/kg THC

either before CCA, at time of reperfusion, after

reperfusion or daily for 2 days before surgery.

Cannabis was found to significantly increase GSH

and to alleviate the increase in nitric oxide levels in

the ischaemic brain tissue. Cannabis given before or

at time of CCA occlusion also significantly reduced

brain tumour necrosis factor-α (TNF-α). Cannabis

given as a single dose 1h before cerebral ischaemia

or as two days pretreatment conferred histologic

protection against the ischaemic/reperfusion

neuronal injury. In contrast, cannabis given at time

of CCA occlusion exacerbated brain damage with

widespread severe spongiform changes and

neuronal loss [41].

Interestingly, cannabis resin extract was found to

protect against neurotoxicity caused in the rat by the

organophosphorus compound malathion. The

extract was given at doses of 10 or 20 mg/kg

(expressed as THC) 30 min prior to i.p. injection of

malathion. Cannabis did not alter MDA level but

prevented the depletion of in GSH and the decrease

in paraoxonase-1 activity in the brain of malathion-

treated animals. Spongiform changes, neuronal

damage in cerebral cortex and the degeneration of

Purkinje cells in cerebellum were prevented by

cannabis 20 mg/kg [42]. Cannabis was shown to

modulate the activities of cholinesterases in brain

and serum of rats [43,44]. THC has also been

reported to competitively inhibit acetylcolinesterase

(AChE) by binding to the allosteric peripheral

anionic binding site of the enzyme [45]. Several

terpenoids in the plant Cannabis sativa e.g.,

pulegone, limonene, and limonene oxide were also

shown to inhibit AChE in vitro [46]. THC and

cannabis other constituents thus might act to prevent

the irreversible binding of the organophosphate

metabolites onto the AChE and thus prevent the

malathion induced neurotoxicity [42].

Other studies, however, failed to demonstrate a

neuroprotective effect for cannabis extracts on brain

histology despite evidence of reduced brain

oxidative stress. One study investigated the effect of

cannabis on AlCl3 neurotoxicity was at

neurobehavioral, biochemical and histopathological

levels. AlCl3 induced brain oxidative stress, a

cognitive deficit detected by the water maze test and

brain damage in the form of shrunken neurons with

pyknotic nuclei and eosinophilic cytoplasm.

Cannabis sativa extract (10 and 20 mg/kg THC) was

given daily in combination with AlCl3 for 6 weeks.

Cannabis significantly alleviated the increase in

MDA, nitric oxide and the GSH depletion in brain

of AlCl3-treated rats. Cannabis, however, failed to

alter the cognitive deficit or the damage in cerebral

cortex and hippocampus induced by AlCl3 [47]. In

the epilepsy model induced in rats by the GABA

(A) receptor antagonist pentylenetetrazole (PTZ),

cannabis treatment (20 mg/kg THC) caused

significant elevation of seizure scores. In PTZ

treated rats, cannabis resulted in significant increase

in brain MDA. Histopathological changes induced

by PTZ such as degenerated and necrotic neurons,

inflammatory cells, and gliosis in cerebral cortex

and cerebellar Purkinje cells degeneration were not

improved by cannabis treatment [48]. In brain of

thioacetamide-treated rats, the increments in MDA

and nitric oxide were significantly decreased by

cannabis (10 and 20 mg/kg THC). Brain sections

from only thioacetamide-treated rats showed some

neurons with dark small nuclei. Cannabis enhanced

the damaging effect of thioacetamide with neurons

showing ballooning and degeneration and increased

number of neurons with dark nuclei [49]. Rotenone,

a naturally occurring pesticide of plant origin [50] is

used in rodents to model human Parkinson’s disease

[51,52]. In mice, daily i.p. injection of rotenone, the

inflammogen LPS or their combination for 2 weeks

increased oxidative/nitrosative stress in brain and

induced nigrostriatal neuronal damage. Cannabis

(20 mg/kg THC) s.c., co-injected with the toxicants,

reduced brain oxidative stress but did not reduce

neuronal damage [53]. In another study, cannabis

resin extract was s.c. given for 2 days prior to and at

the time of i.p. LPS endotoxin injection

administration. Cannabis 20 mg/kg (expressed as

THC) lessened the increase in MDA, nitric oxide

and restored GSH levels in the brain of LPS-treated

mice. Cannabis, however, increased histologic

brain damage with cellular atrophy, shrinkage,

necrosis, pyknosis, and deeply stained and dark

nuclei being observed in sections from the cerebral

cortex. Caspase-3 immunostaining was markedly

increased in degenerating neurons of the cerebral

cortex by LPS/cannabis compared with only LPS

treatment [54].

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

4 Cannabis and Brain Oxidative

Stress

Oxidative stress is the term applied to the situation

in which the balance between reactive oxygen

species (ROS) and antioxidant mechanisms in the

cell is tilted in favor of the oxidant side. This occurs

because of either too much ROS or insufficient

antioxidants. The result is oxidative damage to cell

biomolecules eg., membrane lipids, enzymes, and

DNA, cell perturbation and even death [55].

Reactive species are produced within the cell during

normal metabolism eg., the mitochondrial

respiratory chain where the mitochondrial

complexes I and III leak electrons to O2 forming

superoxide anion radical (O2˙ˉ). Superoxide can then

result in the formation of several intermediates such

as hydrogen peroxide (H2O2), and hydroxyl radical

(OH˙) or react with nitric oxide to generate the

highly reactive peroxynitrite (ONOOˉ) [56.57]. The

mitochondria is the major source for ROS in the cell

but is also subject to attack by ROS that may cause

mitochondrial dysfunction and initiation of cell

death cascade [58] and mitochondrial dysfunction

has been linked to aging and age-related

neurodegenerative diseases [59,60].

4.1 Human Studies

There are few studies that have measured oxidative

stress biomarkers in cannabis smokers. The effects

of cannabis were studied by Toson [61] in a group

of long-term marijuana smokers with smoking

duration of 5-10 years. Compared to healthy

controls, cannabis smokers had significant increase

in blood malondialdehyde (MDA), a marker of lipid

peroxidation. Serum levels of nitric oxide were

markedly raised as well. Meanwhile, reduced

glutathione (GSH) in blood, and the total

antioxidants capacity (TAC) in serum were

significantly reduced in cannabis users. Moreover,

serum C-reactive protein showed 40% increase in

users of cannabis. Other researchers found

significant increase in serum MDA and urinary 8-

hydroxydeoxyguanosine (a biomarker of oxidative

DNA damage) and decreased serum TAC in tobacco

and tobacco/marijuana smokers compared to healthy

controls [62]. Bayazit et al. [63] measured total

antioxidant status, total oxidant status and

proinflammatory cytokines levels in serum in

patients with cannabis use disorder. Patients aged

between 18 and 35 years of age and were using

cannabis at time of study. Compared with their

healthy controls, cannabis-dependent subjects

exhibited significant increase in total oxidant status,

and oxidative stress index. Moreover, there were

significant increments in the interleukins 1β, 6, 8,

and tumor necrosis factor-α in subjects with

cannabis use disorder. Another study in patients

with cannabis dependence reported a significant

increase in lipid hydroperoxide, and decreased free

thiol levels but increased brain-derived neurotrophic

factor, and ceruloplasmin in serum [64].

In contrast to the above studies, Bloomer et al. [65]

reported no significant effect for smoking marijuana

on oxidative stress. In their study, young (23-24

years) frequent marijuana users and non-smokers

participated in regular exercise and then tested for

biomarkers of oxidative stress and cardio-metabolic

health. Participants smoke marijuana on average of

4.5 ± 2.3 sessions per week for at least three months

before the study. The study found no significant

differences in MDA or advanced oxidation protein

produces in plasma of marijuana users compared

with non-users which was explained by the

beneficial effect of regular exercise on oxidative

stress (Table 2).

Table 2. Human studies indicating increased oxidative stress or inflammatory markers in cannabis users

Oxidative stress biomarkers

Study

 MDA in blood

 Nitric oxide in serum

 GSH in blood

 TAC in serum

[61]

 MDA in serum

 Urinary 8-hydroxydeoxyguanosine

 TAC in serum

[62]

 Total oxidant status

 Oxidative stress index.

[63]

 Lipid hydroperoxide in serum

 Free thiols in serum

[64]

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

Inflammatory markers

 C-reactive protein in serum

[62]

 IL-1β in serum

 IL-6 in serum

 IL-8 in serum

 TNF-α in serum

 Ceruloplasmin in serum

[63]

Abbreviations: MDA (malondialdehyde); GSH (reduced glutathione); TAC (total antioxidant capacity); IL-1β

(interleukin-1beta); IL-6 (interleukin-6); IL-8 (interleukin-8); TNF-α (tumour necrosis factor- α).

4.2 In Vitro Studies

Sarafian et al. [24] exposed endothelial cell line to

smoke produced from marijuana cigarettes

containing either 1.77 or 3.95% THC. Marijuana

smoke from 3.95% THC cigarettes resulted in a

rapid and sustained decrease in cellular GSH level

by 83% after 10 min. Marijuana smoke (though not

pure synthetic THC) increased ROS by 80%.

Several research groups have shown that THC

causes mitochondrial dysfunction and increase ROS.

In isolated mitochondria extracted from rat brain,

exposure to THC inhibited complexes I, II, and III

of the mitochondrial respiratory chain and decreased

mitochondrial coupling. THC enhanced H2O2

production and mitochondrial free radical leak [28].

THC was also shown to deplete ATP, impair

mitochondrial respiratory function, decrease

mitochondrial membrane potential, increase cellular

ROS and markers of lipid damage in human

trophoblast cell lines. THC also increased

mitochondrial fission and the expression of cellular

stress markers, HSP70 and HSP60 [66].

In contrast, in vitro experiments in a Fenton reaction

system, cannabidiol and THC were able to prevent

Tert-butyl hydroperoxide-induced oxidation of

dihydrorhodamine, an oxidation sensitive

fluorescent dye. THC and cannabidiol were shown

to equally protect rat cortical neurons in culture

against glutamate neurotoxicity (decrease LDH

release) [67,68]. N-methyl-D-aspartate (NMDA)-

induced cell death in AF5 rat mesencephalic cell

line was also prevented by THC (by CBR1

independent mechanism) (3 µM) [69]. THC exerted

antioxidant and anti-apoptotic effects and

significantly reduced dopaminergic cell death in

culture induced by 1-methyl-4-phenylpyridinium

(MPP+), lactacystin and paraquat. These effects of

THC were blocked by peroxisome proliferator-

activated receptor-gamma (PPAR) antagonist [70].

Using differentiated human neuronal SY-SH5Y

cells exposed to H2O2 or amyloid-β1–42 (Aβ1–42)

in the presence of Cu (II), Rajia et al. [71] reported

reduced ROS formation by cannabis extracts with

high (72%) THC content.

4.3 Animal Experiments

The effect of cannabis on oxidative stress is

complex with both antioxidant and prooxidant

effects being reported. Vella et al. [72] investigated

the effect of 8 weeks administration of a small dose

THC (0.15 mg/kg, daily, i.p.) in diabetic rats. There

was marked decrease in serum MDA and NO in

control rats. The increase in serum MDA in diabetic

rats was significantly decreased by treatment with

THC which also decreased IL-1β and increased IL-6

in serum. Coskun and Bolkent [73] found that rats

treated with THC (3 mg/kg, ip.) daily for one week

exhibited significant increase in MDA in the

plasma. The erythrocyte GSH levels, plasma

catalase or superoxide dismutase, however, were not

changed. On the other hand, treatment of diabetic

rats with THC resulted in significant decrease in

plasma MDA. Moreover, erythrocyte GSH levels

and plasma superoxide dismutase levels were

significantly increased in the diabetic group treated

with THC compared with the control diabetes

group. The study showed that THC acted as

antioxidant in diabetic but not in normal rats.

Ebuchi and Solanke [74] treated rats with 25 mg/kg

marijuana extract for two weeks. The authors

reported significant increase in MDA and a decrease

in GSH levels in rat brain and liver. The activities of

the antioxidant enzymes superoxide dismutase and

catalase decreased as well after treatment with the

marijuana extract. Khadrawy et al. [75] investigated

the effects of cannabis extract rich in THC in the

model of reserpine induced depression in rats.

Cannabis sativa extract (10 mg/kg THC, s.c.) given

after 15 days of initiating reserpine and continued

together with reserpine for another 15 days found to

exacerbate the lipid peroxidation (MDA) in the

cortex and hippocampus.

In the study of Kopjar et al. [76] rats were treated

with a single THC dose of 7 mg/kg, orally. The

authors reported significantly increased

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

thiobarbituric reactive substances (TBARS) in brain

after 1 day of treatment with THC together with

significantly elevated brain GSH Level by 37.5%.

Serum TBARS decreased by 29.4%. Meanwhile,

there was a significantly decreased superoxide

dismutase activity in brain of THC-treated rats by

69.8% compared to controls. Kubiliene et al. [77]

investigated the effect of marijuana extract on

oxidative stress induced in mice brain by AlCl3.

The extract was given intragastrically at the dose of

1.6 mg/g for 21 days. Administration of only

marijuana extract had no significant effect on levels

of reduced glutathione in blood or MDA in brain

and liver but significantly increased catalase

activity. In ACl3-treated mice, however, cannabis

alleviated the increase in MDA and the decline in

catalase activity in brain and liver.

Other studies carried out in rodents using only

marijuana or cannabis resin extracts showed a

moderate though a significant decrease in brain

MDA after treatment with cannabis at the dose of 20

mg/kg THC for 4 weeks [53,78]. Rats given

subcutaneous (s.c.) injections of cannabis resin

extract for 6 weeks showed significant increments in

serum MDA. This was especially so for the lower

doses of 5 or 10 mg/kg THC compared with the

higher dose of 20 mg/kg [79]. Reduced glutathione

was significantly increased in brain and serum by

treatment with 20 mg/kg marijuana or cannabis

resin extracts [49,54,78,80]. Moreover, brain

superoxide dismutase activity and ascorbate level

were shown to increase following treatment with

cannabis extracts [81].

Nitric oxide is a free radical that when produced in

excess can be neurotoxic via mechanisms such as

inhibition of cytochrome, excitotoxicity, energy

failure, and apoptosis [82]. These effects are

mediated through interactions with O2˙ˉ to form

peroxynitrite or with O2 to form nitrogen oxides

[83]. Studies showed significant decrease in brain

nitric oxide in mice treated with only marijuana

extract at 10, 15 or 20 mg/kg (expressed as THC)

for 18-30 days [53,78] and in rats treated with

cannabis resin extracts at the dose of 20 mg/kg THC

for 6 weeks [79]. Moreover, in a study by Vella et

al. [72] treatment with THC (15 mg/kg, i.p. for two

months) caused a 24.6% decrease in serum nitric

oxide. Inhibition of nitric oxide release might

therefore account at least in part the ability of

cannabinoids to protect neurons from excitotoxic

injury [84].

5 Cannabis and Brain Energetic

Metabolism

The mechanisms that underlie the detrimental

effects of herbal cannabis on brain structure and

function are not fully understood. Costa and

Colleoni [85] suggested that inhibition of brain

energetic metabolism and a low ATP production

could be a mechanism by which long-term cannabis

causes neuronal injury. The authors found that

single i.p. administration of THC (10 mg/kg) in rats

increased brain mitochondria oxidative

phosphorylation via the cannabinoid CB1 receptor.

Lipoperoxide levels in cerebral cortex were also

increased possibly due to the increase in brain

mitochondria oxygen uptake. In contrast, repeated

administration of THC (10 mg/kg, twice daily for

4.5 days, i.p.) decreased the brain mitochondria

oxygen consumption and uncoupled oxidative

phosphorylation. In pig brain mitochondria in vitro,

THC (also cannabidiol and anandamide) was shown

to inhibit mitochondrial respiration [86].

The transcription factor, nuclear respiratory factor-2

(NRF-2), also known as GA-binding protein,

mediates the expression of a number of nuclear-

encoded mitochondrial proteins required for

mitochondrial respiratory function and oxidative

phosphorylation. NRF-2 is important for the control

of mitochondrial biogensis and functions. Loss of

NRF-2 results in reduced mitochondrial mass,

oxygen consumption and consequent decrease in

ATP production and mitochondrial protein synthesis

[87,88]. It has been shown in rats that treatment

with cannabis extract for 6 weeks was associated

with significant decrease in serum NRF-2, thereby,

suggesting that cannabis could affect mitochondrial

biogenesis and activity [79].

Studies in mice during infancy have also shown a

detrimental and long-lasting effect for THC on brain

bioenergitics. In this context, the repeated exposure

of preadolescent healthy mice to THC (0.5 mg/kg)

i.p. daily for 11 consecutive days disrupted the

expression of mitochondrial proteins (complexes I-

IV), and induced loss of membrane integrity

occluding mitochondrial respiration [89]. In another

study, the single administration of THC in 10-day-

old mice (10 and 50 mg/kg) was found to affect the

transcript levels of genes involved in neurotrophic

and oxidative stress signaling 24 h after exposure

ie., decreased neurotrophic receptor Trkb transcript

levels and increased Nrf2/Keap1 ratio in parietal

cortex and hippocampus. The pro-apoptotic marker

BAX was also increased in the frontal cortex [90]. It

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

was also found that administration of THC (1 or 5

mg/kg) daily to preadolescent mice caused disrupted

expression of mitochondrial proteins (complexes I-

IV), and induced loss of membrane integrity

occluding mitochondrial respiration in hippocampal

neurons. These effects of THC lasted more than 4

months [91].

Using positron emission tomography, Volko et al.

[92] reported decreased cerebellar metabolism

chronic marijuana abusers compared with normal

subjects, which could explain the motor deficits in

marijuana users. Rats treated with cannabis showed

a significant decrease in brain glucose which might

impair brain energetic and account for the effect of

cannabis on memory functioning [78]. Other

researchers found that small doses (≤ 0.01 mg/kg)

and low blood levels of THC (< 1 ng/ml) were

associated with increased glucose uptake especially

in the hypothalamus. In contrast, higher doses ( ≥

0.05 mg/kg) and blood levels (> 10 ng/ml) resulted

in decreased glucose uptake, especially in the

cerebellar cortex [93]. Cannabis (54 mg) given to

healthy cannabis users either orally, through

smoking (6.9%THC cigarette) or via inhalation of

heated vaporized cannabis (Volcano®) caused

significant increases in plasma ammonia

concentrations which positively correlated with

THC concentrations in blood. Experiments in mice

indicated that THC (3 and 10 mg/kg, i.p.)

significantly reduced striatal glutamine synthetase

activity, and increased striatal ammonia

concentration followed by significant increase in

plasma ammonia. The THC-induced increase in

brain ammonia might be neurotoxic [94].

6 Cannabis and Brain Inflammation

In rats, THC (0.5, 1.0 and 2.0 mg/kg, i.p.) was found

to increase brain concentrations of prostaglandins

E2 and F2 alpha [95] while repeated administration

of THC (10 mg/kg) in mice increased brain

cyclooxygenase-2 expression [96], suggesting that

cannabis may cause brain inflammation. In female

rats, chronic administration of increasing doses of

THC during adolescence induces a persistent

neuroinflammatory state in the adult prefrontal

cortex. There were increased expression of the pro-

inflammatory cytokine TNF-α, inducible nitric

oxide synthase (iNOS) and cyclooxygenase-2

(COX-2) and decreased anti-inflammatory cytokine

interleukin-10. Inhibition of microglia activation

inhibited during THC treatment prevented the

neuroinflammatory state and attenuated short-term

memory impairments in adulthood [97].

7 Conclusion

There is evidence from both human studies and

animal research which strongly supports a

detrimental effect for THC-rich cannabis on

neuronal integrity. As for the role of oxidative

stress, although cannabis users showed elevated

blood levels of oxidative stress, in vitro and animal

experiments were less conclusive. Clearly, there is a

need for further research in this context.

References:

[1] World Drug Report 2020 (United Nations

publication, Sales No. E.20.XI.6).

https://www.unodc.org/unodc/en/data-and-

analysis/wdr2021.html.

[2] ElShohly MA. Chemical constituents of

cannabis. In: Cannabis and cannabinoids.

Pharmacology, Toxicology and Therapeutic

Potential (Grotenhermen F, Russo E, eds).

Haworth Press Inc, New York, 2002, pp. 27-

36.

[3] Brenneisen R. Chemistry and analysis of

phytocannabinoids and other cannabis

constituents. In: Forensic Science and

Medicine: Marijuana and the Cannabinoids

(ElSohly MA, ed). Humana,:Totowa, 2006; pp.

17–49.

[4] Radwan MM, ElSohly MA, El-Alfy AT,

Ahmed SA, Slade D, Husni AS. et al. Isolation

and Pharmacological evaluation of minor

cannabinoids from high-potency Cannabis

sativa. Journal of Natural Products 2015;

78(6): 1271-6.

[5] Mechoulam R, Gaoni Y. The absolute

configuration of delta-1-tetrahydrocannabinol,

the major active constituent of hashish.

Tetrahedron Letters 1967,12,1109-11.

[6] Huestis MA. Cannabis (marijuana)—effects on

human behavior and performance. Forensic

Science Review 2002; 14:15.

[7] Pertwee RG. The diverse CB1 and CB2

receptor pharmacology of three plant

cannabinoids: 9-tetrahydrocannabinol,

cannabidiol and 9-tetrahydrocannabivarin.

British Journal of Pharmacology 2008; 153:

199–215.

[8] Mechoulam R, Parker LA. The

endocannabinoid system and the brain. Annual

Review of Psychology 2013; 64:21–47.

[9] Yenilmez F, Fründt O, Hidding U, Buhmann

C. Cannabis in Parkinson's Disease: The

Patients' View. Journal of Parkinson's Disease

2021;11(1):309-321.

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

[10] Fiz J, Durán M, Capellà D, Carbonell J, Farré

M. Cannabis use in patients with fibromyalgia:

effect on symptoms relief and health-related

quality of life. PLoS One 2011; 6:e18440.

[11] Howard J, Anie KA, Holdcroft A, Korn S,

Davies SC. Cannabis use in sickle cell disease:

a questionnaire study. British Journal of

Haematology 2005; 131:123–128.

[12] Grill M, Hasenoehrl C, Storr M, Schicho R.

Medical cannabis and cannabinoids: An option

for the treatment of inflammatory bowel

disease and cancer of the colon? Medical

Cannabis and Cannabinoids 2018; 1: 28–35.

[13] Ellis RJ, Toperoff W, Vaida F, van den Brande

G, Gonzales J, Gouaux B. et al. Smoked

medicinal cannabis for neuropathic pain in

HIV: a randomized, crossover clinical trial.

Neuropsychopharmacology 2009; 34; 672–

680.

[14] Collin C, Ehler E, Waberzinek G, Alsindi Z,

Davies P, Powell K. et al. A double-blind,

randomized, placebo-controlled, parallel-group

study of Sativex, in subjects with symptoms of

spasticity due to multiple sclerosis.

Neurological Research 2010; 32:451–459.

[15] Brady CM, Das Gupta R, Dalton C, Wiseman

OJ, Berkley KJ, Fowler CJ. An open-label pilot

study of cannabis-based extracts for bladder

dysfunction in advanced multiple sclerosis.

Multiple Sclerosis 2004; 10: 425–433.

[16] Hall W, Degenhardt L. Adverse health effects

of non-medical cannabis use. Lancet 2009; 374

(9698): 1383-1391.

[17] Abdel-Salam OME. The harm of cannabis in

adolescents. Biomedical and Pharmacology

Journal 2019; 12(2): 495-498.

[18] Arria AM, Caldeira KM, Bugbee BA, Vincent

KB, O’Grady KE. The academic consequences

of marijuana use during college. Psychology of

Addictive Behaviors 2015; 29(3): 564–575.

[19] Lorenzetti V, Hoch E, Hall W. Adolescent

cannabis use, cognition, brain health and

educational outcomes: A review of the

evidence. European

Neuropsychopharmacology 2020; 36: 169-180.

[20] Bondallaz P, Favrat B, Chtioui H, Fornari E,

Maeder P, Giroud C. Cannabis and its effects

on driving skills. Forensic Science

International 2016; 268: 92-102.

[21] Arseneault L, Cannon M, Witton J, Murray

RM. Causal association between cannabis and

psychosis: examination of the evidence. British

Journal of Psychiatry. 2004; 184: 110-117.

[22] Wolff V, Armspach JP, Lauer V, Rouyer O,

Bataillard M, Marescaux C, Geny B. Cannabis-

related stroke: myth or reality? Stroke 2013;

44: 558-63.

[23] Battistella G, Fornari E, Annoni JM, Chtioui

H, Dao K, Fabritius M. et al. Long-term effects

of cannabis on brain structure.

Neuropsychopharmacology 2014; 39(9): 2041–

2048.

[24] Chan GC, Hinds TR, Impey S, Storm DR.

Hippocampal neurotoxicity of Delta 9-

tetrahydrocannabinol. Journal of Neuroscience

1998; 18: 5322-5332.

[25] Sarafian TA, Magallanes JAM, Shau H,

Tashkin D, Roth MD. Oxidative stress

produced by marijuana smoke: an adverse

effect enhanced by cannabinoids. American

Journal of Respiratory Cell and Molecular

Biology1999; 20: 1286-1293.

[26] Sarafian TA, Kouyoumjian S, Khoshaghideh F,

Tashkin DP, Roth MD. D9-

Tetrahydrocannabinol disrupts mitochondrial

function and cell energetics. American Journal

of Physiology-Cell Physiology 2003; 284:

L298-L306.

[27] Steel RW, Miller JH, Sim DA, Day DJ. Delta-

9-tetrahydrocannabinol disrupts hippocampal

neuroplasticity and neurogenesis in trained, but

not untrained adolescent Sprague-Dawley rats.

Brain Research 2014; 22: 1548:12-19.

[28] Wolff V, Schlagowski AI, Rouyer O, Charles

AL, Singh F, Auger C. et al.

Tetrahydrocannabinol induces brain

mitochondrial respiratory chain dysfunction

and increases oxidative stress: a potential

mechanism involved in cannabis-related stroke.

BioMed Research International 2015;

2015:323706.

[29] Zhu W, Friedman H, Klein TW. 9-

tetrahydrocannabinol induces apoptosis in

macrophages and lymphocytes: Involvement of

Bcl-2 and caspase-1. Journal of Pharmacology

and Experimental Therapeutics 1998;

286:1103-1109.

[30] Downer E, Boland B, Fogarty M, Campbell V.

Delta 9-tetrahydrocannabinol induces the

apoptotic pathway in cultured cortical neurones

via activation of the CB1 receptor.

NeuroReport 2001; 12(18): 3973-8.

[31] Downer EJ, Fogarty MP, Campbell VA.

Tetrahydrocannabinol-induced neurotoxicity

depends on CB1 receptor mediated c-Jun N-

terminal kinase activation in cultured cortical

neurons. British Journal of Pharmacology

2003; 140: 547-557

[32] Gowran A, Campbell VA. A role for p53 in the

regulation of lysosomal permeability by delta

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

9-tetrahydrocannabinol in rat cortical neurones:

implications for neurodegeneration. Journal of

Neurochemistry 2008; 105(4): 1513‒24.

[33] Scallet AC , Uemura E, Andrews A, Ali SF,

McMillan DE, Paule MG. et al. Morphometric

studies of the rat hippocampus following

chronic delta-9-tetrahydrocannabinol (THC).

Brain Research 1987; 436(1): 193-198.

[34] Landfield PW , Cadwallader LB, Vinsant S.

Quantitative changes in hippocampal structure

following long-term exposure to delta 9-

tetrahydrocannabinol: possible mediation by

glucocorticoid systems. Brain Research 1988;

443(1-2): 47-62.

[35] Abdel-Salam OME, Youness ER, Shaffee N.

Biochemical, immunological, DNA and

histopathological changes caused by Cannabis

Sativa in the rat. Journal of Neurology and

Epidemiology 2014; 2: 6-16. doi:

http://dx.doi.org/10.12974/2309-

6179.2014.01.01.2

[36] O'Callaghan JP, Sriram K. Glial fibrillary

acidic protein and related glial proteins as

biomarkers of neurotoxicity. Expert Opinion

on Drug Safety 2005; 4: 433-442.

[37] Lopez-Rodriguez AB, Llorente-Berzal A,

Garcia-Segura LM, Viveros MP. Sex-

dependent long-term effects of adolescent

exposure to THC and/or MDMA on

neuroinflammation and serotoninergic and

cannabinoid systems in rats. British Journal of

Pharmacology 2014; 171:1435-1447.

[38] Abdel-Salam OME, Sleem AA, Youness ER,

Omara EA. Identification of biomarkers for the

detection of subtle brain injury after cannabis

and/or tramadol administration. Egypt.

Egyptian Journal of Forensic Sciences 2019; 9:

58. https://doi.org/10.1186/s41935-019-0165-z

[39] van der Stelt M,Veldhuis WB, Bar PR, Veldink

GA, Vliegenthart JFG, Nicolay K.

Neuroprotection by 9-tetrahydrocannabinol,

the main active compound in marijuana,

against ouabain-induced in vivo excitotoxicity.

Journal of Neuroscience 2001; 21(17):6475–

6479.

[40] Hayakawa K, Mishima K, Nozako M, Ogata A,

Hazekawa M. et al. Repeated treatment with

cannabidiol but not Delta9-

tetrahydrocannabinol has a neuroprotective

effect without the development of tolerance.

Neuropharmacology 2007; 52: 1079-1087.

[41] Abdel-Salam OME, Abdel Jaleel G, Morsy FA.

Acute effects of Cannabis sativa on

ischaemia/reperfusion injury in the rat brain.

Journal of Neurology and Epidemiology 2017;

5: 25-34. doi: https://doi.org/10.12974/2309-

6179.2017.05.06

[42] Abdel-Salam OME, Sleem AA, Youness ER,

Morsy F. Preventive effects of cannabis on

neurotoxic and hepatotoxic activities of

malathion in rat. Asian Pacific Journal of

Tropical Medicine 2018; 11(4): 272-279.

[43] Abdel-Salam OME, Youness ER, Khadrawy

YA, Sleem AA. Acetylcholinesterase,

butyrylcholinesterase and paraoxonase 1

activities in rats treated with cannabis,

tramadol or both. Asian Pacific Journal of

Tropical Medicine 2016; 9: 1066-1071.

[44] Abdel-Salam OME, Khadrawy YA.The

inhibition of serum cholinesterases by

Cannabis sativa and/or tramadol. Journal of

Neurology Forecast 2019; 2(1): 1005. doi:

10.1016/j.apjtm.2016.09.009.

[45] Eubanks LM, Rogers CJ, Beuscher AE, Koob

GF, Olson AJ, Dickerson TJ. et al. A molecular

link between the active component of

marijuana and Alzheimer's disease pathology.

Molecular Pharmacology 2006; 3: 773-777.

[46] Partland JM, Russo EB. Cannabis and cannabis

extracts: greater than the sum of their parts?

Journal of Cannabis Research 2001; 1: 103-132

[47] Abdel-Salam OM, El-Shamarka ME-S, Omara

EA. Modulation of neurobehavioral and

biochemical alterations induced by aluminum

chloride with Cannabis sativa extract. Cell

Biology: Research & Therapy 2015; 4: 1.

[48] Abdel-Salam OME, Sleem AA, Sayed MAEM,

Khadrawy YA, Morsy FA. Cannabis sativa

increases seizure severity and brain lipid

peroxidation in pentylenetetrazole-induced

kindling in rats. Biomedical and Pharmacology

Journal 2018; 11(3): 1187-1197

[49] Abdel-Salam OME, El-Shamarka M.E-S,

Shaffee N, Gaafar AE-DM. Study of the effect

of Cannabis sativa on liver and brain damage

caused by thioacetamide. Comparative Clinical

Pathology 2014; 23(3): 495-507.

[50] Hien PP, Gortnizka H, Kraemer R. Rotenone-

potential and prospect for sustainable

agriculture. Omonrice 2003; 11: 83–92.

[51] Alam M, Schmidt WJ. Rotenone destroys

dopaminergic neurons and induces

parkinsonian symptoms in rats. Behavioural

Brain Research 2002; 136: 317–324.

[52] Abdel-Salam OME. The rotenone model of

parkinson’s disease in studying the

mechanisms of nigrostriatal cell death. J. J.

Pharma. Pharmacovigilance 2015; 1(1): 007.

[53] Abdel-Salam OME, Omara EA, El-Shamarka

ME-S, Hussein JS. Nigrostriatal damage after

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

systemic rotenone and/or lipopolysaccharide

and the effect of cannabis. Comparative

Clinical Pathology 2014; 23: 1343-58

[54] Abdel-Salam OME, Nada SA, Salem NA, El-

Shamarka M.E-S, Omara E. Effect of Cannabis

sativa on oxidative stress and organ damage

after systemic endotoxin administration in

mice. Comparative Clinical Pathology 2014;

23 (4): 1069-1085.

[55] Sies H. Oxidative stress: a concept in redox

biology and medicine. Redox Biology 2015; 4:

180–183.

[56] Halliwell B. Reactive oxygen species in living

systems: source, biochemistry, and role in

human disease. American Journal of Medicine

1991; 91: 14S–22S.

[57] Floyd RA, Hensley K. Oxidative stress in brain

aging. Implications for therapeutics of

neurodegenerative diseases. Neurobiology of

Aging 2002, 23, 795-807

[58] Figueira TR, Barros MH, Camargo AA,

Castilho RF, Ferreira JC, Kowaltowski AJ. et

al. Mitochondria as a source of reactive oxygen

and nitrogen species: from molecular

mechanisms to human health. Antioxidants &

Redox Signaling 2013; 18(16): 2029–74.

[59] Finkel T, Holbrook NJ. Oxidants, oxidative

stress and the biology of ageing. Nature 2000;

408: 239-249.

[60] Angelova PR, Abramov AY. Role of

mitochondrial ROS in the brain: from

physiology to neurodegeneration. FEBS.

Letters. 2018; 592: 692–702.

[61] Toson EA. Impact of marijuana smoking on

liver and sex hormones: Correlation with

oxidative stress. Nature and Science 2011;

9(12): 76-87.

[62] Mohamed A, Ibrahim KS, Mahdy-Abdallah H,

Mohamed HA. Leukocyte telomere length in

heavy tobacco and marijuana Egyptian

smokers. International Journal of PharmTech

Research 2016; 9(4):501-508.

[63] Bayazit H, Selek S, Karababa IF, Cicek E,

Aksoy N. Evaluation of oxidant/antioxidant

status and cytokine levels in patients with

cannabis use disorder. Clinical

Psychopharmacology and Neuroscience

2017;15(3):237-242.

[64] Bayazit H, Dulgeroglu D, Selek S. Brain-

derived neurotrophic factor and oxidative stress

in cannabis dependence. Neuropsychobiology

2020;79:186–190.

[65] Bloomer RJ, Butawan M, Smith NJG. Chronic

marijuana smoking does not negatively impact

select blood oxidative stress biomarkers in

young, physically active men and women.

Health 2018; 10: 960-970.

[66] Walker OS, Ragos R, Gurm H, Lapierre M,

May LL, Raha S. Delta-9-

tetrahydrocannabinol disrupts mitochondrial

function and attenuates syncytialization in

human placental BeWo cells. Physiological

Reports 2020; 8:e14476.

[67] Hampson AJ, Grimaldi M, Axelrod J, Wink D.

Cannabidiol and (-)9-tetrahydrocannabinol are

neuroprotective antioxidants. Proceedings of

the National Academy of Sciences of the

United States of America 1998; 95(14): 8268–

8273

[68] Hampson AJ, Grimaldi M, Lolic M, Wink D,

Rosenthal R, Axelrod J. Neuroprotective

antioxidants from marijuana. Annals of the

New York Academy of Sciences 2000;

899:274-282.

[69] Chen J, Lee CT, Errico S, Deng X, Cadet JL,

Freeda WJ. Protective effects of Δ9-

tetrahydrocannabinol against N-methyl-D-

aspartate-induced AF5 cell death. Brain

Research Molecular Brain Research 2005;

134(2): 215–225.

[70] Carroll CB, Zeissler ML, Hanemann CO,

Zajicek JP. 9-tetrahydrocannabinol (9-THC)

exerts a direct neuroprotective effect in a

human cell culture model of Parkinson’s

disease. Neuropathology and Applied

Neurobiology 2012; 38: 535–547.

[71] Raja A, Ahmadi S, de Costa F, Li N, Kerman

K. Attenuation of oxidative stress by

cannabinoids and cannabis extracts in

differentiated neuronal cells. Pharmaceuticals

(Basel) 2020; 13(11): 328.

[72] Vella RK, Jackson DJ, Fenning AS. Δ9-

tetrahydrocannabinol prevents cardiovascular

dysfunction in STZ-diabetic Wistar-Kyoto rats.

BioMed Research International 2017;

2017:7974149.

[73] Coskun ZM, Bolkent S. Evaluation of Δ9-

tetrahydrocannabinol metabolites and oxidative

stress in type 2 diabetic rats. Iranian Journal of

Basic Medical Sciences 2016; 19:154-158.

[74] Ebuehi OAT, Solanke AS. Cannabis sativa and

‘Karole’ induced oxidative stress and altered

brain serotonin in adult Wistar rats. Nigerian

Quarterly Journal Of Hospital Medicine 2014;

24(3): 205-211.

[75] Khadrawy YA, Abdel-Salam OME, Hosny EN.

Cannabis exacerbates depressive symptoms in

rat model induced by reserpine. Behavioural

Brain Research 2017; 324: 41-50.

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

[76] Kopjar N, Fuchs N, Žunec S, Mikolic A,

Micek V, Kozina G, et al. DNA damaging

effects, oxidative stress responses and

cholinesterase activity in blood and brain of

Wistar rats exposed to Δ9-

tetrahydrocannabinol. Molecules 2019; 24:

1560.

[77] Kubiliene A, Mickute K, Baranauskaite J,

Marksa M, Liekis A, Sadauskiene I. The

Effects of Cannabis sativa L. extract on

oxidative stress markers in vivo. Life 2021; 11:

647.

[78] Abdel-Salam OME, Salem NA, El-Shamarka

ME-S, Ahmed NA-S, Hussein JS, El-Khyat

ZA. Cannabis-induced impairment of learning

and memory: Effect of different nootropic

drugs. EXCLI. J. 2013l 12: 193-214.

[79] Abdel-Salam OME, Sleem AA, Youness FR,

Omara EA. Oxidative stress in brain tissue and

serum of rats treated with cannabis resin,

tramadol or both. ES Journal of Neurology

2020; 1(1): 1003.

[80] Abdel-Salam OME, El-Shamarka ME-S,

Salem NA, Gaafar AE-DM. Effects of

Cannabis sativa extract on haloperidol-induced

catalepsy and oxidative stress in the mice.

EXCLI J 2012; 11: 45-58.

[81] El-Hiny MA, Abdallah DM, Abdel-Salam

OME, Salem NA, El-Khyat ZA, Kenawy SA.

Co-administration of nicotine ameliorates

cannabis-induced behavioral deficits in normal

rats: role of oxidative stress and inflammation.

Comparative Clinical Pathology 2019; 28 (5):

1229-1236.

[82] Brown GC. Nitric oxide and neuronal death.

Nitric Oxide 2010; 23(3): 153‒165.

[83] Wink DA, Mitchell JB. Chemical biology of

nitric oxide: Insights into regulatory, cytotoxic,

and cytoprotective mechanisms of nitric oxide.

Free Radical Biology and Medicine 1999;

25(4‒5): 434‒456.

[84] Kim SH, Won SJ, Mao XO, Jin K, Greenberg

DA. Molecular mechanisms of cannabinoid

protection from neuronal excitotoxicity.

Molecular Pharmacology 2006; 69(3): 691-6

[85] Costa B, Colleoni M. Changes in rat brain

energetic metabolism after exposure to

anandamide or delta9-tetrahydrocannabinol.

Eurpean Journal of Pharmacology 2000;

395(1): 1–7.

[86] Fišar Z, Singh N. Hroudová J. Cannabinoid-

induced changes in respiration of brain

mitochondria. Toxicology Letters 2014;

231(1): 62-71.

[87] Scarpulla RC. Nuclear control of respiratory

chain expression by nuclear respiratory factors

and PGC-1-related coactivator. Annals of the

New York Academy of Sciences 2008; 147:

321–334.

[88] Yang ZF, Drumea K, Mott S, Wang J,

Rosmarin AG. GABP transcription factor

(nuclear respiratory factor 2) is required for

mitochondrial biogenesis. Molecular and

Cellular Biology 2014; 34(17): 3194-201.

[89] Kolb B, Li Y, Robinson T, Parker LA. THC

alters morphology of neurons in medial

prefrontal cortex, orbital prefrontal cortex, and

nucleus accumbens and alters the ability of

later experience to promote structural

plasticity. Synapse 2018; 72: e22020.

[90] Philippot G, Forsberg E, Tahan C, Viberg H,

Fredriksson R. A single 9-

tetrahydrocannabinol (THC) dose during brain

development affects markers of neurotrophy,

oxidative stress, and apoptosis. Frontiers in

Pharmacology 2019; 10: 1156.

[91] Beiersdorf J, Hevesi Z, Calvigioni D,

Pyszkowski J, Romanov RA, Szodorai E. et al.

Adverse effects of Δ9-tetrahydrocannabinol on

neuronal bioenergetics during postnatal

development. JCI Insight 2020; 5(23):e135418.

[92] Volkow ND, Gillespie H, Mullani N, Tancredi

L, Grant C, Valentine A. et al. Brain glucose

metabolism in chronic marijuana users at

baseline and during marijuana intoxication.

Psychiatry Research 1996;67(1):29-38

[93] Miederer I, Uebbing K, Röhrich J, Maus S,

Bausbacher N, Krauter K. et al. Effects of

tetrahydrocannabinol on glucose uptake in the

rat brain. Neuropharmacology 2017; 117: 273-

281.

[94] Abulseoud OA, Zuccoli ML, Zhang L, Barnes

A, Huestis MA, Lin DT. The acute effect of

cannabis on plasma, liver and brain ammonia

dynamics, a translational study. Eur.

Neuropsychopharmacology 2017; 27(7): 679-

690.

[95] Bhattacharya SK. delta-9-tetrahydrocannabinol

(THC) increases brain prostaglandins in the rat.

Psychopharmacology (Berl) 1986; 90(4): 499-

502.

[96] Chen R, Zhang J, Fan N, Teng ZQ, Wu Y,

Yang H, Tang YP, Sun H. et al. 9-THC-

caused synaptic and memory impairments are

mediated through COX-2 signalling. Cell

2013; 155: 1154–1165.

[97] Zamberletti E, Gabaglio M, Grilli M, Prini P,

Catanese A, Pittaluga A. et al. Long-term

hippocampal glutamate synapse and astrocyte

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022

dysfunctions underlying the altered phenotype

induced by adolescent THC treatment in male

rats. Pharmacological Research 2016; 111:

459-470.

Competing Interests:

No competing interests to disclose.

Contribution of Individual Authors to the

Creation of a Scientific Article (Ghostwriting

Policy)

Abdel-Salam OME contributed solely to the

manuscript.

Sources of Funding for Research Presented

in a Scientific Article or Scientific Article

Itself

This work is not supported by research grants.

Creative Commons Attribution License 4.0

(Attribution 4.0 International, CC BY 4.0)

This article is published under the terms of the

Creative Commons Attribution License 4.0

https://creativecommons.org/licenses/by/4.0/deed.en

_US

Publication Ethics for Researches Involving

Human Subjects

Not applicable.

Publication Ethics for Researches Involving

Animals

Not applicable.

Publication Ethics for Researches Involving

Plants

Not applicable.

MOLECULAR SCIENCES AND APPLICATIONS

DOI: 10.37394/232023.2022.2.3

Omar M. E. Abdel-Salam

E-ISSN: 2732-9992

Volume 2, 2022