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Synergistic effects of lysergic acid diethylamide
(LSD) and cannabidiol (CBD)
, E. Billard
, E. Grant
, A. Markopoulous
, M. Haque
, A. Oveisi
, J. Singer
, D. De
, T. Hébert
, G. Gobbi
McGill University, Neurobiological Psychiatry Unit, Mon-
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-
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
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
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
= 56.58, P < 0.0001) and the
= 44.45, P < 0.0001).
LSD acts as a partial agonist at the 5-HT
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
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.
 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.
 Inserra, A., De Gregorio, D., Gobbi, G., 2021. Psychedelics in
Psychiatry: Neuroplastic, Immunomodulatory, and Neurotrans-
mitter Mechanisms. Pharmacological Reviews, 73 (1), 202–277.