(Cross-posted from the subreddit - HUGE shout out to tfgust on reddit who wrote this entire thing like 3 years ago)

Kanna (sceletium tortuosum) contains multiple psychoactive alkaloids which have distinct pharmacological profiles and effects. Kanna products and extracts can have vastly different alkaloid compositions depending on the strain of the plant, time harvested, and preparation methods used.

Different kanna products often standardize for one or several of these alkaloids. For example, the makers of the kanna supplement Zembrin specifically attempt to reduce the amount of mesembrine in their product to achieve a certain affect. Liftmode, however, attempts to have a high amount of mesembrine in some of their products.

This post will be broken into 3 parts. The first will cover the general effects of kanna. The second will discuss the major psychoactive alkaloids present in kanna, their pharmacological profiles, and their subjective effects. The third will explain the pharmacological functions of kanna and their effects.

I. Your Guide to the Effects of Kanna

This section summarizes the known effects of kanna and all of its alkaloids.

Common Subjective Effects

These effects vary based on the dosage, ROA, and alkaloid composition:

• Antidepressant effects (comparable in strength to prescription SSRI medications)
• Anxiety suppression (significant)
• (Very) Mild physical euphoria (in high doses or when smoked/snorted)
• Mild cognitive euphoria (in high doses or when smoked/snorted). Don't expect to get "high" like you would from alcohol, marijuana, or hard drugs. This effect is often described as a feeling of "tranquility", "bliss", or "post-orgasm", and although quite noticeable, the sheer euphoria itself from kanna is not very intense. Please note that the combined effects of kanna are not mild.
• Dose-dependent sedation or stimulation
• A "rush" of stimulation (especially when smoked/snorted)
• Increased or decreased heart rate, as well as either vasodilation/vasoconstriction
• Tranquil "afterglow"
• Appetite suppression
• Mild pain relief
• Mild tactile enhancement
• Pupil dilation (usually mild, but acute in some people)
• Mild empathogenic effects (e.g. empathy, affection, feelings of interconnectedness)
• Increased sociability
• Increased libido
• Motivation enhancement
• Mild motor control impairment (when taken in extreme doses)
• IN VERY HIGH DOSES (8x the minimum noticeable dosage, NOT recommended):
  • Extreme pupil dilation
  • Very blurry vision, light sensitivity
  • May worsen pre-existing HPPD
  • Increased body temperature
  • Heavy sweating
  • Mild discomfort in chest
  • Muscle relaxation
  • Inexplicable numbness in teeth or facial region (locals once used kanna to treat toothaches)
  • Mildly-moderately strong, unique state of intoxication - no impairment of motor function. Mildly resembles dissociation. Sounds will feel far away.
  • Euphoria does not appear to increase with higher doses - it is still mild.
  • Panic attacks or feelings of anxiety are likely to occur.

Duration of Action

Relatively little is known about the half-life of kanna's alkaloids in humans. Subjective reports indicate that when taken orally, kanna's duration of action is 4-6 hours long, and its onset occurs after 30-60 minutes. When taken via intranasal administration (snorted), the effects of kanna lasts for 30-90 minutes (peaking around 5-10 minutes) and its onset occurs between 0-5 minutes.

Kanna's apparently brief duration of action is the primary reason it is seldom used as an antidepressant in modern medicine. SSRI medications are thought to work by slowly increasing neuroplasticity due to their long duration of action, and therefore, kanna was initially (and perhaps wrongfully) dismissed for its supposed inability to affect neuroplasticity like typical SSRIs. It has since been shown that kanna may actually cause increases in neuroplasticity more quickly than typical SSRI medications due to its PDE4 inhibition and VMAT-2 upregulation. In other words, whereas most antidepressants supposedly take 4-6 weeks to start working, kanna might begin working immediately.

II. Pharmacology of Kanna's Alkaloids

Mesembrine

Mesembrine is the most notable psychoactive alkaloid present in kanna. Mesembrine acts as a VMAT-2 upregulator, serotonin reuptake inhibitor, PDE4 inhibitor, mild MAO-A inhibitor (this effect is nearly negligible), and a mild reversible AChE inhibitor. VMAT-2 upregulation appears to be the primary function of mesembrine, although this alkaloid is also a very potent serotonin reuptake inhibitor (SRI).

Mesembrine-rich kanna extracts/products have antidepressant and anxiolytic activity that feels similar to clinically used SSRIs. Mesembrine may prevent drug and food cravings, and may have other medical applications besides the treatment of depression. In addition, however, mesembrine-rich kanna can cause a stimulating "rush", mild euphoria, and mild intoxicating effects (these are most notable when mesembrine-rich kanna extracts are insufflated/snorted). Mesembrine is why some people are able to get mildly "high" on kanna. Despite this mild "euphoria", mesembrine has been shown to have minimal to negligible abuse liability and does not cause physical addiction nor withdrawal (long term use of kanna may cause a minor withdrawal syndrome that is similar to but weaker than that of clinically used SSRIs). Mesembrine can also induce mild empathogenic effects and tactile enhancement in high doses. Mesembrine does not have hallucinogenic effects (despite incorrect reports of kanna acting as a psychedelic from older research, which have been disproved). For some people, acute high doses of mesembrine can induce transient anxiety or even panic attacks (these negative side-effects fade away quickly). Many people compare the feeling induced by mesembrine to either microdosing MDMA or very powerful coffee mixed with an antidepressant. This is why kanna is frequently marketed as a legal "MDMA alternative", although this marketing is blatantly misleading as kanna's potency, safety profile, and mechanisms of action are all very different from MDMA. In small doses, mesembrine is stimulating, but in higher doses, mesembrine can cause sedation.

Mesembrenone

Mesembrenone is an SRI and a PDE4 inhibitor, but does not appear to affect VMAT-2. Its strength as an SRI is weaker than that of mesembrine. Mesembrenone-rich kanna extracts have consistently been shown to be effective at treating anxiety in multiple studies, and research indicates that they may also be effective at treating depression. Mesembrenone-based extracts are most useful in their therapeutic utility, especially because they typically do not create the transient anxiety that mesembrine causes in some people. Mesembrenone lacks the craving reduction, weight-loss potential, and some neuroprotective properties of mesembrine. It also may be less effective at treating severe depression due to lack of VMAT-2 activity and being a weaker SRI. Mesembrenone does not cause a stimulating "rush" and is generally not thought to produce the mild euphoria associated with mesembrine.

Mesembrenol

Mesembrenol has the exact same functions as mesembrenone (but is weaker?).

Mesembranol

No information found at this time, but mesembranol has been shown to have notable psychoactive effects.

III. Kanna's Pharmacological Functions

Serotonin Reuptake Inhibition

It is well known that kanna is a powerful serotonin reuptake inhibitor (SRI). It works in a nearly identical fashion to selective serotonin reuptake inhibitors (SSRIs), i.e. citalopram, fluoxetine, etc. Please note that SSRIs are SRIs, and that the only difference between the two is that SSRIs only inhibit serotonin transporters, whereas SRIs do the exact same thing but can do other things as well. SSRIs are used in the clinical treatment of depression, anxiety, and OCD. They, like kanna, work by preventing serotonin from being transported back into the presynaptic neuron from the synapse via inhibiting the activity of serotonin transporters (SERT). This increases the amount of serotonin in synapses in the brain, boosting serotonergic activity. Kanna's activity as an SRI has been shown to be more powerful than several synthetic antidepressant medications that are used as first-line treatments for depression, and kanna has been shown to be as effective in treating acute depression as the antidepressant citalopram in several case studies. Mesembrine's binding affinity for SERT is almost as high as citalopram (it has an IC-50 of 4.3 for SERT inhibition). A large body of peer-reviewed research definitively shows that certain kanna extracts are clinically effective at treating anxiety. A small number of studies report that kanna, like other potent SRIs, may cause a withdrawal syndrome in some individuals after long-term use, however, this withdrawal syndrome is more mild than that of clinically used SSRIs and other research indicates that kanna doesn't cause any withdrawal symptoms.

VMAT-2 Upregulation

Recent, preliminary research has shown that kanna increases the activity of VMAT-2. VMAT-2 is a the primary protein that selectively carries serotonin, dopamine, norepinephrine, GABA, and other monoamines out of the presynaptic neuron and into the synapse. By boosting the levels/activity of VMAT-2, kanna effectively causes monoamine release into the synapse, meaning it acts as a mildly to moderately strong monoamine releasing agent. Most monoamine releasing agents usually act via alternative mechanisms and are often selective for specific monoamines, thus having a variety of applications that include treating ADHD, treating binge eating disorder, potentially treating depression, potentially treating autism, and recreational drug abuse. Adderall, fenfluramine, MDMA, and other amphetamines all are monoamine releasing agents.

The mechanism causing kanna's monoamine release, VMAT-2 upregulation, is fairly unique among known drugs. This VMAT-2 upregulation may be what causes the mild "euphoric" effects of kanna in high doses as well as some of its stimulant effects. It further may cause mild empathogenic effects and tactile enhancement. It should be noted that these mildly euphoric, intoxicating effects are only found in certain kanna strains/products, not all of them. Unlike many amphetamines, however, kanna has negligible liability for abuse and research consistently shows that kanna does not cause physical addiction. Further, VMAT-2 upregulation may have neuroprotective properties (especially against amphetamine toxicity), be a potential treatment for depression, be a potential treatment for obesity (may cause weight loss), and may reduce both addiction to and abuse of stimulant drugs (like cocaine and methamphetamine).

Note: There is a large amount of interest among the pharmaceutical industry in creating drugs that potently increase the activity of VMAT-2 for the treatment of addiction and mental disorders because "none are known to exist", yet I personally have found very little research done into mesembrine's ability to upregulate VMAT-2. Again, this function makes kanna quite unique.

PDE4 Inhibition

Kanna strongly inhibits phosphodiesterase 4 (PDE4). PDE4 is predominantly responsible for breaking down cyclic adenosine monophosphate (cAMP) within both immune cells and cells in the central nervous system. cAMP is used for intracellular signal transduction, for example, it transfers the effects of hormones like adrenaline into cells. "PDE4 inhibitors are known to possess pro-cognitive (including long term memory-improving), wakefulness-promoting, neuroprotective, and anti-inflammatory effects. PDE4 inhibitors have been investigated as treatments for a diverse group of different diseases, including central nervous system disorders such as major depressive disorder (clinical depression), anxiety disorders, schizophrenia, Parkinson's disease, Alzheimer's disease, multiple sclerosis, attention deficit-hyperactivity disorder, Huntington's disease, stroke, autism and inflammatory conditions such as chronic obstructive pulmonary disease (COPD), asthma and rheumatoid arthritis." (Wikipedia, information verified from alternate sources) Kanna's ability to inhibit both SERT and PDE4 has attracted especial attention, as this combination may be particularly useful in treating depression.

Other Mechanisms of Action

Mild Inhibition of MAO-A: Kanna mildly inhibits MAO-A. This inhibition, however, is so weak as to nearly be negligible. MAO-A is an enzyme that helps break down certain neurotransmitters, including dopamine, norepinephrine, and serotonin. In people with chronic depression, MAO-A levels may be elevated, and dysfunction of this protein is also implicated in bipolar disorder, Alzheimer's, aggression, panic disorder, and ADHD.

Mild Inhibition of AChE: Kanna is a mild reversible inhibitor of acetylcholinesterase (AChE). AChE inhibitors or anti-cholinesterases inhibit the cholinesterase enzyme from breaking down ACh, increasing both the level and duration of the neurotransmitter action. Reversible AChE inhibition may have applications in the treatment of Alzheimer's. Note that kanna is a reversible inhibitor rather than an irreversible one, as irreversible AChE inhibitors are used in chemical warfare as nerve agents.

Anti-inflammatory: Kanna has anti-inflammatory activity (in other words, it reduces inflammation or swelling), possibly due to its PDE4 inhibition. Anti-inflammatory agents make up over half of analgesics (for example, aspirin or naproxen). This may explain why case studies report that kanna can provide relief from bee stings.

Limits Reuptake of Dopamine and Norepinephrine at High Doses: When taken in high doses, kanna may mildly limit the reuptake of dopamine and norepinephrine into the presynaptic neuron by their respective transporters. This action is slightly similar to that of NDRIs (like Ritalin), however, this effect is quite weak and only occurs in very high doses.

Cannabinoid Receptor Inhibition: Plain kanna has been shown to inhibit cannabinoid receptor type 1 (CB1). It is currently unclear which alkaloid in kanna affects CB1. CB1 inhibition may cause antidepressant and anorectic effects.

Sources

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Chiu, S., et al. "Exploring Standardized Zembrin® Extracts from the South African plant Sceletium tortuosum in Dual Targeting Phosphodiesterase-4 (PDE-4) and Serotonin Reuptake Inhibition as potential treatment in Schizophrenia." Int J Complement Alt Med 6.5 (2017): 00203.

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