Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.

AIMS: Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored. MAIN METHODS: Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS. KEY FINDINGS: The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure. SIGNIFICANCE: Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids.

Kratom (Mitragyna Speciosa) Liver Injury: A Comprehensive Review.

Kratom (Mitragyna speciosa) leaves contain the mu opioid partial agonists mitragynine and 7-hydroxymitragynine. The US Drug Enforcement Agency considers it a 'drug of concern', and the US FDA is reviewing kratom, but there is a paucity of information regarding health effects. Liver injury is often cited as a potential health consequence, however the same few case reports are repeatedly referenced, without a broader context. Furthermore, reports have largely lacked standardized causality assessment methods. The objective is to evaluate causality in kratom liver injury, through a comprehensive scoping review of human cases, and by reviewing epidemiologic, animal, and mechanistic reports that relate to kratom liver injury. Hepatotoxicity causality was systematically examined using the Roussel Uclaf Causality Assessment Method (RUCAM) for case reports. Biopsy findings, potential pathophysiologic mechanisms, and management options are discussed. This review identified 26 case reports and abstracts, in addition to 7 cases reported from the Drug-Induced Liver Injury Network, 25 in FDA databases, and 27 in internet user forums. Latency periods to symptom onset had a median of 20.6 days and mean of 21 days (range 2-49). Common presenting signs and symptoms were abdominal discomfort, jaundice, pruritis, and dark urine. Histologic findings were predominantly cholestatic, although, biochemically, the condition was heterogenous or mixed; the median R ratio was 3.4 and the mean was 4.6 (range 0.24-10.4). Kratom likely causes liver injury based on the totality of low-quality human evidence, and, in the context of epidemiologic, animal, and mechanistic studies. It remains unclear which subgroups of users are at heightened risk.

Risk of breast cancer in relation to the use of rauwolfia alkaloids.

In a case-control study of 1881 women with breast cancer and 1523 controls with benign conditions, 65 cases (3.5%) and 64 controls (4.2%) reported having used a drug that contained rauwolfia, giving a rate ratio estimate of 0.8 (95% confidence interval, 0.5-1.1). Use that ended more than a year previously was negatively associated with breast cancer (rate ratio, 0.5; 95% confidence interval, 0.2-0.9). The risk of breast cancer did not vary significantly according to duration of use. Nor did it vary within strata of varying base-line risk, such as age at first pregnancy. The data suggest that rauwolfia alkaloids do not increase the risk of breast cancer.

Rauwolfia and breast cancer: no relation found in long term users age fifty and over.

It has been suggested that conflicting findings regarding rauwolfia drugs as predisposing factors for breast cancer can be explained by the hypothesis that use for a long duration predisposes to breast cancer occurring after age 50. In a follow-up study of 2077 women who received prescriptions for rauwolfia drugs there was no excess risk for breast cancer diagnosed at age 50 or greater (morbidity ratio = 0.9 compared to 1.0 expected). In comparing 35 patients in this age group with 168 women who received rauwolfia but remained free of breast cancer, there was no excess risk for long (greater than or equal to 5 yr) duration of use (relative risk = 0.9). Thus, the hypothesis could not be confirmed in this study group. It is likely that the excess risk among long-duration rauwolfia users, if present at all, is less than 2-fold.

Plasma prolactin levels in women at postmenopausal age with a family history of breast cancer or a prescription for antihypertensive Rauwolfia treatment.

An investigation was made of daytime plasma prolactin levels in three groups of women aged 50 to 64 years: (1) 139 women with a family history of breast cancer; (2) 50 women on Rauwolfia treatment for hypertension, and (3) 90 women of a control group. A significant difference in prolactin levels was found between groups 2 and 3 but not between 1 and 3. These findings are considered in relation to the results of a breast cancer screening programme in which the women took part. Here, it was the women with a family history of breast cancer who showed an increased breast cancer risk, whereas the risk in women on Rauwolfia was not significantly higher than expected on the basis of the experience among controls. It is concluded that the role of prolactin in the etiology of breast cancer is still not clear.

Neuroleptic-induced prolactin level elevation and breast cancer: an emerging clinical issue.

This article reviews the evidence that neuroleptics may increase the risk of breast cancer via their effects on prolactin secretion. All available neuroleptics, including reserpine, raise serum prolactin levels. Elevated serum prolactin level increases the incidence of spontaneously occurring mammary tumors in mice, and increases the growth of established carcinogen-induced mammary tumors in rats. Caution is necessary in extrapolating this relationship to human mammary tumors because human and rodent tumors differ in some important characteristics, including hormone responsiveness. Serum prolactin levels in women with, or at risk for, breast cancer have generally been normal, and only a minority of human mammary tumors respond to changes in serum prolactin levels. Epidemiologic studies have failed to demonstrate an increased risk of breast cancer associated with the use of neuroleptics or reserpine. Thus, although some human mammary tumors are prolactin dependent, the available evidence does not demonstrate an increased risk of breast cancer in women receiving neuroleptics. We conclude that (1) additional epidemiologic studies of the incidence of mammary tumors in women treated with neuroleptics are desirable; (2) it is premature to mandate warning patients of an unknown and undemonstrated increase in the risk of developing breast cancer associated with neuroleptic treatment; (3) detection of existing mammary tumors by breast examination prior to administration of neuroleptics is desirable; and (4) development of antipsychotic drugs that do not increase serum prolactin level may be indicated.

Rauwolfia derivatives and breast cancer in hypertensive women.

Three groups of women were selected from a sample of death certificates that had been coded by the Office of Population Censuses and Surveys for all conditions mentioned on them: (1) all women with reference to both breast cancer and hypertension; (2) all women with reference to hypertension and other cancers; (3) a group of women with reference to hypertension without cancer, selected to match the breast-cancer patients with respect to five features. When the women with breast cancer were compared with both the women with other cancers and the women without cancer, there was a positive association between breast cancer and the use of rauwolfia derivatives, although neither the differences in the frequency nor duration observed were statistically significant. The association appeared to be strongest for use near the time of diagnosis of the cancer. This agrees with nearly all other data and would be expected if rauwolfia derivatives promoted the development of breast cancer from previously initiated cells.

Rauwolfia derivatives and breast cancer. A case/control study in Olmsted County, Minnesota.

In response to three reports of an association between rauwolfia derivatives and breast cancer, a case/control study was undertaken in Olmsted County, Minnesota. Comparison of a cohort of women with breast cancer to an age-match cohort of women with cholelithiasis failed to show any meaningful differences in the two groups except with respect to a history of hypertension. The rates of use of rauwolfia derivatives by hypertensive cases and controls were identical--which, along with other considerations, leads to the conclusion that an association between the use of rauwolfia derivatives and breast cancer is unlikely.

Reserpine and breast cancer in a retirement community.

In an attempt to confirm three reports suggesting a causal link between rauwolfia antihypertensive drugs and female breast carcinoma, all cases of such cancer appearing among the residents of an affluent retirement community were compared with controls chosen from a roster of all women in the same community. Most residents use a single care facility, and patterns of hypertension diagnosis, rauwolfia and other drug use, and medical-care-system patronage were abstracted from medical records. The prevalence of recorded rauwolfia use among the controls were 20 per cent, and that of other drug use was correspondingly high. The risk ratio for rauwolfia use was estimated to be 1.2 (95 per cent confidence interval, 0.7 to 2.2). Risk ratios between 1.0 and 2.0 were also found for other drug use and for measures of care-system patronage. These results do not support the hypothesis that reserpine causes breast cancer.

[Breast cancer in women as a paradigm for ageing as a hidden syncarcinogenic factor]. / Das Altern als larvierter synkarzinogener Faktor. Beispiel: Das Mammakarzinom der Frau

In man the application of so-called cancerogenic factors and the latency period of a neoplasm until its manifestation includes the factor of biological ageing. There are in humans relationships between age, localisation and incidence of tumour which can retrospectively appear as syncarcinogenic factors. Using breast carcinoma in women as an example, it is shown that a carcinogenic effect cannot be demonstrated for two of the supposed carcinogenic factors, namely repeated diagnostic radiographic measures and administration of Rauwolfia-alkaloid containing drugs.