Table 4 Studies of the anxiogenic/anxiolytic effect of THC and other cannabinoids in animals

Acute administration

McLendon et al.1976 [65]

Male Rhesus monkeys

THC (0.2, 0.5, 1.0 mg/kg)

Cardiac conditioned response

Intravenous

All does produced an anxiolytic-like effect

Valjient et al. 2002 [21]

Male CD-1 mice

THC (0.03, 0.1, 1.0, 2.5, 5.0 mg/kg)

Light–dark (LD) box

Intraperitoneal

The lowest dose of 0.03 mg/kg produced an anxiolytic-like effect and the highest dose of (5.0 mg/kg) produced an anxiogenic-like effect. All other doses produced no effect.

Berrendero and Maldonado 2002 [20]

Male CD1 mice

THC (0.3 mg/kg)

Light–dark box

Intraperitoneal

The dose of 0.3 mg/kg produced an anxiolytic-like response

Schramm-Sapyta et al. 2007 [68]

Adolescent and adult Male CD rats

THC (0.5, 2.5 mg/kg)

Light–dark box,

Elevated plus-maze (EPM)

Intraperitoneal

All doses produced anxiogenic-like responses

Braida et al. 2007 [42]

Male Sprague–Dawley rats

THC (0.015, 0.075, 0.75 mg/kg)

Elevated plus-maze

Intraperitoneal

All doses produced anxiolytic-like responses

Rubino et al. 2007 [67]

Male Sprague–Dawley rats

THC (0.015, 0.075, 0.374, 0.75, 1.5, 3.0 mg/kg)

Elevated plus-maze

Intraperitoneal

At all doses except 3.0 mg/kg, an anxiolytic-like response was observed. When 3.0 mg/kg was administered, no response was seen.

Long et al. 2010 [69]

Male C57BL/6JArc mice

CBD (1.0, 50.0 mg/kg)

Elevated plus-maze

Intraperitoneal

No effect was observed at either dose

Fokos et al. 2010 [64]

Male Sprague–Dawley rats

THC (0.5, 1.0 mg/kg)

Elevated plus-maze

Intraperitoneal

In stressed rats, 0.5 mg/kg THC produced an anxiogenic-like effect and 1 mg/kg produced an anxiolytic-like effect. On the other hand, in non-stressed rats, both doses produced an anxiolytic-like response

Kasten et al. 2019 [72]

Adolescent and adult male and female C57Bl/6 J mice

THC (1.0, 5.0, 10.0 mmg/k)

CBD (5.0, 10.0, 20.0 mg/kg)

THC + CBD (10.0 + 20.0 mg/kg)

Elevated plus-maze,

Open field (OF) test

Intraperitoneal

Male and Female,

Adult and Adolescent mice (we have looked ta adult mice only in this section)

In the elevated plus maze and the open field test, all doses of THC produced an anxiogenic-like response. For both tests, all doses of CBD produced no effect. When the combination of THC and CBD was given, an anxiogenic-like response was observed in both the elevated plus maze and the open field test

Zieba et al. 2019 [71]

Male Fmr1 KO mice

CBD (5.0, 20.0 mg/kg)

Elevated plus-maze,

Open field test

Intraperitoneal

In the EPM, both 5.0 and 20.0 mg/kg CBD produced an anxiolytic-like response. On the other hand, in the OF test, no effect was observed at either dose

Malone et al. 2009

Male Sprague–Dawley rats

CBD (5.0, 20.0 mg/kg)

THC (1.0, 3.0, 10.0 mg/kg)

THC + CBD (1.0 + 5.0 mg/kg, 1.0 + 20.0 mg/kg, 3.0 + 5.0 mg/kg, 3.0 + 20.0 mg/kg, 10.0 + 5.0 mg/kg, 10.0 + 20.0 mg/kg

Social Interaction

Intraperitoneal

All dose effects are comparative to each other (see results discussion above)

Chronic administration

Long et al. 2010 [69]

Male C57BL/6JArc mice

THC (0.3, 1.0, 3.0, 10.0 mg/kg)

CBD 1.0, 5.0, 10.0, 50.0 mg/kg)

Light–dark box, Elevated plus-maze, Open-field test,

Social interaction

Intraperitoneal

At 10 mg/kg THC, there was an increase in the time spent in the light and the distance ratio. Further, There was a trend towards an effect of on time spent in the inner open arm in the EPM but no effect on the open-arm in the EPM. In the OF test, there was a significantly decrease in the time spent in the central zone of the on test on day 15 and decreased the distance ratio on day one. THC did not alter total SI time, but decreased the combined frequency of the social behaviors.

In the LD test, CBD (1 mg/kg) significantly increased the time spent in the light compartment and the distance ratio. No effect on the open-arm entry ratio or percentage of time spent on open arms in the EPM. There was an Increase in the time spent in the central zone of the OF test on day 15.

Rock et al. 2017 [73]

Male Sprague–Dawley rats

THC (1.0, 10.0 mg/kg)

CBD (5.0 mg/kg)

Light–dark box

Intraperitoneal

At a dose of 1 or 10 mg/kg, THC decreased the amount of time spent in the light box on days one and 21, suggesting an anxiogenic-like effect. As well, at a dose of10 mg/kg only, THC increased the latency to enter the light box, but only on day one. The addition of prior stress increased thus anxiogenic effect

A prior stressor produced anxiogenic-like behavior, but administration of CBD abolished this effect

Schleicher et al. 2019 [70]

Male and Female C57BL/6 J mice

CBD (20.0 mg/kg)

Light–dark box, Open Field Test, Elevated Plus Maze

Intraperitoneal

No changes in anxiolytic/anxiogenic behavior was observed in the light–dark box and the open field test, but a decreased amount of time was spent in the open arms of the EPM

Direct administration into brain

Rubino et al. 2008 [41]

Male Sprague–Dawley rats

THC (0.0025, 0.005, 0.01, 0.025 mg into the prefrontal cortex, 0.0025, 0.005, 0.01 mg into the ventral hippocampus, 0.001, 0.0025, 0.005, 0.01 mg into the the basolateral amygdala

Elevated plus-maze

Microinjection

THC at doses of 0.0025 and 0.005 mg microinjected into the prefrontal cortex

did not significantly affect anxiety behaviour, while 10 mg THC increase the percentage of time and entries onto the open arm, consistent with an anxiolytic effect. The anxiolytic-like response of 0.01 mg THC was also confirmed by the analysis of ethological parameters. At 0.025 mg the anxiolytic effect was lost in favour of an anxiogenic profile

In the ventral hippocampus the dose of 0.005 mg THC significantly increased the percentage of open arm time as well as the percentage of open arm entries. This anxiolytic effect was confirmed by the significant decrease in the ethological parameter closed arm returns. In contrast, 0.01 mg THC seemed to switch to an anxiogenic response as shown by the reduction in open arm time and head dips, although not reaching statistical significance

In the basolateral amygdala the dose of 0.001 mg induced a significant decrease in the percentage of open arm time and head dips and a tendency to decrease in the open arm entries, consistent with an anxiogenic-like response. Higher THC doses did not affect rat anxiety behaviour in the EPM. THC at all doses did not change closed arm entries