Table 1 Summary of Evidence of Opioid-Sparing Effects from Pre-Clinical Studies

Cichewicz et al, 1999

Tail-flick test (male ICR mice)

Morphine p.o.

Delta-9-THC (20 mg/kg p.o.)

13.1 mg/kg (8.8, 19.5)

28.8 mg/kg (20.2, 41)

Potency ratio: 2.2

Codeine p.o.

Delta-9-THC (20 mg/kg p.o.)

5.9 mg/kg (1.4, 24.9)

139.9 mg/kg (75.2, 260.5)

Potency ratio: 25.8

Oxymorphone p.o.

Delta-9-THC (20 mg/kg p.o.)

0.5 mg/kg (0.3, 0.8)

2.6 mg/kg (1.7, 3.9)

Potency ratio: 5.0

Hydromorphone p.o.

Delta-9-THC (20 mg/kg p.o.)

0.4 mg/kg (0.2, 0.8)

5.6 mg/kg (3.2, 9.7)

Potency ratio: 12.6

Methadone p.o.

Delta-9-THC (20 mg/kg p.o.)

2.7 mg/kg (1.4, 5.2)

12.0 mg/kg (8.1, 17.9)

Potency ratio: 4.1

LAAM p.o.

Delta-9-THC (20 mg/kg p.o.)

2.6 mg/kg (1.7, 3.9)

8.0 mg/kg (6.4, 10.1)

Potency ratio: 2.5

Heroin p.o.

Delta-9-THC (20 mg/kg p.o.)

5.4 mg/kg (1.7, 16.9)

26.1 mg/kg (12.7, 53.4)

Potency ratio: 4.1

Meperidine p.o.

Delta-9-THC (20 mg/kg p.o.)

11.1 mg/kg (4.2, 29.4)

86.2 mg/kg (52.8, 140.6)

Potency ratio: 8.9

Fentanyl p.o.

Delta-9-THC (20 mg/kg p.o.)

0.5 mg/kg (0.3, 0.8)

6.1 mg/kg (estimated from an extrapolated curve)

Not determined (50% MPE not seen)

Pentazocine p.o.

Delta-9-THC (20 mg/kg p.o.)

838.6 mg/kg (estimated from an extrapolated curve)

625.9 mg/kg (estimated from an extrapolated curve)

Not determined (50% MPE not seen)

Cichewicz and Welch, 2003

Tail-flick test (male ICR mice)

Morphine p.o.

Codeine p.o.

Delta-9-THC (5–35 mg/kg and 1–27 mg/kg p.o.)

Delta-9-THC (5–30 and 5–18 mg/kg p.o.)

13.6 mg/kg±1.94

20.1 mg/kg±3.0

24.5 mg/kg±4.8

78.2 mg/kg ±14.4

For each ratio tested, experimental values were less than the calculated additive values (synergism)

For each ratio tested, experimental values were less than the calculated additive values (synergism)

Fixed-ratio combinations of 9-THC with either morphine or codeine were tested for antinociceptive effects. The experimentally derived ED₅₀ for each combination was compared with the theoretical additive ED₅₀, using an

isobolographic analysis. All the fixed-ratio combinations tested produced greater antinociception (synergy) than predicted from simple additivity

Cichewicz et al, 2005

Pin-prick test (IAF hairless guinea pigs)

Fentanyl s.c.

Delta-9-THC (50 mg/kg i.p.)

6.8 μg/kg (3.3, 14.2)

50.8 μg/kg (41.0, 63.0)

Greater than additive effect on antinociception. Potency ratio: 6.7 (1.8–17.0)

Buprenorphine s.c.

Delta-9-THC (50 mg/kg i.p.)

0.02 mg/kg (0.01, 0.05)

2.97 mg/kg (1.84, 4.81)

Greater than additive effect on antinociception. Enhanced potency in a non-parallel fashion

Not possible to compare the change in potency produced by delta-9-THC due to the non-parallel nature of the two dose–response curves for buprenorphine

Fentanyl t.d.

Delta-9-THC (400 mg/kg t.d.)

2 h: 254.9 μg/kg (202.90, 320.6)

4 h: 176.3 μg/kg (144.3, 215.5)

2 h: 928.6 μg/kg (599.5, 1438.3)

4 h: 1067.0 μg/kg (840.4, 1356.1)

Potency ratio at 2 h: 3.7

Potency ratio at 4 h: 5.8

Buprenorphine t.d.

Delta-9-THC (400 mg/kg t.d.)

2 h: 4.3 mg/kg (2.8, 6.8)

4 h: 2.2 mg/kg (1.1, 4.6)

2 h: 26.1 mg/kg (17.1, 39.9) 4 h: 15.6 mg/kg (10.0, 24.5)

Potency ratio at 2 h: 8.2

Potency ratio at 4 h: 7.2

Cox et al, 2007

Paw pressure test (Male Sprague–Dawley rats)

Morphine i.p. (normal rats)

Morphine i.p. (arthritic rats)

Delta-9-THC (0.4 mg/kg±0.5 i.p.) (1 : 1 ratio THC : Morphine)

Delta-9-THC (0.6 mg/kg±0.55 i.p.) (1 : 1 ratio THC : Morphine)

0.4 mg/kg±0.5

0.6 mg/kg±0.55

2.4 mg/kg (2.2, 2.8)

2.2 mg/kg (1.9, 2.4).

The combination of delta-9-THC and morphine showed synergism in both non-arthritic and arthritic rats

Results from normal rats included in the meta-analysis only

Finn et al, 2004

Formalin-evoked nociceptive behavior (adult male Lister-Hooded rats)

Morphine i.p.

Delta-9-THC (1 mg/kg i.p.)

Not reported

Not reported

Not clearly synergistic. Potentially additive. Morphine (2 mg/kg) + delta-9-THC (1 mg/kg) had a significant effect on nociceptive behavior (compared to morphine alone but not delta-9-THC alone).

Katsuyama et al, 2013

Capsaicin test (Male mice of ddY strain)

Morphine (1.0 mg/kg s.c. and 100 pmol i.t.)

Beta-caryophyllene (2.25 mg i.pl., CB2 receptor agonist)

ID₅₀ 1.16 mg/kg (1.03, 1.32, systemic, s.c.) and 130.1 pmol (111.9, 156.4, spinal, i.t.)

ID₅₀ 2.51 mg/kg (2.17, 2.97) (systemic, s.c.) and 193.7 pmol (165.7, 225.6, spinal, i.t.)

Morphine + beta-caryophyllene decreased licking/biting response p<0.05 compared to morphine + saline or beta-caryophyllene + jojoba wax.

Ineffective doses of beta-caryophyllene significantly enhanced morphine-induced antinociception.

Li et al, 2008

Thermal antinociception (rhesus monkeys)

Morphine s.c.

Delta-9-THC (0.32 and 1.0 mg/kg s.c.)

ED₈₀ 2.42 mg/kg

ED₈₀ 6.36 mg/kg (3.81, 8.91)

Pre-treatment with delta-9-THC enhanced the antinociceptive effects of morphine.

Morphine dose dependently increased the latency for monkeys to remove their tails from 50°C and 55°C water.

Maguire et al, 2013

Warm water tail withdrawal (rhesus monkeys)

Morphine s.c.

CP 55 940 (0.01 mg/kg s.c.)

WIN 55 212 (0.32 mg/kg s.c.)

Mean (n=3)

CP 0.23 mg/kg

WIN 0.24 mg/kg

1.26 mg/kg (mean, n=3)

Pre-treatment with CP 55 940 resulted in a mean leftward shift to of –6.73-fold. Pre-treatment with WIN 55 212 resulted in mean leftward shift of –5.5-fold.

Antinociception from the combination appeared to be achieved without an increase in abuse liability.

Pugh et al, 1996

Tail-flick test (mail ICR mice)

Morphine i.t.

Delta-9-THC (6 μcg/mouse i.t., inactive analgesic dose)

0.01 mcg/mouse

0.318 mcg/mouse (2.825, 0.036)

Greater than additive effect observed, clear leftward shift of graph.

Reche et al, 1996

Tail-flick and hot plate test (Swiss albino mice)

Morphine i.p.

Delta-9-THC i.p.

NA

Only one dose of morphine (2 mg/kg i.p.) examined. Study measured change in ED₅₀ of delta-9-THC.

NA

Morphine pre-administration shifted the dose–response curve for delta-9-THC to the left (a 2.5-fold shift for the tail-flick test and a three-fold shift for the hot plate test). Analgesic effect blocked by SR-141 716 (cannabinoid antagonist) and naloxone.

Smith et al, 1998

Tail-flick and hot plate test (male ICR mice)

Morphine s.c.

Morphine p.o.

Tail-flick: delta-9-THC (4 mg/kg s.c.)

Tail-flick: delta-9-THC (20 mg/kg p.o.)

0.29 mg/kg (95% CI 0.04, 1.94)

2.8 mg/kg (2.0, 3.9)

2.81 mg/kg (2.24, 3.53)

31.7 mg/kg (22.4, 44.9)

Potency ratio: 8.5

Potency ratio: 7.6

Multiple conditions tested different combinations of s.c and p.o morphine. Only s.c. + s.c. and p.o. + p.o. for the tail-flick test are reported here. A paw withdrawal test was also conducted to demonstrate that enhancement of antinociception was not limited to the tail.

Smith et al, 2007

Paw withdrawal test (male Sprague–Dawley rats)

Morphine s.c.

Delta-9-THC (0.75 mg /kg i.p.)

ED₈₀ morphine + delta-9-THC (0.75 mg/kg)

ED₈₀ morphine alone (100 mg/kg)

Tolerance to morphine alone rapidly established; no loss of effect with low-dose combinations of morphine + delta-9-THC

A morphine pellet arm and delta-9-THC alone arm were not reported in this table due to difficulties in comparing doses between morphine formulations.

Tham et al, 2005

Tail-flick and hot plate test (Swiss male mice)

Morphine s.c.

Tail-flick: CP 55 940 (0.1–3 mg/kg s.c.)

Hot plate: CP 55 940 (0.1–3 mg/kg s.c.)

3.31 mg/kg

7.54 mg/kg

11.3 mg/kg (9.6, 13.4)

29.4 mg/kg (27.3, 31.6)

Analyses showed greater than additive results (synergism).

Wakley and Craft, 2011

Paw pressure test (male Sprague–Dawley rats)

Methadone i.p.

Delta-9-THC (0.32–3.2 mg/kg i.p.)

Not reported (dose–response curve shown)

ED₅₀ in naive rats, 1.27 mg/kg (95% CI 0.91, 1.91), ED₅₀ in rats trained for discrimination, 3.49 mg/kg (95% CI 2.59, 5.31)

In opioid and delta-9-THC naive rats, methadone 1.0 mg/kg significantly enhanced the antinociceptive effect of delta-9-THC, however this was not observed in rats that were previously trained for drug discrimination tasks.

The rats trained for drug discrimination tasks had received repeated administration of opioids and cannabinoids over many months and may have been tolerant to drug effects at the doses administered.

Welch and Stevens, 1992

Tail-flick and hot plate test (mice)

Morphine i.t.

Delta-9-THC (3.133 mcg/mouse)

0.15 mcg/mouse (0.11, 0.21)

0.61 mcg/mouse (0.26, 1.44)

Yes

Delta-9-THC (6.25 mcg/mouse)

0.05 mcg/mouse (0.03, 0.08)

Yes

Delta-8-THC (25 mcg/mouse)

0.05 mcg/mouse (0.02, 0.10)

Yes

Levonantradol (0.005 mcg/mouse)

0.06 mcg/mouse (0.01, 0.24)

Yes

CP 55 940 (0.01 mcg/mouse)

0.3 mcg/mouse (0.0, 0.10)

Additive

CP 56 667 (0.5 mcg/mouse)

0.26 mcg/mouse (0.08, 0.82)

Additive

11-hydroxy-delta-9-THC (3 mcg/mouse)

0.08 mcg/mouse (0.04, 0.19)

Yes

Dextronantradol (25 mcg/mouse)

0.51 mcg/mouse (0.36, 0.89)

No

Williams et al, 2006

Tail-flick test (mail ICR mice)

Study 1: low-dose codeine (30 mg/kg) and morphine (20 mg/kg) and fully efficacious ED₈₀, codeine (100 mg/kg) and morphine (80 mg/kg). Study 2: high-dose codeine (200 mg/kg) and morphine (100 mg/kg) (all p.o.)

Delta-9-THC (20 mg/kg p.o., inactive analgesic dose)

ED₈₀ codeine (30 mg/kg)

ED₈₀ morphine (20 mg/kg)

ED₈₀ codeine (200 mg/kg)

ED₈₀ morphine (100 mg/kg)

A low dose of morphine (20 mg/kg) or codeine (30 mg/kg) with a single pre-treatment of an inactive dose of delta-9-THC produced the same efficacy (ED₈₀) as the high doses of each opioid alone. For codeine, delta-9-THC pre-treatment also increased the duration of action of the ED₈₀ dose of codeine.

Study 1: pre-treatment with delta-9-THC did not enhance the fully efficacious dose of morphine but enhanced low-dose morphine and both doses of codeine, in addition to extending the time course. Study 2: delta-9-THC restored analgesic efficacy after the time that the opioids had ceased being effective on their own (360 min post dose for morphine and 120 min post dose for codeine).

Williams et al, 2008

Tail-flick test (diabetic and non-diabetic mice and rats)

Morphine s.c.

Morphine s.c.

Delta-9-THC (20 mg/kg p.o.) in non-diabetic mice

Delta-9-THC (20 mg/kg p.o.) in diabetic mice

2.5 mg/kg (1.8, 3.4)

0.84 mg/kg (0.79, 0.89)

5.6 mg/kg (4.3, 7.2)

6.1 mg/kg (5.2, 7.1)

Yes

Yes

Delta-9-THC significantly enhanced morphine-induced antinociception in both diabetic and non-diabetic mice.

Wilson et al, 2008

Hot plate test (male Sprague–Dawley rats)

Morphine microinjections into PAG

HU-210 (5 μg)

Not reported (dose–response curve shown)

Not reported (dose–response curve shown)

No evidence of synergism. Morphine + HU-210 showed the greatest increase in hot plate latency (39.9 s±1.1 s), but was not significantly different from morphine alone (33.1 s ±4.0 s)

HU-210 shown to prevent development of tolerance to morphine’s antinociceptive effects. HU-210 pre-treatment enhanced subsequent morphine antinociception. Co-administration of HU-210 into the PAG attenuated morphine antinociception. The authors suggested that opioids and cannabinoids may have opposing actions within the PAG.

Yesilyurt et al, 2003

Tail-flick test (adult female Bulb-C mice)

Morphine topical

WIN 55, 212-2 (20 mg/ml, topical, mixed CB1-CB2 receptor agonist)

Morphine (20 mg/ml) + WIN sustained analgesic effect of 50% analgesia over 4 h

Morphine (20 mg/ml) alone produced 18% analgesic effect, peak at 20 min then reduced.

Antinociceptive effects were markedly potentiated (they peaked and were sustained at 30 min) compared to morphine response alone.