Sceletium tortuosum

Also known as Kanna, sceletium tortusoum is a herb that is traditionally chewed prior to stressing endeavours. It suggest that it may play a role in reducing state anxiety although more evidence is required.

This page features 27 unique references to scientific papers.

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Summary

All Essential Benefits/Effects/Facts & Information

Sceletium tortuosum is a herb known as Kanna which is traditionally known as a psychoactive herb. It is not known to be hallucinogenic nor habit forming but is taken prior to stressing events such as hunting (traditional use) for its cognitive effects.

Limited evidence does not suggest any improvement in reaction time or many parameters of cognitive performance such as memory although there may be an attenuation of state anxiety. State anxiety refers to the increase in anxiety experienced during a high stress event (such as a cognitive or physical test) and administration of Kanna prior to these events may reduce how much anxiety is experienced and thus the deleterious effects of anxiety on performance.

While the mechanisms as to why Kanna exerts these effects is not conclusively known, it is known to influence the amygdala of the brain (a brain region central in emotional processing) and is known to also have inhibitory effects on both the serotonin transporter as well as an enzyme known as phosphodiesterase 4 (PDE4); both of these proteins existing in the amygdala.

While there is not enough evidence to currently recommend Kanna, its main role of reducing state anxiety appears promising and there are a few other claims (such as antidepressive effects) which remain untested.

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Things To Know

Also Known As

Kanna, Channa, Kougoed

Things to Note

  • Kanna is referred to as a hallucinogen, but does not appear to have this property when taken in isolation

  • Due to having high affinity for the serotonin transporter, it is plausible that Kanna can interfere with SSRI pharmaceuticals

Is a Form Of

Caution Notice

May interfere with neurally active pharmaceuticals due to having a similar mechanism

Examine.com Medical Disclaimer

How to Take

Recommended dosage, active amounts, other details

Currently studies using Kanna have used the brand name Zembrin® at doses of 8-25mg prior to cognitive testing. This brand name is a 2:1 concentration of Kanna based on dry weight and is considered equivalent to 16-50mg of the dry weight of the plant itself.

Kanna has been studied as oral administration (capsules) but traditionally the leaves have been chewed and saliva swallowed for similar effects.

Optimal frequency of dosing (ie. either only on testing days or daily) is currently not known.

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Human Effect Matrix

The Human Effect Matrix looks at human studies (it excludes animal and in vitro studies) to tell you what effects sceletium tortuosum has on your body, and how strong these effects are.

Grade Level of Evidence
Robust research conducted with repeated double-blind clinical trials
Multiple studies where at least two are double-blind and placebo controlled
Single double-blind study or multiple cohort studies
Uncontrolled or observational studies only
Level of Evidence
? The amount of high quality evidence. The more evidence, the more we can trust the results.
Outcome Magnitude of effect
? The direction and size of the supplement's impact on each outcome. Some supplements can have an increasing effect, others have a decreasing effect, and others have no effect.
Consistency of research results
? Scientific research does not always agree. HIGH or VERY HIGH means that most of the scientific research agrees.
Notes
Anxiety Minor - See study
In high cognitive load tests, there appears to be a reduction in state anxiety (anxiety that arises during the testing) associated with Kanna compared to placebo. This reduction in anxiety does not occur during low load tests, and chronic anxiety has not yet been assessed.
Cognition Minor - See study
A general increase in cognition has been noted with Kanna usage prior to testing in otherwise healthy middle-aged adults, potentially related to the reduction in state anxiety during testing.
Executive Function Minor - See study
According to the CNS Vital SignR test in middle aged adults, pre-testing administration of Kanna appeared to increase executive function when compared to placebo.
Sleep Quality Minor - See study
There appeared to be a barely significant increase in self-reported sleep quality with Kanna usage compared to placebo when taken prior to a cognitive test.
Blood Pressure - - See study
Three weeks Kanna usage does not appear to influence blood pressure compared to placebo.
Heart Rate - - See study
Three weeks Kanna usage does not appear to influence heart rate when compared to placebo.
Memory - - See study
Acute supplementation of Kanna prior to testing does not appear to influence acute memory formation or retention when compared to placebo.
Reaction Time - Very High See 2 studies
In response to cognitive testing involving reaction time, administration of Kanna prior to testing does not appear to outperform place in improving reaction time.
Subjective Well-being - - See study
While there are isolated instances of increased well-being, they do not appear to occur frequently enough in otherwise healthy adults to cause a whole-group increase in well-being.


1Sources and Composition

1.1. Origin and Composition

Sceletium tortuosum (of the family Aizoaceae; subfamily Mesembryanthemaceae) is an African herb more commonly known as Kanna, which is traditionally chewed (traditionally by hunter-gatherers) for its mood altering properties and for coping[1][2] and modernly used as a 'legal high' despite not having any known hallucinogenic properties and likely related to reports that it may increase the euphoric effect of Marijuana when coadministered.[1]

The related species known as sceletium crassicaule also appears to produce the main four psychoactive alkaloids and is visually similar.[3] Kanna plants are produced in South Africa[3] where many[4][5] (but not all[6]) human studies arise from.

Kanna is a plant that has traditionally been chewed by people in the areas it grows (Southern African regions) for its mood-enhancing properties, typically used in cognitively stressing situations such as hunting or coping

Sceletium tortuosum (henceforth Kanna) tends to contain the alkaloids:

Mesembrine and Mesembrenone are thought to be the major alkaloids, as the former is confirmed to be a potent serotonin reuptake inhibitor (SRI) in vitro whereas the latter is a dual SRI and PDE4 inhibitor. The crude plant is said to have a variable range of 0.05-2.3% alkaloids by weight.[4][10]

The major components of Kanna are the four alkaloids which are known to have psychoactive properties. Further components of the plant do not appear to be well fleshed out in Western literature

1.2. Formulations and Variants

A brand name known as Zembrin® has been used in human[6][4] and rodent toxicology studies[11] which is a 2:1 concentration of the plant, standardized to a range of 0.35-0.45% alkaloids by weight[11] (human studies had 0.4%[6][4]) and a 70/30 ethanolic/water extraction. Of the alkaloids, mesembrenone and mesembrenol collectively form more than 60-70% while mesembrine is less than 20%.[11][4]

Zembrin® is a brand name of Kanna that has been used in many studies assessing Kanna, and appears to simply be a two-fold concentrated product (where 25mg of Zembrin® is equivalent to 50mg of the dried plant mass) which retains the alkaloids

The plant is traditionally fermented for its psychoactive properties[9] and is thought to have a lower oxalic acid content due to fermentation[1] although unfermented plant parts still appear active when orally administered.[12] This prepared product which is produced via week-long fermentation is referred to as 'Kougoed', can also be made from sceletrium emarcidum, is claimed to have a psychostimulatory effect "not unlike that of tobacco".[2][1]

There is a fermented product of Kanna referred to as 'Kougoed' which also has psychoactive properties although they are reported to differ from raw Kanna products. No comparative studies have yet been conducted


2Pharmacology

2.1. Absorption

When assessing the four alkaloids of Kanna across oral (buccal and sublingual) and intestinal membranes it appeared that all four alkaloids were able to cross membranes with the greatest absorption across mesembrine followed by mesembranol while mesembrenol and mesembrenone were lower;[13] all compounds were absorbed through both intestinal and oral membranes, with higher absorption rates in the intestines when compared to the oral cavity and absorption occurring both in pure forms as well as extracts.[13]

Traditional usage of Kanna involved chewing the herb and is thought to rely on buccal absorption.[13]

In vitro studies suggest that the alkaloids of Kanna pass through most membranes, thought to implicate its activity following both oral ingestion and chewing of the product

2.2. Metabolism

Mesembrenone appears to be metabolized into N-demethyl and N-demethyl-dihydro metabolites which are eliminated in the urine (of the rat) and in human liver slices while mesembrine appeared to have multiple metabolites involving demethylatio and/or hydroxylation.[14]

There appears to be partial conjugation of these metabolites by both glucuronidation (via UGT enzymes) and sulfation (via SULTs) in phase II metabolism.[14]

The alkaloids of Kanna are subject to both Phase I and Phase II metabolism and can produce various metabolites; the activity of these metabolites in the body, relative to the parent compounds, has not yet been assessed


3Neurology

3.1. Serotonergic Neurotransmission

Kanna appears to have inhibitory effects on the serotonin transporter (SERT) with an IC50 of 4.3μg/mL[8] thought to be due to its alkaloid content as one of them, mesembrine, has an affinity (Ki) of 1.4nM towards this transporter.[8]

It is thought that this is relevant to supplementation of Kanna as serotonin reuptake inhibits are used in the treatment of anxiety[15] and oral ingestion of 25mg of a 2:1 concentrated extract has been noted to affect the amygdala of humans reducing state anxiety.[5]

Some alkaloids in Kanna have affinity towards the serotonin transporter, particularly mesembrine, which is thought to occur after administration of Kanna due to the low concentration required

3.2. Miscellaneous Mechanisms

Phosphodiesterase 4 (PDE4) is an enzyme that degrades the signalling molecule cAMP, a stimulatory signalling molecule within neurons via activating the protein known as CREB (CREB activation helps mediate synaptic plasticity and growth[16]). Overactive PDE4 degrades cAMP and thus reduces CREB activation while inhibiting PDE4 can increase CREB activation from not degrading as much cAMP.

Inhibiting PDE4 has been noted with the pharmaceutical Rolipram[17] and some other nutraceuticals such as Caffeine[18] or Resveratrol[19] and is thought to be a mechanism by which Kanna acts. The other known mechanism, serotonin reuptake, has been noted by other drugs to upregulate PDE4[20] leading to suggestions that the two mechanisms may be complementary (serotonin reuptake inhibitors are also anti-emetic, which is the main side-effect of PDE4 inhibitors in practise[5][21] even when highly selective for PDE4[22]).

When tested in vitro, the plant extract of Kanna is able to inhibit PDE4 with an IC50 of 8.5μg/mL.[8] The alkaloid mesembrenone appears to be most effective in inhibiting PDE4 with an IC50 lesser than 1μM.[8]

Another main mechanism of Kanna is inhibition of PDE4, which would promote the accumulation of cAMP in the regions where PDE4 is inhibited. As this enzyme and its isoforms are present in numerous brain regions it is thought to contribute to the psychoactive effects of Kanna

3.3. Addiction and Obsession

In rats administered Kanna there did not appear to be any influence of conditioned place preference suggesting no habit forming properties.[23]

Limited evidence suggest no habit forming properties of Kanna when tested in rats

3.4. Anxiety and Stress

When tested in rats, 5mg/kg or 20mg/kg of a Kanna extract for just over two weeks alongside restraint stress noted that supplementation reduced anxiety (assessed by elevated maze test) and attenuated the increase in corticosterone;[12] the lower dose appeared to be slightly more effective than the higher dose for these parameters while the higher dose seemed better at preventing immune system-related abnormalities (assessed by serum biomarkers).[12]

State anxiety refers to an anxious feeling in response to a high-load situation which involves higher than normal activity in the brain region known as the amygdala.[24] State anxiety can impair cognitive performance during high load tests, and is not inherently related to chronic anxiety. Agents which can reduce state anxiety are said to have a calming effect during testing.

25mg of a 2:1 extract of Kanna taken prior to a perceptual-load task (PLT; assesses reaction time and can induce state anxiety) found that while supplementation of Kanna failed to improve performance that it reduced the reactivity of the amygdala in response to the test, thereby reducing state anxiety relative to placebo.[5]

State anxiety, or anxiety induced by cognitive stress, appears to be attenuated when Kanna is taken prior to the testing. This effect is thought to underlie the traditional claims of coping and usage prior to high stress situations

3.5. Depression

In rats, administration of the herb appears to have some antidepressive properties as assessed by a forced swim test but also produced ataxia (loss of voluntary muscle control) as assessed by a rotarod test.[23]

When assessing mood, it has been noted that there was a trend for improvement in the HAM-D of nondepressed subjects given 25mg of a 2:1 plant extract when compared to placebo (26.9% decrease relative to 13.8% in placebo)[6] while elsewhere supplementation of this does or a lower one (8mg of the same 2:1 extract) during a side-effect assessment there were unsolicited reports of 'uplifted spirits' with supplementation but not placebo.[4]

The herb may influence depression, but currently there is no good evidence to support this claim. No studies currently exist in subjects with depressive symptoms at baseline

3.6. Memory and Learning

One study in 16 otherwise cognitively healthy middle-aged adults (45-65yrs) found supplementation of 25mg of a 2:1 Kanna extract containing 0.4% total alkaloids (mesembrenone, mesembrenol, mesembrine, and mesembranol) was able to improve executive function and cognitively flexibility when compared to control and assessed by the CNS Vital Signs test;[6] this same study failed to find improvements in parameters of memory (verbal, visual, and composite memory), reaction speed, and complex attention when compared to placebo treatment.[6]

An improvement in general cognition has been noted in one study although not related to any acute improvements in memory formation and function


4Safety and Toxicology

4.1. General

Administration of Kanna in rats at high doses over two weeks failed to show any toxicological signs up to the no observable adverse effect limit (NOAEL) of 5,000mg/kg bodyweight, which is approximately 1,800-fold higher than the recommended human intake of 25mg daily.[11] Supplementation of the highest dose in the 90 day group (600mg/kg) also failed to exert any clinical, hematological, or histological toxic effects in the tested rats.[11]

Supplementation of 8mg or 25mg of a 2:1 Kanna extract daily for three months in otherwise healthy adult subjects did not appear to be associated with any alterations in cardiovascular parameters (blood pressure, pulse or breathing rate) or subjectively reported side-effects;[4] hematological measurements not taken.

Preliminary studies on Kanna have not found any apparent toxicological effects when taken in humans over three weeks at the supplemental dose (25mg) or in rats given higher than recommended doses

Scientific Support & Reference Citations

References

  1. Smith MT1, et al Psychoactive constituents of the genus Sceletium N.E.Br. and other Mesembryanthemaceae: a review . J Ethnopharmacol. (1996)
  2. Stafford GI1, et al Review on plants with CNS-effects used in traditional South African medicine against mental diseases . J Ethnopharmacol. (2008)
  3. Shikanga EA1, et al A novel approach in herbal quality control using hyperspectral imaging: discriminating between Sceletium tortuosum and Sceletium crassicaule . Phytochem Anal. (2013)
  4. Nell H1, et al A randomized, double-blind, parallel-group, placebo-controlled trial of Extract Sceletium tortuosum (Zembrin) in healthy adults . J Altern Complement Med. (2013)
  5. Terburg D1, et al Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus . Neuropsychopharmacology. (2013)
  6. Chiu S1, et al Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia . Evid Based Complement Alternat Med. (2014)
  7. Roscher J1, et al Forensic analysis of mesembrine alkaloids in Sceletium tortuosum by nonaqueous capillary electrophoresis mass spectrometry . Electrophoresis. (2012)
  8. Harvey AL1, et al Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids . J Ethnopharmacol. (2011)
  9. Patnala S1, Kanfer I Investigations of the phytochemical content of Sceletium tortuosum following the preparation of "Kougoed" by fermentation of plant material . J Ethnopharmacol. (2009)
  10. Gericke N1, Viljoen AM Sceletium--a review update . J Ethnopharmacol. (2008)
  11. Murbach TS1, et al A toxicological safety assessment of a standardized extract of Sceletium tortuosum (Zembrin(®)) in rats . Food Chem Toxicol. (2014)
  12. Smith C1 The effects of Sceletium tortuosum in an in vivo model of psychological stress . J Ethnopharmacol. (2011)
  13. Shikanga EA1, et al In vitro permeation of mesembrine alkaloids from Sceletium tortuosum across porcine buccal, sublingual, and intestinal mucosa . Planta Med. (2012)
  14. Meyer GM1, et al GC-MS, LC-MSn, LC-high resolution-MSn, and NMR studies on the metabolism and toxicological detection of mesembrine and mesembrenone, the main alkaloids of the legal high "Kanna" isolated from Sceletium tortuosum . Anal Bioanal Chem. (2014)
  15. Pringle A1, et al A cognitive neuropsychological model of antidepressant drug action . Prog Neuropsychopharmacol Biol Psychiatry. (2011)
  16. Benito E1, Barco A CREB's control of intrinsic and synaptic plasticity: implications for CREB-dependent memory models . Trends Neurosci. (2010)
  17. MacKenzie SJ1, Houslay MD Action of rolipram on specific PDE4 cAMP phosphodiesterase isoforms and on the phosphorylation of cAMP-response-element-binding protein (CREB) and p38 mitogen-activated protein (MAP) kinase in U937 monocytic cells . Biochem J. (2000)
  18. Rivera-Oliver M1, Díaz-Ríos M2 Using caffeine and other adenosine receptor antagonists and agonists as therapeutic tools against neurodegenerative diseases: a review . Life Sci. (2014)
  19. Chung JH1 Metabolic benefits of inhibiting cAMP-PDEs with resveratrol . Adipocyte. (2012)
  20. Ye Y1, Jackson K, O'Donnell JM Effects of repeated antidepressant treatment of type 4A phosphodiesterase (PDE4A) in rat brain . J Neurochem. (2000)
  21. Cashman JR1, et al Stereoselective inhibition of serotonin re-uptake and phosphodiesterase by dual inhibitors as potential agents for depression . Bioorg Med Chem. (2009)
  22. Rock EM1, et al Potential of the rat model of conditioned gaping to detect nausea produced by rolipram, a phosphodiesterase-4 (PDE4) inhibitor . Pharmacol Biochem Behav. (2009)
  23. Loria MJ1, et al Effects of Sceletium tortuosum in rats . J Ethnopharmacol. (2014)
  24. Bishop SJ1, Jenkins R, Lawrence AD Neural processing of fearful faces: effects of anxiety are gated by perceptual capacity limitations . Cereb Cortex. (2007)
  25. Chiu S, et al Proof-of-Concept Randomized Controlled Study of Cognition Effects of the Proprietary Extract Sceletium tortuosum (Zembrin) Targeting Phosphodiesterase-4 in Cognitively Healthy Subjects: Implications for Alzheimer's Dementia . Evid Based Complement Alternat Med. (2014)
  26. Terburg D, et al Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus . Neuropsychopharmacology. (2013)
  27. Nell H, et al A randomized, double-blind, parallel-group, placebo-controlled trial of Extract Sceletium tortuosum (Zembrin) in healthy adults . J Altern Complement Med. (2013)

(Common misspellings for Sceletium tortuosum include kana, seletium)