Reviewed: Nell H, Siebert M, Chellan P, Gericke N. A randomized, double-blind, parallel-group, placebo-controlled trial of extract Sceletium tortuosum (Zembrin^®) in healthy adults. J Altern Complement Med. February 2013; [epub ahead of print]. doi: 10.1089/acm.2012.0185.

Sceletium (Sceletium tortuosum, Aizoaceae) is a short-lived perennial plant that is indigenous to the Namaqualand and Karoo region of South Africa. The plant has a documented history of use as a medicinal herb in this region that dates back to the mid-1600s. In 1738, it was proclaimed “the greatest cheerer of the spirits, and the noblest restorative in the world.”¹ In S. tortuosum, there exists a wide intraspecies chemotypic variation that has resulted in an extremely broad range of clinical applications. According to the authors, preparations (dry herb used as a masticatory, and, less often, as a tea) made from S. tortuosum leaves, stems, and sometimes roots are used to relieve thirst, hunger, and fatigue, and for the plant’s restorative, mood-elevating, and sedative effects, including its therapeutic use for anxiety and depression. Intoxication and euphoria are also reported with its use, particularly with fermented material that includes roots.² In clinical case reports, anxiolytic and antidepressant activities have been observed with consumption of tablets and capsules of milled sceletium above-ground plant material.³

These authors conducted a randomized, double-blind, parallel-group, placebo-controlled trial to evaluate the safety and tolerability of two different doses of Zembrin^® (extract manufactured by Gehrlicher GmbH; Eurasburg, Germany; capsules manufactured by Pharmaceutical Contractors [Pty] Ltd.; Isando, South Africa) — a proprietary standardized and characterized commercial dry extract of sceletium aerial parts — in healthy adults.

Zembrin is a 2:1 dry aqueous-ethanolic extract of the entire aboveground portions of a cultivated selection of naturally occurring S. tortuosum, with an alkaloid content of not less than 0.38% by weight and having a specific profile of the mesembrine alkaloids. Safe daily doses of raw, unprocessed S. tortuosum herb are reported to vary from 50 mg to 5,000 mg, a range that is due to both the chemotypic variability and the intended use. The authors selected low doses of 8 mg and 25 mg of Zembrin (equivalent to 16 mg and 50 mg, respectively, of crude S. tortuosum herb), considering the doses to be safe and to have potential for inclusion in functional food and dietary supplement products. The Zembrin used in this study was standardized to 0.4% w/w total for four alkaloids, including mesembrenol, mesembrenone, mesembrine, and mesembranol. Each gelatin capsule contained 0 mg, 8 mg, or 25 mg of the sceletium dry extract, as well as various excipients.

A preliminary screening visit was followed by a two-week placebo run-in period during which 37 subjects recorded their daily use of placebo medication to assess compliance. At the third visit, the subjects were randomly assigned to one of the following three treatment groups for three months: 12 subjects were allocated to the 8 mg Zembrin group, 12 to the 25 mg Zembrin group, and 13 to the placebo group. All but one subject completed the trial. The 37 healthy men and nonpregnant women (no gender differentiation provided) were between 18 and 55 years of age, weighed >50 kg (>110.2 lb), and had a body mass index ranging from 18.5 to 29.9 kg/m².

Visits three, four, five, and six were scheduled monthly. At visits two, three, four, and five, the subjects were given a diary and asked to record the occurrence of adverse events (AEs), their daily use of the study product, and the intake of other medications. Safety assessments performed at the screening visit and at visits four, five, and six included vital signs; physical examination; hematology, biochemistry, and urine analysis; 12-lead electrocardiogram (ECG); and the recording of patient-reported adverse events AEs.

The authors report that the greatest incidence of AEs occurred in the placebo group, followed by the 25 mg and 8 mg Zembrin groups. Twenty-two of the 37 total assigned subjects (59%) experienced at least one AE. Four of the 12 subjects (33.3%) in the 8 mg group reported six AEs. Seven of the 12 subjects (58.3%) in the 25 mg group reported 14 AEs, and 11 of the 13 subjects (84.6%) in the placebo group reported 22 AEs.

Headache was the most common AE, with eight incidences reported by seven of the 37 subjects (18.9%). Of those, four occurred in four subjects in the placebo group, three in two subjects in the 25 mg Zembrin group, and one in one subject in the 8 mg Zembrin group. Other AEs included abdominal pain (five incidences in three of the 13 subjects in the placebo group), upper respiratory tract infection (four incidences in four of the 13 subjects who received placebo), and influenza (three incidences in three subjects; one from each group).

All but two AEs were mild or moderate and were considered unrelated to the study medication. The two severe AEs were reported in the placebo group. One subject reported abdominal pain, which was considered as possibly related to the study product. One subject who complained of headache, which was considered as probably related to the study product, withdrew from the trial.

The authors reported no marked, clinically relevant differences in the changes in vital signs among the three treatments, except for a difference in diastolic blood pressure (DBP) between the placebo and the 8 mg Zembrin groups. Among those in the 8 mg group, a mean increase in DBP of 1.92 mmHg occurred from the screening visit to visit six; the subjects in the placebo group experienced a mean decrease in DBP of 6.17 mmHg. This resulted in a mean difference of 8.08 mmHg (95% confidence interval: 1.51-14.65) between those two treatments (P=0.02). No such significant difference in DBP was seen between the 25 mg Zembrin group and the placebo group.

Other safety results showed no differences among the three treatments in ECG or physical examination findings during the three months, and no significant changes were observed in laboratory parameters or in body weight.

Five subjects offered unsolicited positive comments in their study diaries about changes in their mental/emotional health. These comments were from one subject (8.3%) in the 8 mg Zembrin group, three subjects (25%) in the 25 mg Zembrin group, and one subject (7.7%) in the placebo group, and included sleeping better at night, coping better with stressful situations, and feeling better in general.

According to the authors, the spectrum of reported sceletium uses suggests a dose response that is specific to the alkaloid content and profile. The lowest doses are ingested at the food side of the spectrum, higher doses at the botanical medicine side, and the highest doses at the intoxicating end of the spectrum. “In addition to dose-response for total alkaloid content, the alkaloid composition is likely to be a key factor that determines effects and adverse effects,” wrote the authors.

The results of this trial show that both treatments of Zembrin at doses of 8 mg and 25 mg once daily for three months were well tolerated and safe.

One of the authors, Nigel Gericke, discloses that he is the director of medical and scientific affairs of HG&H Pharmaceuticals (Pty) Ltd in South Africa, the company that developed Zembrin.

—Shari Henson

References

1. Kolben P. Medley G, trans. The Present State of the Cape of Good-Hope. Vol. 1, 2nd ed. London, UK: Printed for W. Innys and R. Manby; 1738.
2. Gericke N, Viljoen AM. Sceletium — a review update. J Ethnopharmacol. 2008;119(3):653-663.
3. Gericke N. Clinical application of selected South African medicinal plants. Australian Journal of Medical Herbalism. 2001;13(1):3-7,9-11,13-15.