Kratom Alkaloids, Natural and Semi-Synthetic, Show Less Physical Dependence and Ameliorate Opioid Withdrawal

Abstract

Chronic administration of opioids produces physical dependence and opioid-induced hyperalgesia. Users claim the Thai traditional tea "kratom" and component alkaloid mitragynine ameliorate opioid withdrawal without increased sensitivity to pain. Testing these claims, we assessed the combined kratom alkaloid extract (KAE) and two individual alkaloids, mitragynine (MG) and the analog mitragynine pseudoindoxyl (MP), evaluating their ability to produce physical dependence and induce hyperalgesia after chronic administration, and as treatments for withdrawal in morphine-dependent subjects. C57BL/6J mice (n = 10/drug) were administered repeated saline, or graded, escalating doses of morphine (intraperitoneal; i.p.), kratom alkaloid extract (orally, p.o.), mitragynine (p.o.), or MP (subcutaneously, s.c.) for 5 days. Mice treated chronically with morphine, KAE, or mitragynine demonstrated significant drug-induced hyperalgesia by day 5 in a 48 °C warm-water tail-withdrawal test. Mice were then administered naloxone (10 mg/kg, s.c.) and tested for opioid withdrawal signs. Kratom alkaloid extract and the two individual alkaloids demonstrated significantly fewer naloxone-precipitated withdrawal signs than morphine-treated mice. Additional C57BL/6J mice made physically dependent on morphine were then used to test the therapeutic potential of combined KAE, mitragynine, or MP given twice daily over the next 3 days at either a fixed dose or in graded, tapering descending doses. When administered naloxone, mice treated with KAE, mitragynine, or MP under either regimen demonstrated significantly fewer signs of precipitated withdrawal than control mice that continued to receive morphine. In conclusion, while retaining some liabilities, kratom, mitragynine, and mitragynine pseudoindoxyl produced significantly less physical dependence and ameliorated precipitated withdrawal in morphine-dependent animals, suggesting some clinical value.

Keywords: Kratom; Mitragynine; Opioid; Physical dependence; Withdrawal.

Fig. 1

Assessment of treatment-induced hyperalgesia using the 48 °C warm-water tail-withdrawal test. Mice were first tested on day 1 to establish a baseline reading prior to any treatment. Mice were then subjected to a dosing regimen with saline (i.p.), morphine (10–75 mg/kg, i.p.), kratom alkaloid extract (30–125 mg/kg, p.o.), mitragynine (10–75 mg/kg, p.o.), or mitragynine pseudoindoxyl (1–35 mg/kg, s.c.) for 4 days. On day 5, prior to final dosing and withdrawal testing, mice were evaluated a final time in the warm-water tail-withdrawal assay. Data are shown as mean ± SEM of pre- and post-dosing testing. *p < 0.05 versus baseline, Two-way RM ANOVA with Sidak’s multiple comparisons post hoc test. n = 10 mice/treatment

Fig. 2

Assessment of direct kratom alkaloid extract, mitragynine, and mitragynine pseudoindoxyl treatment-induced physical dependence. a Dosing schematic for treatment groups. Increasing diamond (◊) size indicates increased dosage of morphine, KAE, MG or MP. The triangle (△) indicates naloxone treatment. Days 1–4: Treated with (a.m. and p.m.): Group 1: (n = 10) Saline, i.p. × 2/day. Group 2: (n = 10), Morphine × 2/day. Day 1: 10 + 15 mg/kg, i.p. Day 2: 20 + 30 mg/kg, i.p. Day 3: 50 + 60 mg/kg, i.p. Day 4: 70 + 75 mg/kg, i.p. Group 3: (n = 10) kratom alkaloid extract (KAE) × 2/day: day 1: 30 + 35 mg/kg, p.o. Day 2: 45 + 60 mg/kg, p.o. Day 3: 100 + 100 mg/kg, p.o. Day 4: 125 + 125 mg/kg, p.o. Group 4: (n = 10) Mitragynine (MG) × 2/day Day 1: 10 + 15 mg/kg, p.o. Day 2: 20 + 30 mg/kg, p.o. Day 3: 50 + 60 mg/kg, p.o. Day 4: 70 + 75 mg/kg, p.o. Group 5: (n = 10) Mitragynine Pseudoindoxyl (MP) × 2/day: day 1: 1 + 3 mg/kg, s.c. Day 2: 3 + 10 mg/kg, s.c. Day 3: 15 + 20 mg/kg, s.c. Day 4: 30 + 35 mg/kg, s.c. Group 6: (n = 10), Morphine × 2/day. Day 1: 10 + 15 mg/kg, i.p. Day 2: 20 + 30 mg/kg, i.p. Day 3: 50 + 60 mg/kg, i.p. Day 4: 70 + 75 mg/kg, i.p. Day 5: Group 1: (n = 10) Saline, i.p.; Group 2: Morphine (25 mg/kg, i.p.); Group 3: KAE (25 mg/kg, p.o.); Group 4: MG (25 mg/kg, p.o.); Group 5: MP (1 mg/kg, s.c.); Group 6: Morphine (25 mg/kg, i.p.). 90 min post-morphine treatment on day 5, group 6 was additionally administered an acute dose of clonidine (5 mg/kg, i.p.). All groups were administered naloxone (10 mg/kg, s.c.) 120 min post-respective day 5 am treatment then observed for withdrawal behaviors (i.e., forepaw licking (b), mouse straightening (c), rearing (d), frequency of diarrhea (e), forepaw tremor (f), teeth chattering (g), wet dog shakes (h), and jumping (i)) for 15 min. *p < 0.05 versus vehicle control, # p < 0.05 versus morphine, one-way RM ANOVA with Tukey’s multiple comparisons post hoc test. ^†Mean and SEM lower than 1

Fig. 3

Evaluation of fixed doses of mitragynine’s and mitragynine pseduoindoxyl’s ability to ameliorate naloxone-precipitated opioid withdrawal symptoms in morphine-dependent mice. a Dosing schematic for treatment groups. Increasing diamond (◊) size indicates increased dosage of morphine. The circles (○) represent fixed doses of either mitragynine or MP. The triangle (△) indicates naloxone treatment. Days 1–4: Treated with (a.m. and p.m.): Group 1: (n = 10) Saline, i.p. × 2/day. Groups 2–4: (n = 9–10/group), Morphine × 2/day. Day 1: 10 + 15 mg/kg, i.p. Day 2: 20 + 30 mg/kg, i.p. Day 3: 50 + 60 mg/kg, i.p. Day 4: 70 + 75 mg/kg, i.p. Days 5–7: Treated with (a.m. and p.m.) Group 1: Saline, i.p. × 2/day; Group 2: Morphine × 2/day: 80 mg/kg, i.p. Group 3: Mitragynine (MG) × 2/day: 80 mg/kg, p.o. Group 4: Mitragynine Pseudoindoxyl (MP) × 2/day: 30 mg/kg,s.c. Day 8: Group 1: (n = 10) Saline, i.p.; Group 2: Morphine (25 mg/kg, i.p.); Group 3: MG (25 mg/kg, p.o.); Group 4: MP (3 mg/kg, s.c.). All groups were administered naloxone (10 mg/kg, s.c.) 120 min post-respective day 5 am treatment then observed for withdrawal behaviors [i.e., forepaw licking (b), mouse straightening (c), rearing (d), frequency of diarrhea (e), forepaw tremor (f), teeth chattering (g), wet dog shakes (h), and jumping (i)] 120 min post-respective day 5 am treatment then observed for withdrawal behaviors [i.e., forepaw licking (b), mouse straightening (c), rearing (d), frequency of diarrhea (e), forepaw tremor (f), teeth chattering (g), wet-dog shakes (h), and jumping (i)] for 15 min. *p < 0.05 versus vehicle control, ^#p < 0.05 versus morphine, one-way RM ANOVA with Tukey’s multiple comparisons post hoc test. ^†Mean and SEM lower than 1

Fig. 4

Evaluation of tapering doses of kratom alkaloid extract, mitragyine, and mitragynine pseudoindoxyl’s ability to reduce naloxone-precipitated opioid withdrawal symptoms in morphine-dependent mice. a Dosing schematic for treatment groups. Increasing diamond (◊) size indicates increased dosage of morphine. The decreasing size of the circles (○) represent tapering doses of either kratom alkaloid extract, mitragynine, or MP. The triangle (△) indicates naloxone treatment. Days 1–4: Treated with (a.m. and p.m.): Group 1: (n = 10) Saline, i.p. × 2/day. Groups 2–5: (n = 9–10/group), Morphine × 2/day. Day 1: 10 + 15 mg/kg, i.p. Day 2: 20 + 30 mg/kg, i.p. Day 3: 50 + 60 mg/kg, i.p. Day 4: 70 + 75 mg/kg, i.p. Days 5–7: Treated with (a.m. and p.m.) Group 1: Saline, i.p. × 2/day; Group 2: Morphine × 2/day: 80 mg/kg, i.p. Group 3: Kratom alkaloid extract (KAE) × 2/day: Day 5: 100 mg/kg, p.o. Day 6: 80 + 70 mg/kg, p.o. Day 7: 60 + 50 mg/kg, p.o. Group 4: Mitragynine (MG) × 2/day: Day 5: 80 mg/kg, p.o. Day 6: 70 + 60 mg/kg, p.o. Day 7: 50 + 40 mg/kg, p.o. Group 5: Mitragynine Pseudoindoxyl (MP) × 2/day: Day 5: 30 + 20 mg/kg, s.c. Day 6: 15 + 10 mg/kg, s.c. Day 7: 3 + 1 mg/kg, s.c. Day 8: Group 1: (n = 10) Saline, i.p.; Group 2: Morphine (25 mg/kg, i.p.); Group 3: KAE (40 mg/kg, p.o.); Group 4: MG (25 mg/kg, p.o.); Group 5: MP (1 mg/kg, s.c.). All groups were administered naloxone (10 mg/kg, i.p.) 120 min post-respective day 5 am treatment then observed for withdrawal behaviors [i.e., forepaw licking (b), mouse straightening (c), rearing (d), frequency of diarrhea (e), forepaw tremor (f), teeth chattering (g), wet dog shakes (h), and jumping frequency (i)] 120 min post-respective day 5 am treatment then observed for withdrawal behaviors [i.e., forepaw licking (b), mouse straightening (c), rearing (d), frequency of diarrhea (e), forepaw tremor (f), teeth chattering (g), wet dog shakes (h), and jumping (i)] *p < 0.05 versus vehicle control, ^#p < 0.05 versus morphine, one-way RM ANOVA with Tukey’s multiple comparisons post hoc test. n = 9–10 mice/treatment. ^†Mean and SEM lower than 1