Magnolia and Midazolam Injection: Interaction Details

a) Honokiol, a neolignane derivative present in magnolia bark, has central nervous system depressant activity and at lower doses, anxiolytic activity. Anxiolytic activity (as shown by prolonged time spent in the open arms of the maze) was noted in a plus-maze test in mice of a single oral dose of 20 milligrams/kilogram (mg/kg) honokiol (p less than 0.05). Honokiol did not affect traction performance, whereas diazepam 0.5 mg/kg to 2 mg/kg prolonged time spent in open arms of the maze and disrupted traction performance. After 7 days of treatment with 0.2 mg/kg honokiol and after a single treatment with 1 mg/kg diazepam, performance in the plus-maze was nearly equivalent. The effect of honokiol was reversed following subcutaneous administration of flumazenil 0.3 mg/kg. Combination treatment with honokiol and diazepam significantly prolongd the time spent in open arms of the maze over treatment with either alone (p less than 0.05). Honokiol reduced the effect of diazepam on motor activity, but did not affect diazepam-induced inhibition of traction performance. The authors concluded based on their findings that honokiol induces an anxiolytic effect with less liability of causing sedation, disinhibition, or motor dysfunction than diazepam. Possible mechanisms proposed were that honokiol selectively stimulates GABA-A receptors, or honokiol binds to other sites related to the anxiolytic effect ¹.

b) Honokiol administered intravenously to 5 rats resulted in an elimination rate constant of 0.08 +/- 0.01 Liters/minute (L/minute) after a 5 mg/kg loading dose, and 0.06 +/- 0.02 L/minute after a 10 mg/kg loading dose. Half-life was 49.22 +/- 6.78 minutes after a 5 mg/kg loading dose, and 56.24 +/- 7.30 minutes after a 10 mg/kg loading dose. The bioavailability as expressed as area under the curve (AUC) was 58.87 +/- 4.19 micrograms/milliliter/minute (mcg/mL/minute) after a 5 mg/kg loading dose, and 133.89 +/- 16.26 mcg/mL/minute (p less than 0.05) after a 10 mg/kg loading dose ².

c) Magnolol and honokiol at 100 mg/kg, 200 mg/kg, and 400 mg/kg administered intraperitoneally to mice suppressed grip strength in a dose-dependent manner. Grip strength was lost within 30 minutes, which was sustained for 3 hours after a 400 mg/kg dose of either compound. Spinal reflexes in the chick were inhibited in a dose-dependent manner with magnolol and honokiol at 12.5 mg/kg, 25 mg/kg, 50 mg/kg, and 100 mg/kg intraperitoneally ³.

d) Magnolol and honokiol may cause depression of the ascending activating systems and the spinal cord based on mice studies demonstrating sedation, ataxia, muscle relaxation, and anticonvulsant activities of magnolol and honokiol. Magnolol at 63 mg/kg intraperitoneally produced hypomotility, ptosis, and sedation. Magnolol 125 mg/kg produced sedation, ataxia, and muscle relaxation; at 250 mg/kg magnolol produced ataxia, loss of righting reflex, and muscle relaxation of 4 legs. Honokiol produced similar effects at 125 mg/kg, 250 mg/kg, and 500 mg/kg. Both magnolol and honokiol compounds at 50 mg/kg suppressed spinal reflexes in chicks. In mice, pretreatment with magnolol 100 mg/kg inhibited tonic extensor convulsion and death induced by an intracerebroventricular injection of penicillin G potassium 50 micrograms (mcg) ⁴.

e) The ether extract of magnolia bark and its purified constituents, magnolol and honokiol were examined in terms of muscle relaxant properties in the mouse model. Magnolol at 100 mg/kg produced muscle relaxation for 2 hours; magnolol 250 mg/kg induced loss of righting reflex and muscle relaxation extending beyond 3 hours. Honokiol 250 mg/kg exhibited muscle relaxation properties for 3 hours with 500 mg/kg producing loss of righting reflex. Muscle relaxing properties of both compounds subsided fully within 24 hours after injection. The ether extract at 1 gram/kg induced loss of righting reflex 30 minutes after injection for nearly 60 minutes ⁵.