Kanna / Zembrin

The short version: Kanna is a traditional South African herbal medication. Zembrin is an extract of kanna marketed for people with depression and anxiety. Kanna is probably an SSRI with additional PDE4 activity, though its pharmacology still isn’t exactly clear. If you’re depressed or anxious and have no contradindications, you might benefit from taking Zembrin 25 mg daily, which you can get here.

The long version:

1. What’s the evidence that Zembrin works?

A long history of traditional use, anecdotal evidence from users, and a tiny and unsatisfying handful of real studies.

The San (“Bushmen”) of South Africa have traditionally used kanna in various ways; depending on dose and preparation, it can be an anxiolytic, intoxicant, narcotic, stimulant, or sedative. An early European explorer wrote:

There is a root, gathered in the Hottentot Countries, called Kanna; which is in such Esteem among the Hottentots for its great vertues that they almost adore it…they look upon it as the [greatest] Chearer of the Spirits, and the [noblest] Restorative in the world. They will give [almost] any Thing in exchange for it, and will, any of ’em, run Twenty Miles upon an Errand, or perform a hard Day’s Work, for a very small Bit of it…

I have often seen the effects of Kanna upon Hottentots. They chew and retain it a [considerable] Time in their Mouths. But taking generally too much of it at a Time, it drowns ’em in Intoxications. They chew it not long, before their spirits [visibly] [rise], their Eyes brighten, their Faces take a jovial Air, and they [Sport] and wanton under a [thousand] gaieties of Imagination. But in the End it [Strips] ’em of their [Senses], and throws ’em into the [wildest] Deliria.

San (and some Europeans in South Africa) continue to use the plant more or less the same way up to the present. In the late 20th and early 21st century, Nektium Pharmaceuticals, working with locals and ethnobotanists, came out with Zembrin, the first standardized extract of kanna. I don’t have a great understanding of this process, except that (according to Nigel Gericke), the locals pointed out plants that were “tamer” and less likely to cause intoxication and weird drug-like effects, and the pharma company iterated until they had something that supposedly preserved the mood-lifting properties without the “wildest Deliria”.

Reports from Zembrin users are pretty positive. Anyone who looks into it comes across stories like “I started taking Zembrin last wek and I feel like it has already changed my life” or “Last week I began taking [Zembrin] and it’s been the most effective thing I’ve tried so far.” We need to be careful with these kinds of stories – thanks to the placebo effect everything has a few people who say it’s amazing – but Zembrin seems to produce more than its share. In 2020 I surveyed 852 users of mental health related supplements. Zembrin received the highest rating of 37 substances studied (although some complications in how the questions were asked make it hard for me to say this with certainty; I’ll link the survey once it’s published).

There are several terrible studies that probably shouldn’t be treated as much more than anecdotal evidence. Among these are some studies by Japanese veterinarians with hilarious titles like Clinical application of South African tea on dementia dog, lots of case reports, and trials of safety where some people offhandedly mention it seems efficacious.

The only study I can really endorse is Effect of Zembrin® on Brain Electrical Activity in 60 Older Subjects after 6 Weeks of Daily Intake. A Prospective, Randomized, Double-Blind, Placebo-Controlled, 3-Armed Study in a Parallel Design. It does a placebo controlled trial on EEG results, and finds Zembrin produces EEG changes consistent with decreased anxiety and improved well being – but EEG findings are kind of easy to manipulate and not really trustworthy. However, the authors also gave subjects the HAM-A anxiety questionnaire before and after the study, and they found the group taking Zembrin improved significantly. In particular, the placebo group’s anxiety was 9.3, the Zembrin 25 mg group was 6.65, and the Zembrin 50 mg group was 6.37. The 50 mg group was barely inside the significance threshold (p = 0.03) and the 25 mg group barely outside of it, but realistically these numbers are very similar and probably justify the standard 25 mg dose.

I don’t know of any credible studies that explicitly show Zembrin does not work. If you know of any other useful Zembrin studies I should include here, please let me know.

Overall I admit the scientific evidence for Zembrin is relatively weak. I base my interest primarily off anecdotal reports, surveys of users, and its interesting pharmacology.

2. What is the pharmacology behind Zembrin?

The only really extensive look at this question suggests it is a dual serotonin reuptake inhibitor and PDE4 inhibitor. From Pharmacological actions of the South African medicinal and functional food plant Sceletium tortuosum and its principal alkaloids:

The extract was a potent blocker in 5-HT transporter binding assays (IC50 4.3 μg/ml) and had powerful inhibitory effects on phosphodiesterase 4 (PDE4) (IC50 8.5 μg/ml), but not other phosphodiesterases…The activity of the sceletium tortuosum extract on the 5-HT transporter and PDE4 may explain the clinical effects of preparations made from this plant.

A serotonin reuptake inhibitor is better known as an SSRI. If this study is correct, Zembrin works the same way as the most common class of antidepressants. This would be exciting, since Zembrin is off-patent, unregulated, and available without prescription.

The PDE4 inhibition is also exciting. PDE4 (phosphodiesterase 4) is an enzyme that plays a role in “second messengers”, chemicals that help receptors and different parts of a cell communicate with each other. PDE4 inhibitors had previously been identified as potentially promising antidepressants, but were dropped because the best-known example caused severe vomiting. In 2009 a team of researchers wrote a paper arguing that a dual SSRI/PDE4 inhibitor might be an especially powerful antidepressant, since PDE4 might be involved in compensating for the effects of SSRIs. If Zembrin were such an agent, that would be exciting and justify further study and use.

But although the pharmacology lines up with this, there are still some things that confuse me. The San used kanna to get high. There is no dose of SSRIs that will make you high, and I’ve never heard claims that PDE4 should be able to do this either. That suggests whatever was making the San high was unrelated to the SSRI/PDE4 properties of Zembrin. But is it just a coincidence that a drug that can be used to become euphoric and sedated also has antidepressant/anti-anxiety properties? I would expect that Zembrin would help treat depression and anxiety through some much weaker version of whatever was making the Khoi-San high. But I don’t think anyone has discovered this chemical yet. So I’m not sure what’s going on here.

Also, Zembrin seems to at least sometimes work immediately (SSRIs take a month) and have low rates of sexual side effects (SSRIs have a high rate). It’s possible that this is the PDE4 inhibition doing its job, but I’m not sure. This substance really does not “feel” SSRI-like (aside from its ability to treat depression and anxiety), so I’m not sure what to think here.

A few teams (1, 2) find scattered evidence that Zembrin has at least some effect on AMPA receptors, current relevance unclear.

3. How do I take Zembrin, and what should I expect?

If you’re currently dealing with depression or anxiety, are not bipolar, aren’t taking any medications that might interact with it (eg MAOIs, 5-HTP), and haven’t had previous bad reactions to SSRIs, taking Zembrin might be a reasonable choice.

Since Zembrin is already a proprietary extract, there’s no real difference between brands; I recommend one that’s inexpensive and doesn’t have too many other things mixed in. This Doctor’s Best Calm-Z supplement is fine.

The usual dose is 25 mg (one capsule) once a day. The one small study that investigated this didn’t find much advantage to going higher. Expect to feel effects sometime between a few days and a few weeks. There are few known side effects, but a theoretical risk of sexual side effects. There are no actual reports of withdrawal, and some anecdotal reports of people stopping long-term use without noticeable withdrawal, but in theory an SSRI-like discontinuation syndrome is possible.