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P.0835 Synergistic effects of lysergic acid diethylamide (LSD) and cannabidiol (CBD)

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doi: 10.1016/j.euroneuro.2021.10.693
Synergistic effects of lysergic acid diethylamide
(LSD) and cannabidiol (CBD)
A. Inserra
, E. Billard
, E. Grant
, A. Markopoulous
M. Pilegggi
, M. Haque
, A. Oveisi
, J. Singer
, D. De
, T. Hébert
, G. Gobbi
McGill University, Neurobiological Psychiatry Unit, Mon-
treal, Canada;
McGill University, Pharmacology and Ther-
apeutics, Montreal, Canada;
San Raffaele University, Phar-
macology, Milan, Italy
Background: Serotonergic psychedelics and phytocannabi-
noids induce antidepressant effects [ 1 , 2 ]. However, it
is unknown whether they elicit synergistic antidepres-
sant and/or euphoric effects. Therefore, we investigated
whether cannabidiol (CBD) and lysergic acid diethylamide
(LSD) generate synergistic antidepressant- and euphoric-
like effects, and the electrophysiological and serotonin 2A
) receptor correlates.
Methods: Forced swim test (FST), head-twitch response
(HTR), and open field test (OFT) were performed. Dosage:
Low-dose: 30 mg/kg CBD, 30 μg/kg LSD, or their combina-
tion. High-dose: 200 mg/kg CBD, 220 μg/kg LSD, or their
combination. CBD was administered subcutaneously 45
minutes prior to testing, and LSD intraperitoneally imme-
diately prior.
Acute pharmacological challenges were performed in the
Dorsal Raphe Nucleus (DRN), and medial prefrontal cortex
(mPFC) via in vivo single unit extracellular recordings. 5-
activation was assessed using a bioluminescence reso-
nance energy transfer (BRET)-based biosensor monitoring 5-
-mediated diacylglycerol production in transfected HEK
293 cells.
Data was analysed with One-Way ANOVA followed by Dun-
nett’s multiple comparison test. When SDs were significantly
different and data passed the normality test, Welch’s ANOVA
was used. Electrophysiology: One-Way ANOVA followed by
Dunnett’s test. BRET: unpaired T- test test. Post-hoc tests
were considered for significant ANOVAs.
Results: LSD and CBD alone had no behavioural effects at
the doses tested (P > 0.05). In combination, they elicited
synergistic antidepressant-like effects in the FST at high
= 6.213, P = 0.011, post-hoc CBD 200 mg/kg + LSD 220
μg/kg compared to CBD 200 mg/kg P = 0.0470, compared to
LSD 220 μg/kg P = 0.0068), but not low doses (F
= 2.991,
P = 0.0380, post-hoc P > 0.05).
CBD pre-treatment decreased the HTR induced by
LSD both at low (F
= 31.82, P < 0.0001, post-hoc CBD
30 mg/kg + LSD 30 μg/kg compared to LSD 30 μg/kg
P = 0.0392) and high (F
= 73.86, P < 0.0001, post-hoc CBD
200 mg/kg + LSD 220 μg/kg compared to LSD 220 μg/kg
P < 0.0001) doses, suggesting an antipsychotic-like effect.
CBD pre-treatment prevented the LSD-induced hyper-
locomotion (Dunnett post-hoc CBD 30 mg/kg + LSD 30 μg/kg
compared to LSD 30 μg/kg P = 0.0099) and anxiolytic-like
effects (Kruskal-Wallis test P = 0.0005, Dunnett post-hoc
P = 0.0025). High-dose CBD + LSD induce a sedative-like ef-
fect (post-hoc P = 0.0127).
CBD and LSD in combination decreased spontaneous neu-
ronal cell firing in the DRN (F
2, 11
= 56.58, P < 0.0001) and the
3, 14
= 44.45, P < 0.0001).
LSD acts as a partial agonist at the 5-HT
receptor, while
CBD had no agonist effects alone. 10 minutes pre-treatment
with CBD (10 μM) decreased LSD efficacy while increas-
ing its potency (unpaired T-test P = 0.0002 for efficacy and
P = 0.0130 for potency), illustrated by a downward left shift
in the concentration-response curve.
Conclusion: Our findings suggest that CBD and LSD given
in combination acutely might have greater antidepressant
effects than each compound alone, potentially due to an
allosteric modulation of the 5-HT
2A receptor by CBD, re-
sulting in an abrupt attenuation of serotonergic and gluta-
matergic neurotransmission. Given the high doses required
to achieve such effects, the translational value of these
findings remains to be further elucidated. Our findings sug-
gest that individuals seeking the combination of cannabi-
noids/psychedelics on the illicit market might be due to
a fast relief from anxiety and depression which is not
achieved with each compound alone.
Conflict of interest
Disclosure statement:
G.G. and D.D.G. are consultants at Diamond Therapeutics
Inc, Tor o n t o , ON, Canada. G.G. and D.D.G. are inventors of
a provisional patent regarding the use of LSD.
[1] Jiang, W., et al., 2005. Cannabinoids promote embryonic and
adult hippocampus neurogenesis and produce anxiolytic- and
antidepressant-like effects. The Journal of Clinical Investiga-
tion 115 (11), 3104–3116.
[2] Inserra, A., De Gregorio, D., Gobbi, G., 2021. Psychedelics in
Psychiatry: Neuroplastic, Immunomodulatory, and Neurotrans-
mitter Mechanisms. Pharmacological Reviews, 73 (1), 202–277.
doi: 10.1016/j.euroneuro.2021.10.694
... Additional repeating of LSD administration (0.13 mg/kg) for 11 days was able to reverse deficits in active avoidance learning in bulbectomised rats, a model of depression [214]. Furthermore, cannabidiol (CBD) seems to exert a synergistic effect in combination with LSD on the antidepressant effect in mice, probably due to an allosteric modulation of the 5-HT2A receptor by CBD, which causes a powerful and rapid inhibition of serotonergic and glutamatergic transmission [239]. An additional potential therapeutic application of LSD concerns its positive effect on social behaviour, which can be applied in the context of mental illnesses characterized by dysfunction in social behaviour, such as autism spectrum disorders (ASD) and social anxiety disorder. ...
... In the past, several clinical trials were carried out and from these it emerged that LSD may be a useful pharmacological compound for the treatment of drug dependence, anxiety and mood disorders, especially in treatment-resistant patients [222,239,242,243]. Furthermore, many clinical studies carried out in the 60s and 70s investigated the possible use of LSD for the treatment of people with ASD and positive evidence emerged. ...
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