Table 2.
Characteristics of the animal studies focused on the effect of cannabis on the brain and cognition
| Sample | Characteristics of cannabis exposure | IV(s) | DV(s) | Design | Risk, resilience, or null | ||
|---|---|---|---|---|---|---|---|
| Synthetic cannabis | |||||||
| O’Shea et al. [49] | N = 58; 100% female Wistar rats | Prolonged abstinence (21 days washout): 21 days of repeated exposure to CP or a control by injection. 0.15, 0.20, and 0.30 mg/kg for 3, 8, and 10 days, respectively | Age [(40 adolescents (30-day old) vs. 18 adults (56-day old))] BY treatment (control or CP) BY delay (2 or 6 h) | Object recognition (Novel Object Recognition Task) | Half of the rats at each developmental period were injected with the CP on each day of testing and half were tested with the vehicle | Null for age BY treatment BY delay on object recognition | |
| O’Shea et al. [50] | N = 72; 100% male Wistar rats | Prolonged abstinence (28 day washout): 21 days of repeated exposure to CP or a control by injection. 7 days per dosage (0.15, 0.20, 0.30 mg/kg) | Age [(24 perinatal (4 days old) vs. 24 adolescents (30 days old) vs. 24 adults (56-day old))] BY treatment (control or CP) BY delay (2, 6, or 48 h) | Object recognition (Novel Object Recognition Task) | Half of the rats at each developmental period were injected with the CP on each day and half were injected with the vehicle | Null for age BY treatment BY delay on object recognition | |
| Gleason et al. [51] | N = 40; C57BL6 mice (sex not presented) | Prolonged abstinence (110 day and 77-day washout for adolescents and adults, respectively): 3–5 day or 10-day exposure to 1 daily injection of WIN at 2 mg/kg or control | Age [(20 adolescents (30–35 days old) vs. 20 adults (63–70 days old))] BY treatment (control) | Cued and contextual fear conditioning; PPI | Half of the rats at each development time window were administered WIN; half were administered the vehicle control. After exposure, rats had a washout until they reached post-natal day 120, at which point they were administered conditioning tasks and PPI measures |
Null for age BY treatment on contextual or cued fear conditioning after the 3- to 5-day exposure Risk for age BY treatment on contextual and cued fear conditioning and pre-pulse inhibition after the 10-day exposure Interpretation Adolescents showed reduced PPI (at pre-pulses of 4 dB and 8 dB) and contextual and cued fear conditioning |
|
| Bambico et al. [54] | N unclear; 100% male Sprague–Dawley rats | Prolonged abstinence (20 day washout): 20-day exposure to WIN at 0.2 mg/kg or 1.0 mg/kg or to a control |
Age [(adolescents (30–50 days old) vs. adults (50–70 days old))] BY treatment (0.2 mg/kg WIN, 1.0 mg/kg WIN, or vehicle) Number of adolescent and adult animals missing |
Firing rate of serotonergic activity in DR 5-HT neurons and noradrenergic activity in LC (extracellular single unit recording was used) | Adolescents and adult rats were split into 3 groups and received either 0.2 mg/kg WIN, 1.0 mg/kg WIN, or control |
Risk for age BY treatment on serotonergic activity in the DR 5-HT neurons at 0.2 mg/kg and at 1.0 mg/kg Interpretation Adolescents experienced a greater reduction in serotonergic activity in the DR at 0.2 mg/kg and at 1.0 mg/kg compared to adults Null for age BY treatment on noradrenergic activity in the LC |
|
| Acheson et al. [57] | N = 22; 100% male Sprague–Dawley rats | No prolonged abstinence (no washout): 5-day exposure to either 1.0 mg/kg of WIN or control | Age [(11 adolescents (30-day old) vs. 11 adults (65-day old))] BY treatment (control or WIN55212-2) BY day (5 days) before and after controlling for anxiety-related behavior | Spatial learning (Morris Water Maze) |
Half of the rats at each developmental period were injected with the WIN on each day of testing and half were tested with the vehicle For behavioral testing, animals were given 4 trials per day for 5 days |
Null for age BY treatment BY day on spatial learning after controlling for anxiety | |
| Fox et al. [58] | N = 79; 100% male Sprague–Dawley rats |
No prolonged abstinence (30 min washout): a single dose of 3.0 mg/kg WIN or control 7-day exposure to one injection of 3.0 mg/kg WIN or control |
Age [(46 adolescents (30-day old) vs. 33 adults (weighed 200–224 g; age not mentioned))] BY treatment (control or WIN) | Novelty seeking (Hole Board Task) |
For the single dose: 12 adolescent and 6 adult rats received WIN whereas 12 adolescent and 5 adult animals received the control For the 7-day exposure: 12 adolescent and 12 adult rats received WIN whereas 10 adolescent and 10 adult rats received the control |
Null for age BY treatment on novelty seeking for the 1-day exposure Null for age BY treatment on novelty seeking for the 7-day exposure |
|
| Carvalho et al. [59] | N = 36; 100% male Sprague–Dawley rats | No prolonged abstinence (24 h washout): 14-day exposure to 1 daily injection of either 3.0 mg/kg of WIN or control |
Age [(adolescents (27–30 days old) vs. adults (55–60 day old))] BY treatment (control or WIN) Number of adolescent and adult rats was not explicitly specified and varied by analysis in the results section |
Prefrontal cortical and nucleus accumbens neuronal morphology; aversion (Conditioned Place Aversion Task) |
12 rats were anesthetized post-injections to conduct neuronal morphology tests For the remaining rats (N = 24), half of the rats at each developmental period were injected with a vehicle across behavioral sessions and half were injected with WIN |
Null for age BY treatment on nucleus accumbens and prefrontal cortical neuronal morphology Inconclusive for age BY treatment on aversion, as authors did not present interaction despite it being part of the proposed analyses |
|
| Klugman et al. [60] | N = 92 for whole study; 100% male Wistar rats | No prolonged abstinence (1 h washout): single dose of 1.2 mg/kg of WIN |
Age [(adolescents (40-day old) vs. adults (100-day old))] BY treatment (control or WIN) Amount of animals per adolescent and adult age groups was not presented. Although 17 were used for the DVs reported in the fifth column |
Scaffold protein levels (i.e., Homer); NMDAR subunits: NR1 and NR2b in the mPFC and striatum |
Half of the rats at each developmental period were injected with the WIN one time and half were tested with the vehicle one time Rats were sacrificed, and the ventral striatum and mPFC were dissected |
Risk for age BY treatment on NR1 subunits and Homer protein expression in striatum and mPFC Interpretation WIN administration increased NR1 expression and levels and Homer protein expression in adolescents compared to adults Inconclusive for age BY treatment on NR2b as significance of the interaction was not presented, despite presentation of NR1 interaction |
|
| Verdurandet al [61] | N = 118; 100% male Wistar rats |
No prolonged abstinence (24 h washout): 1-day exposure to 0.10 mg/kg HU either on day 4 or day 14, with vehicle control being administered on the previous days 4-day or 14-day exposure to HU at 0.025 mg/kg, 0.05 mg/kg, 0.10 mg/kg, or control |
Age [(5 adolescents (5–7 weeks old) vs. 6 adults (10 weeks old))] BY dose (0.025 mg/kg, 0.05 mg/kg, 0.10 mg/kg, or control) BY regimen (1-day, 4 days, 14 days) | GABAA receptor binding in the nucleus accumbens, amygdala, CA1 of hippocampus, cingulate cortex, caudate putamen, and dentate gyrus of hippocampus |
Adolescents and adults were randomly allocated to the five treatment groups for 4-day exposure (1-day 0.10 mg/kg and 3 days control, 0.025 mg/kg for 4 days, 0.05 mg/kg for 4 days, 0.10 mg/kg for 4 days, or control for 4 days) For 14-day exposure, adolescent and adult rats were also randomly allocated to the 5-treatment groups. The 14-day exposure group was administered vehicle for 13 days before receiving the single dose, instead of 3 days |
Null for age BY dose BY regimen on GABAA density in all brain areas | |
| Kang-Park et al. [62] | N = 80; 100% male Sprague–Dawley rats |
No prolonged abstinence (no washout) Application of 0.1–5 µΜ WIN was applied for 10–15 min after a baseline was recorded |
Age [(12 adolescents (28–35 days old) vs. 12 adults (75–110 days old))] Treatment (WIN) was not a level of the IV as they used baseline recordings to determine pre-treatment differences |
EPSC; IPSC in CA1 hippocampal neurons | Brains were removed from the rats when they were under anesthesia. After incubation, a single slice of each rat brain was transferred to a chamber where recording of neurotransmission took place before and after WIN administration (10–15 min after and again 20–25 min after) |
Null for age BY treatment on amplitude of the evoked excitatory neurotransmission Risk for age BY treatment on the amplitude of evoked inhibitory neurotransmission in CA1 hippocampal neurons Interpretation Adolescents treated with WIN experienced a greater reduction in inhibitory neurotransmission than adults |
|
| THC | |||||||
| Cha et al. [46] | N = 32, 120, and 40; 100% male Sprague–Dawley rats |
No prolonged abstinence (30 min washout): experiment 1: 5 mg/kg of THC or control solution was administered for 5 days Experiment 2: 2.5 mg/kg of THC, 10.0 mg/kg of THC, or control solution was administered for 5 days Prolonged abstinence (28 day washout before testing began): Experiment 3: 5 mg/kg of THC or control was administered daily for 21 days |
Experiment 1: age [(16 adolescents (30–32 days old) vs. 16 adults (65–70 day old))] BY treatment (THC vs. control) Experiment 2: age [(60 adolescents (30–32 days old) vs. 60 adults (65–70 day old))] BY treatment (THC vs. control) Experiment 3: age [(20 adolescents (30–32 days old) vs. 20 adults (65–70 day old))] BY treatment (THC vs. control) |
Spatial learning, non-spatial learning for all experiments (Morris Water Maze) |
Experiments 1 and 2: half of the rats at each developmental period were injected with the THC on the day of testing and half were tested with the vehicle for 5 days. 30 min after injection each day behavioral testing was conducted Experiment 3: half of the rats at each developmental period were injected with THC and half were tested with the vehicle for 21 days. After a 28-day washout, behavioral testing was conducted |
Experiment 1 (no prolonged abstinence): Inconclusive for age BY treatment. No main effects of cannabis treatment on learning in adolescents and adults Experiment 2 (no prolonged abstinence): Risk for age BY treatment on learning Interpretation THC administration inhibited both spatial and non-spatial learning in adolescent rats to a greater degree than adult rats at both dosages Experiment 3 (prolonged abstinence): Inconclusive for age BY treatment on spatial and non-spatial learning. No main effects of cannabis treatment on learning in adolescents and adults |
|
| Cha et al. [47] | N = 128 per experiment; 50% male Sprague–Dawley rats |
No prolonged abstinence (30 min washout): experiment 1: 5 mg/kg of THC or control was administered daily for 5 days Experiment 3: 2.5, 5.0, or 10.0 mg/kg of THC or control solution was administered daily for 5 days Prolonged abstinence (28 day washout): experiment 2: 5 mg/kg of THC or control was administered daily for 21 days |
Experiments 1 and 2: age [(64 adolescents (25 days old) vs. 64 adults (65 days old))] BY treatment (THC vs. control) experiment 3: age [(64 adolescents (25 days old) vs. 64 adults (65 days old))] BY treatment (2.5, 5.0, 10.0, or vehicle) |
Experiment 1: spatial learning Experiment 2: spatial and non-spatial learning Experiment 3: spatial learning (Morris Water Maze task) |
Experiments 1 and 3: half of the rats at each developmental period were injected with the THC on the day of testing and half were tested with the vehicle for 5 days. 30 min after injection each day behavioral testing was conducted Experiment 2: Same procedure as 1 and 3 but THC and control were injected daily for 21 days. After a 28-day washout, behavioral testing was conducted |
Experiment 1 (no prolonged abstinence): Risk for age BY treatment on spatial learning Interpretation THC administration following no abstinence period inhibited spatial learning in adolescent rats to a greater degree than adult rats Experiment 2 (prolonged abstinence): Inconclusive for age BY treatment on spatial and non-spatial learning. No main effects of cannabis treatment on learning in adolescents and adults Experiment 3 (no prolonged abstinence dose–response): Null for age BY treatment on spatial learning |
|
| Kasten et al. [48] | N = 40; 100% male, B6 and D2 mice |
No prolonged abstinence (72 h washout): a 10 mg/kg of THC or control solution was administered every 72 h over the course of 24 days Prolonged abstinence (4-week washout period before testing began) Rats were re-tested with behavioral paradigms |
Age [(20 adolescents (27–29 days old) vs. 20 adults (68–70 days old))] BY treatment (10 mg/kg or control) B6 and D2 mice analyzed separately |
Object recognition (Novel Object Recognition Task) | Half of the rats at each developmental period were injected with the THC on the day of testing and half were tested with the vehicle for a total of 6 injections (2 of which were during behavioral tests) | Null for age BY treatment on object recognition with no prolonged abstinence and with prolonged abstinence for B6 or D2 mice | |
| Moore et al. [55] | N = 40; 100% male; Sprague–Dawley rats | No prolonged abstinence (30 min washout): a 10 mg/kg of THC or control solution was administered daily for 5 days | Age [(20 adolescents (30–35 days old) vs. 20 adults (70–75 days old))] BY pre-treatment (10 mg/kg or control) BY challenge | Spatial learning (Morris Water Maze), CB1 hippocampal distribution (immunofluorescence), CB1 hippocampal number, CB1 coupling to downstream G protein, CB1 desensitization | Half of the rats at each developmental period were injected with the THC and half with the vehicle for 5 days. On days 6 and 10, the THC pre-treated rats were injected with another dose of THC, whereas the other rats were exposed to the vehicle again. 30 min after the injection of THC or vehicle behavioral testing was administered. For neural-related DVs, the rats were euthanized post-behavioral testing to conduct analyses |
Risk for age BY pre-treatment BY challenge on spatial learning Interpretation: Adults pre-treated with THC showed lower reductions in spatial learning after the challenge then treatment-matched adolescents Inconclusive for age BY pre-treatment BY challenge on hippocampal CB1 number, distribution, or coupling |
|
| Schramm-Saptya et al. [56] | N = 64–66; 100% male, Sprague–Dawley rats | No prolonged abstinence (0–10 min washout): 0.5 or 5 mg/kg of THC or control solution was administered daily for 5 days | Age [(32–33 adolescents (28 days old) vs. 32–33 adults (64–66 days old))] BY treatment (0.5, 5 mg/kg, or control) | Aversion (Conditioned Taste Place Aversion tasks) | Half of the rats at each developmental period were injected with the THC on the day of testing and half were tested with the vehicle for 5 days. For Conditioned Taste Aversion Testing and Place Aversion Testing, rats were injected immediately after the saccharin drinking session and 10 min before being placed in the chamber, respectively |
Risk for age BY treatment on place aversion Interpretation 5 mg/kg THC administration caused a greater place aversion in adolescents and adults compared to vehicle administration. However, adults spent less time in the drug-associated place than adolescents (i.e., greater place aversion). There were no age-related differences for the lower dosage Null for age BY treatment on taste aversion |
|
IV(s) independent variables, DV(s) dependent variables, WIN WIN 55212-2, CP 55,940, HU HU210, CB1 and CB2 cannabinoid receptor type 1 and 2, DR Dorsal raphe, LC locus coeruleus, mGluR5 metabotropic glutamate receptors type 5, mPFC medial prefrontal cortex, PPI pre-pulse inhibition, EPSC excitatory postsynaptic current, IPSC inhibitory postsynaptic current, CA1 cornu ammonis. Numbers in brackets correspond to the studies placement in the reference section. We determined adolescents’ risk, resilience, or null classification based on the statistical tests. The risk, resilience, or null interpretation is from the adolescent’s perspective. Only the analyses that statistically explored age as a moderator for cannabis and cognition were reported. For the DV(s) listed, the measure used to assess this cognitive domain is listed in parentheses