Kanna

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^[7][8] (can be fermented to form Δ⁷-Mesembrenone^[9])
• Mesembrenone^[7][8]
• Mesembrenol^[7][8]
• Mesembranol^[7][8]

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

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

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

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

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 (K_i) 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

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

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

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

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

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

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