5 min read · Neuroscience · biology · quantum phyiscs
When the Signal Disappears
What kratom, kava, and withdrawal can reveal about a body adapting beneath the surface
Someone starts drinking a kratom–kava tonic every day.
At first, nothing about the routine has to feel dramatic. Maybe the drink is calming. Maybe it offers relief, energy, or simply a state that starts to feel familiar.
Then they stop.
Instead of returning neatly to how they felt before, the absence of the drink brings anxiety, sleeplessness, restlessness, physical discomfort—or, in some reported cases, much more severe symptoms.
Clinical reports have documented serious withdrawal after heavy use of products containing both kratom and kava. One patient developed hallucinations, insomnia, anxiety, and involuntary muscle movements after stopping a kratom–kava beverage. A later case series described several similar presentations, although other substance use and individual histories made it difficult to determine exactly which substance was responsible for which symptoms. (Bleifuss et al., 2025; Kiyokawa et al., 2026)
The strange part is easy to miss:
Nothing new has been added. Something has been removed.
So what changed while the substances were still there?
One drink, more than one signal
Kratom and kava often appear in the same bottle, but the body does not necessarily experience them as one chemical event.
Kratom contains several active compounds, including mitragynine. After mitragynine enters the body, some of it can be converted into 7-hydroxymitragynine, or 7-OH. Human research has directly shown that this conversion occurs. (Mongar et al., 2024)
Both mitragynine and 7-OH can interact with the mu-opioid receptor, a receptor system involved in pain, reward, stress, and the body’s own opioid signaling. 7-OH activates this receptor more strongly than mitragynine, although neither behaves exactly like a classical opioid such as morphine. (Kruegel et al., 2016)
Kava brings in another group of compounds called kavalactones.
One of them, kavain, has been shown in laboratory experiments to strengthen signaling through GABA-A receptors. GABA is one of the brain’s major inhibitory messengers: it helps regulate how readily neurons become active.
Kavain does not act at the usual benzodiazepine binding site, so calling kava a “natural benzodiazepine” would be misleading. But it does give us evidence that kava can influence another system involved in regulating neural activity. (Chua et al., 2016)
One drink can therefore contain several active compounds entering the nervous system through different routes.
Repeated exposure gives those systems time to respond.
The part happening underneath
The immediate effect of a substance is only half of the interaction.
Biological systems regulate themselves.
A useful example comes from decades of opioid research.
When mu-opioid receptors are activated, they can reduce activity in a cellular communication pathway involving a molecule called cAMP. For now, the name matters less than the role: it is part of the cell’s internal signaling machinery.
If opioid signaling repeatedly pushes that machinery downward, the cell can begin pushing back.
With continued exposure, parts of the cAMP system become more active. That compensation can bring cellular activity closer to its earlier range—even while the opioid is still present.
Show the mechanism Watch compensation become visible Signal → adaptation → rebound
Follow one well-studied opioid mechanism through repeated exposure and removal of the signal.
From the outside, the system may look as though it has settled down.
It has not returned to its original state.
It has found a new balance.
Then remove the opioid signal.
The opposing adjustment does not disappear at the same instant. For a while, the body’s compensation remains active without the signal it was counteracting. Activity can rebound in the opposite direction, contributing to the disturbed state we recognize as withdrawal. (Williams et al., 2024; Wang et al., 2025)
That gives us something more useful than saying the body simply “gets used to” a substance.
Repeated exposure can change the system receiving the signal.
Those changes may be hardest to see while the signal and the body’s response to it are still balancing one another.
But there are two plants in the bottle
The opioid side gives us a well-studied model of adaptation.
Kava gives us another set of neural effects, but we do not yet have the same detailed map of what repeated heavy kava exposure does in humans.
Severe kava withdrawal has been reported, including symptoms resembling withdrawal from other sedating substances. But these reports are rare, and they do not prove that kava produces the same kind of adaptation as benzodiazepines or other GABA-acting drugs.
So we have to resist an attractive shortcut:
kratom affects opioid signaling + kava affects GABA signaling = two known withdrawal mechanisms added together.
We do not know that.
What we have is a reason to ask whether more than one changing system could be involved.
They may even meet before the brain
There is another possible interaction hiding upstream.
An enzyme called CYP3A4 helps convert mitragynine into 7-OH.
Laboratory studies have found that kava extracts and some kavalactones can interfere with CYP3A4. (Mathews et al., 2002)
That creates an interesting possibility: kava might alter how the body processes kratom before either plant’s full effects reach the brain.
But this is exactly where the evidence line matters.
No controlled human study has yet shown that ordinary kava consumption meaningfully changes mitragynine-to-7-OH conversion.
What we do know is that when researchers gave people a pharmaceutical drug that strongly blocks CYP3A4, mitragynine levels increased while formation of 7-OH dropped substantially. (Mongar et al., 2024)
So the metabolic pathway can be changed.
Whether kava changes it enough to matter in real-world use is still an open question.
Change the assumption
Suppose someone stops a kratom–kava tonic and develops withdrawal.
The simplest explanation might be:
Kratom acts on opioid receptors, so this is kratom withdrawal.
There may be a great deal of truth in that explanation.
But what if one drink has been producing several signals at once? What if the nervous system has been adjusting to those signals on different timelines? What if metabolism changes the mixture along the way?
A short controlled study helps show why duration matters. Healthy adults consumed a commercial kratom–kava tonic for six days and did not develop clinically significant withdrawal, although the highest-dose group showed a small increase on an opioid-withdrawal scale after stopping. (Dufour et al., 2024)
Six days tells us something about six days.
It does not tell us what happens after thirty, sixty, or several hundred days of repeated exposure.
An observational study of people who use kratom and kava also found that those reporting use of both were more likely to report using more kratom than intended and needing larger amounts for the same effect. That does not show that kava caused the difference, but it gives researchers another reason to study the combination directly. (Grundmann et al., 2025)
What remains when the signals disappear?
We started with someone removing a drink from their routine.
At first, withdrawal can make it seem as though the absence itself is causing the problem.
But the absence may be revealing something that was already happening.
Repeated signals can produce repeated responses. Those responses can trigger compensations. Once the system has adapted, the next exposure no longer enters quite the same system as the first.
A kratom–kava tonic may feel like one experience while several biological processes shift underneath it.
Some may overlap.
Some may not.
And some of the most important changes may remain almost invisible until the signals that helped create them are gone.
What has repeated exposure changed—and why do some of those changes become noticeable only when the substances disappear?
Show the source trail Follow the evidence Clinical observations → mechanism → open questions
The evidence behind this piece does not all sit at the same level. Some studies follow people using kratom or kava. Others isolate molecules, receptors, or metabolic pathways in the laboratory. Broader opioid research gives us mechanisms that can help explain parts of what we observe.
This source trail keeps those levels separate: what was observed, what a mechanism supports, and what remains an open connection.
Direct & human evidence
Clinical observations and human studies that establish parts of the problem directly.
Direct evidence · Clinical case report Bleifuss et al., 2025 Severe withdrawal after stopping a kratom–kava beverage
What it supports
A 45-year-old man developed hallucinations, anxiety, insomnia, and involuntary muscle movements after stopping heavy use of a beverage containing both kratom and kava. He had initially received buprenorphine for suspected kratom withdrawal, but clinicians later became concerned about an additional sedative-like withdrawal process.
What it doesn’t establish
A single case cannot tell us which substance caused each symptom, whether kava intensified kratom withdrawal, or how commonly this response occurs.
Why it matters here
It gives us a real clinical observation that a simple opioid-withdrawal explanation may not account for everything happening after the combination is stopped.
Bleifuss W, Boley S, Bardwell J, Goebel C, Wilkinson J. (2025). Severe kava withdrawal managed with phenobarbital. View source ↗
Direct evidence · Clinical case series Kiyokawa et al., 2026 Severe withdrawal across four kratom–kava cases
What it supports
Four patients using kratom and kava developed severe withdrawal presentations resembling withdrawal from sedating substances. All improved after treatment with phenobarbital and/or benzodiazepines.
What it doesn’t establish
The cases cannot cleanly separate the effects of kratom, kava, and other substance exposure. All four patients also had histories of psychiatric illness and alcohol use disorder, which limits how broadly the cases can be generalized.
Why it matters here
It moves the observation beyond one unusual case while making the uncertainty clearer: more than one process may be involved, but the cases cannot tell us exactly which processes.
Kiyokawa M, Okuno C, Nguyen D. (2026). Kava-potentiated Withdrawal in Persons Using Multiple Substances: A Case Series of Kava and Kratom Co-ingestion. View source ↗
Direct evidence · Clinical case report Cassidy et al., 2024 Severe withdrawal after escalating heavy kava use
What it supports
A patient who reported escalating kava use over several weeks developed hyperactive delirium during withdrawal and was treated with phenobarbital.
What it doesn’t establish
One severe case cannot tell us how often kava withdrawal occurs, which exposure patterns produce it, or which cellular mechanism caused the symptoms. Earlier controlled studies at lower exposures had generally not identified a withdrawal syndrome.
Why it matters here
It gives us a reason not to treat kava as a passive second ingredient. Severe withdrawal has been reported in a case centered on heavy kava exposure itself.
Cassidy CM et al. (2024). Kava Withdrawal Treated With Phenobarbital—A Case Report and Literature Review. View source ↗
Human evidence · Pharmacokinetics Mongar et al., 2024 The body converts mitragynine into 7-OH
What it supports
Healthy volunteers consumed kratom tea while researchers measured mitragynine and 7-hydroxymitragynine in blood. When CYP3A4 was inhibited with itraconazole, mitragynine exposure increased while formation of 7-OH decreased. This provides direct human evidence that CYP3A4 contributes to the conversion of mitragynine into 7-OH.
What it doesn’t establish
The experiment used itraconazole, not kava. It does not show that kava changes this conversion in people or tell us how large such an interaction would be during real-world kratom–kava use.
Why it matters here
It shows that the interaction does not begin only at the receptor. Metabolism can change which signals are eventually available to reach the nervous system.
Mongar P, Jaisi A, Inkviya T, Wungsintaweekul J, Wiwattanawongsa K. (2024). Effects of Itraconazole on Pharmacokinetics of Mitragynine and 7-Hydroxymitragynine in Healthy Volunteers. View source ↗
Human evidence · Controlled exposure Dufour et al., 2024 Six days of a commercial kratom–kava tonic
What it supports
Healthy adults consumed different daily amounts of a commercial kratom–kava tonic for six consecutive days. Researchers did not identify clinically significant withdrawal overall, although the high-dose group showed a small statistically significant increase on an opioid-withdrawal scale on day seven.
What it doesn’t establish
Six days cannot tell us what happens after weeks or months of daily exposure. The results also apply to the specific product, doses, and healthy participants studied.
The study was conducted by a contract research organization hired by Botanic Tonics; one author was a Botanic Tonics employee and another was a consultant. That does not invalidate the study, but it is relevant context when weighing the evidence.
Why it matters here
It gives us useful short-term evidence while showing why duration matters. A six-day exposure and months of daily use are not the same biological experiment.
Dufour J et al. (2024). The Safety of Multiple-Dose Liquid Blend Containing Kava and Kratom in Healthy Adults. View source ↗
Human evidence · Observational survey Hill, Boyer & Smith, 2025 What people using kratom and kava report
What it supports
In an online survey of 367 U.S. adults who had used kava or kratom, people reporting past-year use of both were more likely than kratom-only users to report using more kratom than intended and needing larger amounts to obtain the same effect.
What it doesn’t establish
The study was observational and self-selected. It cannot show that adding kava caused those differences. People who choose to use both botanicals may already differ from people who use only kratom.
Why it matters here
The real-world pattern gives researchers another reason to study the combination directly rather than assuming that co-use can be understood simply by studying each plant alone.
Hill K, Boyer EW, Smith KE. (2025). Clinically characterizing adults who use kava or kratom: Substance use disorder assessment challenges for increasingly popular botanical products. View source ↗
Mechanistic support
Evidence that helps explain pieces of the observation without directly reproducing human kratom–kava withdrawal.
Mechanistic support · Receptor pharmacology Kruegel et al., 2016 Kratom alkaloids enter the opioid signaling system
What it supports
Researchers tested mitragynine and related kratom alkaloids directly at human opioid receptors. The work established receptor-level activity at the mu-opioid receptor and showed signaling properties that differ in important ways from classical opioids.
What it doesn’t establish
Receptor activity alone cannot tell us whether a person will develop tolerance, physical dependence, withdrawal, or addiction.
Why it matters here
It gives the opioid side of our mechanism a molecular entry point without requiring us to treat kratom as simply “plant morphine.”
Kruegel AC et al. (2016). Synthetic and Receptor Signaling Explorations of the Mitragyna Alkaloids: Mitragynine as an Atypical Molecular Framework for Opioid Receptor Modulators. View source ↗
Mechanistic support · Animal dependence model Matsumoto et al., 2005 7-OH can produce tolerance and withdrawal-like adaptation
What it supports
Mice repeatedly exposed to 7-hydroxymitragynine developed tolerance to its pain-reducing effects, cross-tolerance with morphine, and withdrawal signs after opioid receptors were blocked with naloxone.
What it doesn’t establish
A mouse experiment using isolated 7-OH cannot tell us how quickly dependence develops in humans consuming kratom products or what happens when kava is present at the same time.
Why it matters here
It connects receptor pharmacology to adaptation: repeated 7-OH exposure can change how an organism responds both to the molecule and to its removal.
Matsumoto K et al. (2005). Antinociception, tolerance and withdrawal symptoms induced by 7-hydroxymitragynine, an alkaloid from the Thai medicinal herb Mitragyna speciosa. View source ↗
Mechanistic support · Receptor experiment Chua et al., 2016 Kavain can alter inhibitory signaling
What it supports
Kavain increased responses produced by several human GABA-A receptor subtypes expressed in Xenopus oocytes. The effect did not depend on the classical benzodiazepine binding site.
What it doesn’t establish
This laboratory receptor experiment does not demonstrate that repeated kava use produces benzodiazepine-like dependence or identify the mechanism responsible for human kava withdrawal.
Why it matters here
It establishes that kava can influence another major neural signaling system while preventing the shortcut “kava = natural benzodiazepine.”
Chua HC et al. (2016). Kavain, the Major Constituent of the Anxiolytic Kava Extract, Potentiates GABA-A Receptors: Functional Characteristics and Molecular Mechanism. View source ↗
Mechanistic support · Metabolism experiment Mathews et al., 2002 Kava compounds can interfere with CYP enzymes
What it supports
Kava extract inhibited several cytochrome P450 enzymes in experiments using human liver microsomes, including CYP3A4. Individual kavalactones did not all behave the same way.
What it doesn’t establish
A liver-microsome experiment cannot tell us whether typical human kava exposure inhibits CYP3A4 strongly enough to meaningfully alter kratom metabolism.
Why it matters here
Placed beside the Mongar human study, it creates a real but unfinished connection: CYP3A4 helps form 7-OH, and kava can affect CYP3A4 in the lab. Whether that interaction matters during human co-use remains open.
Mathews JM, Etheridge AS, Black SR. (2002). Inhibition of human cytochrome P450 activities by kava extract and kavalactones. View source ↗
Established separately
A broader opioid mechanism that supports the conceptual model, but has not been demonstrated as the complete explanation for kratom–kava withdrawal.
Established separately · Opioid adaptation Klein et al., 2026 Why removing an opioid signal can reveal hidden adaptation
What it supports
The study adds to evidence that prolonged opioid signaling can sensitize adenylyl cyclase pathways and produce cAMP overshoot. Acute opioid-receptor activation reduced cAMP signaling in experimental cell models, while chronic exposure produced enhanced cAMP responses. Reducing AC1 also lessened morphine tolerance and precipitated withdrawal in mice.
What it doesn’t establish
The study did not examine kratom, 7-OH, kava, or kratom–kava products. It gives us an opioid-adaptation mechanism, not a direct explanation of the clinical cases.
Why it matters here
This is the biological foundation of our mechanism model: an opioid signal alters a pathway, repeated exposure recruits compensation, and removing the signal can expose the compensatory state that developed underneath.
Klein AH et al. (2026). Inhibition of adenylyl cyclase 1 or exchange protein activated by cAMP restores ATP-sensitive potassium channel activity after chronic opioid exposure. View source ↗
Where the trail ends
What the evidence gets us to—and where it stops
Observed: Severe withdrawal has occurred after heavy kratom–kava use.
Established: Kratom alkaloids can enter opioid signaling, and repeated 7-OH exposure can produce opioid-like tolerance and dependence in animal models.
Established separately: Kava compounds affect other neural and metabolic systems, while broader opioid research shows that repeated opioid signaling can recruit compensatory changes in cAMP pathways.
Still untested: How those processes interact during sustained kratom–kava use, and which adaptations are exposed when both inputs disappear.
The evidence gets us this far. The next connection is a question, not a conclusion.
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