From: Drew Wolfson
To: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected] Subject: 7Oh scheduling
Date: Saturday, August 30, 2025 9:23:57 PM
You don't often get email from [email protected]. Learn why this is important I write to you with sincerity and deep concern. The potential banning of 7-hydroxymitragynine (7-OH) would not only be a devastating blow to countless people who rely on it, but it could create a true public crisis. Not one person has died from this. I am a vendor in the public market im a software engineer worked for some of the top companies in the world. I wanted to make a difference in the world; so I joined this space. I lost countless friends due to the pandemic and precipitation drugs, I refuse to lost any more. Follow the science please; For many, 7-OH has been a godsend — offering relief, stability, and a lifeline where other options have failed. It has helped people step away from far more dangerous substances, giving them a chance at a healthier, safer, and more productive life.
If access is taken away, the reality is that overdose rates will rise. Those who have found safety in 7-OH will be pushed back toward street drugs and high-risk alternatives. Instead of protecting people, such a ban would expose them to far greater harm.
This is not an abstract policy decision. It is about real lives — about mothers, fathers, sons, daughters, and friends who have found hope where there once was none. To remove that is to risk undoing years of progress in harm reduction and public health.
I urge you to consider the human cost. The people who rely on 7-OH are not statistics — they are our neighbors, family members, and community. This compound has been a bridge away from danger for so many, and banning it would close that bridge at the exact moment it is most needed.
With respect and sincerity,
Thank you,
Drew
NEW YORK, NY
[email protected]
516-662-8519
From: wakeup777
To: [email protected]
Subject: Agenda Item 25-704 - Approve for Introduction Ordinance No. 4339 Prohibiting the Sale, Distribution and Possession of Kratom
Date: Saturday, August 30, 2025 10:28:25 PM
You don't often get email from [email protected]. Learn why this is important Hello,
I’m reaching out in regards to Agenda Item 25-704 - Approve for Introduction Ordinance No. 4339 Prohibiting the Sale, Distribution and Possession of Kratom to be discussed during the September 2, 2025 Huntington Beach City Council meeting. I wanted to provide some feedback on what negative affects that the prohibition of selling and possessing of kratom could have.
Kratom is a plant that has been used for centuries in Southeast Asia. It is related to coffee as they are both flowering, sub-tropical plants in the Rubiaceae family. This is a plant that has an alkaloid called mitragynine. Mitragynine has pain relieving properties as it is a partial agonist of the mu-opioid receptor.
Because kratom is a partial agonist of the mu-opioid receptor, it has been shown to help people get off of illicit substances such as fentanyl and heroin and there have been countless testimonies from multitudes of people who have been given their lives back and have once again been brought back to living lives that are productive to society and productive for their families after being addicted and homeless from illicit substances. Making the sale and possession of kratom illegal will rob people in the future from having the potential of being saved from a life on the streets caused by addiction.
Kratom with its pain relieving effects also helps chronic pain patient who can’t afford healthcare to manage their pain with a wholistic alternative. People who pay for insurance, sometimes cannot afford the copays, prescription costs or the lack of coverage for testing that insurance refuses to cover. Some people cannot afford to pay for insurance in the first place, much less copays, prescription costs and testing costs.
It is a fact that kratom causes far less respiratory depression than even FDA approved pharmaceuticals and opioids since it is a partial mu-opioid receptor agonist.
Please consider the treatment that this plant can provide for people to get off of illicit substances and for chronic pain patients to be given relief before making its possession and sale illegal. Thank you.
From: Dakota Crocker
To: [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected]; [email protected] Subject: The Benefit of Keeping 7-hydroxymitragynine (7-OH) Legal Date: Saturday, August 30, 2025 11:48:38 PM
You don't often get email from [email protected]. Learn why this is important 7-hydroxymitragynine (7-OH) is a plant alkaloid that provides a safe and effective alternative for treating pain and various psychiatric conditions. Unlike alcohol, 7-OH does not incite violence or idiotic behavior, and an overdose on 7-OH alone cannot cause death.
Additionally, 7-OH is even less toxic than mitragynine, the primary active alkaloid in kratom.
Banning 7-OH while keeping mitragynine legal would be a misinformed decision, as mitragynine is metabolized into 7-OH in the liver. I believe that keeping 7-OH legal will help reduce opioid-related deaths, as people will have a safe, non-toxic alternative to potentially lethal drugs like fentanyl, heroin, and prescription painkillers.
Big kratom companies have sought to make 7-OH a banned substance. They are merely trying to protect their market share, which has been threatened by 7-OH recently. If public health were the primary concern, then tobacco and alcohol would be targeted, as they are much more dangerous substances. An overdose on 7-OH alone has yet to cause a single death, and it is non-toxic to the body.
Thank you for reading.
From: S Eppard
To: [email protected]
Subject: My son died from Kratom powder, not 7oh
Date: Monday, September 1, 2025 7:54:02 AM
You don't often get email from [email protected]. Learn why this is important My 22 year old son Matthew died from Kratom POWDER (the least potent form of Kratom available in the United States). He did NOT die from 7oh/7hydroxymitragynine. Kratom caused him to have a seizure, go into cardiac arrest and die. His toxicology showed he died from the “TOXIC effects of Mitragynine” an alkaloid found only in krat0m. He had no prescription drugs, no street drugs nor alcohol in his system when he died, and his autopsy showed he had no underlying health conditions.
Please email me if you would like his toxicology and autopsy results. Susan Eppard (Matthew’s Mom)
Sent from my iPad
From: Jared Beam
To: [email protected]
Subject: Agenda Item 25-704: Please Delay or Reconsider Kratom Ban Date: Tuesday, September 2, 2025 8:27:56 AM
You don't often get email from [email protected]. Learn why this is important Dear city council,
I urge you to please delay or reconsider the banning of kratom and its alkaloids (agenda item 25-704). The current push of misinformation against its major alkaloids is driven by lobbying against a safe alkaloid for market interests, not because of any real danger.
The safety profile of 7-OH is demonstrated by over 500 million doses of 7-OH and no confirmed deaths from it alone. Studies also show it’s a partial-agonist that doesn’t bind to the receptors that cause respiratory depression. Kratom, which likewise does not affect those receptors, has been safely used by millions for much longer.
Removing access to these safe harm reduction tools will put people at risk. There is no emerging public health threat from kratom or its alkaloids that justifies a ban.
Thank you for your time. I pray you'll keep the public’s safety in mind and protect safe harm reduction options.
Best,
Jared beam
From: Matthew Weicberger
To: [email protected]
Subject: Matthew An advocate for kratom and 7oh
Date: Tuesday, September 2, 2025 8:28:20 AM
Attachments: icon.png
icon.png
You don't often get email from [email protected]. Learn why this is important Hello my name is Matthew. I am reaching out to you in regards to the upcoming hearing that you have regarding the action to ban kratom in Huntington Beach California. I oppose to this idea. The thought that our political leaders want to take away and alkaloid / medicine that provides relief as well as harm reduction and so many benefits that range from pain relief to emotional relief to anxiety relief and others; In my opinion the idea of banning kratom is nonsensical and will only bring harm to many who are trying to live a decent life. I'm attaching below a document and a written article that is written by the national library of medicine. I welcome you to please read through this information I would like to bet that after doing so there would be a change of heart and this would not come from sympathy or compassion but from scientific proof from studies and due diligence being done on this beautiful plant and alkaloid that millions of us on this planet use so that we can live a normal decent life. Thank you kindly for your time and I hope that the right decision is made; that the decision for the people is made; one that is for the people and not for the money.
Kind regards
Matthew.
Hello my name is Matthew. I am reaching out to you in regards to the upcoming hearing that you have regarding the action to ban kratom in Huntington Beach California. I oppose to this idea. The thought that our political leaders want to take away and alkaloid / medicine that provides relief as well as harm reduction and so many benefits that range from pain relief to emotional relief to anxiety relief and others; In my opinion the idea of banning kratom is nonsensical and will only bring harm to many who are trying to live a decent life. I'm attaching below a document and a written article that is written by the national library of medicine. I welcome you to please read through this information I would like to bet that after doing so there would be a change of heart and this would not come from sympathy or compassion but from scientific proof from studies and due diligence being done on this beautiful plant and alkaloid that millions of us on this planet use so that we can live a normal decent life. Thank you kindly for your time and I hope that the right decision is made; that the decision for the people is made; one that is for the people and not for the money.
Kind regards
Matthew.
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Pharmaceuticals (Basel). 2025 Feb 6;18(2):222.
doi: 10.3390/ph18020222
Exploring the Therapeutic
Potential of Mitragynine and
Corynoxeine: Kratom-Derived
Indole and Oxindole Alkaloids
for Pain Management
Ahmed S Alford 1,*, Hope L Moreno 1, Menny M
Benjamin 1, Cody F Dickinson 1, Mark T
Hamann 1
Editor: Réjean Couture1
Author information Article notes
Copyright and License information
PMCID: PMC11858930 PMID: 40006036
Abstract
The search for effective pain management
solutions remains a critical challenge, especially
amidst growing concerns over the use of
conventional opioids. In the US, opioid-related
mortality rates have surged to as many as 80
deaths per 100,000 people in some states, with
an estimated economic burden of USD 1.5
trillion annually—exceeding the gross domestic
product (GDP) of most US industrial sectors. A
remarkable breakthrough lies in the discovery
that indole and oxindole alkaloids, produced by
several genera within the plant Tribe Naucleeae,
act on opioid receptors without activating the
beta-arrestin-2 pathway, the primary driver of
respiratory depression and overdose deaths.
This systematic review explores the
pharmacological properties, mechanisms of
action, dosing considerations, interactions, and
long-term effects of mitragynine and
corynoxeine, alkaloids from the Southeast Asian
plant Mitragyna speciosa (kratom) and others in
the Tribe Naucleeae. Mitragynine, a partial
opioid receptor agonist, and corynoxeine, known
for its anti-inflammatory and neuroprotective
effects, demonstrate significant therapeutic
potential for managing diverse pain types—
including neuropathic, inflammatory,
nociceptive, visceral, and central pain
syndromes—with a focus on cancer pain. Unlike
traditional opioids, these compounds do not
recruit beta-arrestin-2, avoiding key adverse
effects such as respiratory depression, severe
constipation, and rapid tolerance development.
Their distinct pharmacological profiles make
them innovative candidates for safer, non-lethal
pain relief. However, challenges persist,
including the unregulated nature of kratom
products, inconsistencies in potency due to
crude extract variability, potential for misuse,
and adverse drug interactions. Addressing these
issues requires establishing standardized quality
control protocols, such as Good Manufacturing
Practices (GMP), to ensure consistent potency
and purity. Clear labeling requirements with
dosage guidelines and warnings should be
mandated to ensure safe use and prevent
misuse. Furthermore, the implementation of
regulatory oversight to monitor product quality
and enforce compliance is essential. This review
emphasizes the urgency of focused research to
optimize dosing regimens, characterize the
pharmacodynamic profiles of these alkaloids,
and evaluate long-term safety. By addressing
these gaps, the mitragynine- and corynoxeine-
related drug classes can transition from
promising plant-derived molecules to validated
pharmacotherapeutic agents, potentially
revolutionizing the field of pain management.
Keywords: mitragynine, corynoxeine, pain
management, Mitragyna speciosa, systematic
review, pharmacology, β-arrestin, opioids
1. Introduction
The search for effective pain management
solutions remains a critical challenge, especially
amidst growing concerns over the side effects
and dependency risks associated with
conventional opioids. In the United States,
opioid misuse has led to significant mortality and
economic burden, with opioid-related deaths
estimated at 80 per 100,000 individuals in some
states and an annual cost of approximately USD
1.5 trillion [1
]. Amid this crisis, certain indole and
oxindole alkaloids from the plant tribe
Naucleeae have emerged as promising
alternatives due to their ability to engage opioid
receptors without activating the β-arrestin-2
pathway, a key mediator of respiratory
depression and other severe opioid side effects
[2
].
The alkaloid composition of Mitragyna
speciosa (kratom) is dominated by mitragynine,
which constitutes approximately 66.2% of the
total alkaloid content in commercial kratom
products. In contrast, 7-hydroxymitragynine,
despite its higher potency at opioid receptors, is
a minor component, accounting for only 0.01–
0.03% of the total alkaloids. Other significant
alkaloids include speciociliatine (8.6–16.6%),
paynantheine (9.0–16.0%), and speciogynine
(6.6–8.6%), with trace amounts of additional
alkaloids such as corynoxeine, isocorynoxeine,
and speciophylline. These secondary alkaloids
may also contribute to kratom’s pharmacological
profile but in a less pronounced manner. The
variability in alkaloid composition across kratom
products is influenced by factors such as
genetic differences, environmental conditions,
and processing methods, resulting in
inconsistencies that affect their pharmacological
effects and safety profiles.
Among these compounds, mitragynine and
corynoxeine, derived from the Southeast Asian
plant Mitragyna speciosa (Figure 1
), commonly
known as kratom, stand out as potentially safer
alternatives to traditional opioids. While kratom
contains a range of bioactive alkaloids, the
oxindoles, including corynoxeine and its
stereoisomer isocorynoxeine, are minor yet
significant tetracyclic oxindole alkaloids. Kratom
also contains other active compounds, such as
flavonoids, polyphenols, and terpenoids, which
contribute to the pharmacological effects of the
raw plant products and crude plant extract.
These oxindoles also occur in higher
concentrations in other plants, such as species
within the Uncaria genus, further highlighting
their pharmacological importance [3
].
Mitragynine, an indole alkaloid, is recognized as
a partial agonist of the mu-opioid receptor
(MOR), whereas corynoxeine demonstrates
notable anti-inflammatory and neuroprotective
properties. Unlike conventional opioids, both
mitragynine and corynoxeine lack β-arrestin
recruitment, which reduces risks of adverse
effects such as respiratory depression,
constipation, and tolerance development [4
].
This unique pharmacological profile positions
them as promising candidates for managing
various types of pain—including neuropathic,
inflammatory, nociceptive, visceral, and central
pain syndromes—with a particular focus on
cancer-related pain.
Figure 1.
Figure 1
Open in a new tab
Mitragyna speciosa, commonly known as
kratom, contains bioactive secondary
metabolites, specifically indoles (e.g.,
mitragynine) and oxindoles (e.g., corynoxeine).
This review focuses specifically on mitragynine
and corynoxeine as representative compounds
of the indole and oxindole alkaloid classes,
respectively. Although kratom is traditionally
consumed in its whole form (e.g., crude leaves
or powdered leaves), isolating and examining
these two compounds allows for a targeted
analysis of their unique therapeutic potential,
mechanisms of action, and safety profiles. By
focusing on mitragynine and corynoxeine, this
review seeks to reflect the broader
pharmacological potential of indole and oxindole
alkaloids, addressing their potential applications
in pain management without the confounding
factors present in whole-plant kratom
formulations. For reference, Table 1
and Table
2 present the principal structures of the oxindole
and indole alkaloids derived from Mitragyna
speciosa, providing an overview of these
compounds’ structural diversity relevant to their
pharmacological profiles.
Table 1.
Principal structures of oxindole alkaloids
of Mitragyna speciosa.
Compound R1 3 7 15 20 R2
Corynoxeine H S R S R CHCH2
Corynoxine A H S S S S CH2CH3
Corynoxine B H S R S S CH2CH3
Mitrafoline OH S S S S CH2CH3
Speciofoline OH R R S S CH2CH3
Specionoxeine OCH3 S R S R CHCH2
Rhynchophylline H S R S R CH2CH3
Rotundifoline OH S S S R CH2CH3
Rotundifoleine OH S S S R CHCH2
Open in a new tab
Table 2.
Principal structures of indole alkaloids
of Mitragyna speciosa.
Compound R1 3 15 20 R2
Mitragynine OCH3 S S S CH2CH3
Speciogynine OCH3 S S R CH2CH3
Speciociliatine OCH3 R S S CH2CH3
Mitraciliatine OCH3 R S R CH2CH3
Paynantheine OCH3 S S R CHCH2
Corynantheidine OH S S S CH2CH3
Open in a new tab
Despite these promising pharmacological
profiles, challenges remain, particularly around
the unregulated nature of kratom products,
variability in dosage, and potential for abuse.
This review aims to identify and critically assess
relevant studies to provide an in-depth
understanding of the current evidence
surrounding mitragynine, corynoxeine, and other
kratom-derived alkaloids. While no clinical trials
have yet defined therapeutic doses or
established guidelines, the preclinical and
observational data reviewed here may offer
preliminary insights that could inform future
research. This synthesis is intended to support
clinicians and researchers in gaining a
foundational understanding of these
compounds’ potential pharmacological profiles
and mechanisms, and to encourage further
investigation into their role in pain management
and other therapeutic areas. Policymakers and
the general public may also find this review
beneficial in understanding the complex
landscape of kratom’s benefits and risks as they
relate to public health considerations.
2. Results
2.1. Pharmacodynamics
Corynoxeine’s mechanisms of action suggest
significant potential in the treatment of pain
through several pathways:
Anti-Inflammatory Agent: Corynoxeine’s role as
an anti-inflammatory agent is critical in
managing pain linked to inflammation, a
common cause in conditions such as arthritis
and autoimmune diseases. Through inhibition of
vascular smooth muscle cell (VSMC)
proliferation, particularly by blocking the
extracellular signal-regulated kinase (ERK1/2)
phosphorylation pathway, corynoxeine reduces
inflammatory processes in vascular and tissue
contexts. This anti-inflammatory activity can
help mitigate pain by lessening the release of
pro-inflammatory cytokines and mediators that
typically heighten pain sensitivity. By targeting
inflammation pathways, corynoxeine supports
tissue health and reduces the potential for
chronic pain development [5
,6].
Neuroprotective Actions and Autophagy
Enhancement: Corynoxeine serves as a
neuroprotective agent, offering significant
potential in conditions associated with
neuropathic pain where nerve cell damage or
dysfunction contributes to pain perception.
Through the enhancement of autophagy,
corynoxeine helps clear neurotoxic protein
aggregates such as alpha-synuclein, which can
otherwise accumulate and cause neural stress
and degeneration. By engaging pathways like
Akt/mTOR to induce autophagy, corynoxeine
may reduce neuronal death and maintain nerve
function, effectively lowering pain signals
associated with damaged or impaired nerves.
This neuroprotective mechanism could be
beneficial in conditions like peripheral
neuropathy and neurodegenerative diseases,
where nerve protection aligns with pain
mitigation [6
,7].
Calcium Channel Blockade and Vasorelaxation:
Corynoxeine induces vasorelaxation by blocking
L-type calcium channels in vascular smooth
muscle cells, thus preventing the influx of
calcium ions. Calcium ions play a critical role in
smooth muscle contraction; by limiting their
entry, corynoxeine reduces smooth muscle tone
and relaxes blood vessels. This vasodilation
effect is particularly beneficial in conditions
where vascular constriction is linked to pain,
such as migraines and certain vascular pain
syndromes. Enhanced blood flow from reduced
vascular resistance can alleviate symptoms by
improving oxygenation and nutrient delivery to
affected tissues, thus reducing ischemic or
tension-induced pain [6
,7,8].
Adrenergic Receptor Antagonism: By inhibiting
α1A adrenergic receptors, corynoxeine further
promotes vasodilation, countering the effects of
adrenergic-mediated vasoconstriction.
Adrenergic receptors, when activated, increase
vascular tone, which can exacerbate pain in
conditions like tension headaches and
hypertension-related discomfort. Corynoxeine’s
antagonism of these receptors allows for
relaxation of blood vessels, which can ease pain
by reducing the stress and pressure within the
vascular system. This mechanism adds a layer
of vascular relief in pain conditions where
adrenergic activity contributes to vascular
tightness and discomfort [9
,10].
Potassium Channel Activation and Vascular
Smooth Muscle Relaxation: As a potential
potassium channel opener, corynoxeine
hyperpolarizes vascular smooth muscle cells,
further reducing cellular excitability and
promoting vasodilation. The activation of
potassium channels encourages the efflux of
potassium ions, stabilizing the cellular
membrane potential away from depolarization
thresholds that trigger contraction. This action
complements calcium channel inhibition,
creating a dual mechanism for smooth muscle
relaxation. By decreasing vascular resistance
and enhancing blood flow, corynoxeine’s
potassium channel activation may help alleviate
pain from vascular sources, as seen in migraine
and other vascular pain disorders [6
,7].
Prevention of Vascular Smooth Muscle Cell
Proliferation: Corynoxeine also inhibits the
proliferation of vascular smooth muscle cells
(VSMCs), an effect particularly relevant in
conditions like atherosclerosis and restenosis,
where abnormal cell growth contributes to
vascular narrowing and pain. By blocking the
ERK1/2 pathway, corynoxeine disrupts the
signaling required for VSMC proliferation, which
can prevent or slow down the progression of
vascular blockages. This mechanism is
essential in managing chronic pain linked to
vascular diseases, as maintaining healthy,
unobstructed vessels can reduce ischemic pain
and improve blood circulation to affected
regions [7,8].
In summary, corynoxeine’s multi-faceted
mechanisms—including its roles as an anti-
inflammatory agent, neuroprotective agent,
calcium channel blocker, adrenergic receptor
antagonist, and potassium channel opener—
highlight its potential in effectively managing and
treating various types of pain.
Mitragynine’s mechanisms of actions also
suggest significant potential in the treatment of
pain but through unique polypharmacology
pathways (summarized in Figure 2
).
Figure 2.
Figure 2
Open in a new tab
Polypharmacology of mitragynine, the principal
indole alkaloid derived from Mitragyna speciosa.
Mu-Opioid Receptor (MOR) Partial Agonist:
Mitragynine acts as a partial agonist at mu-
opioid receptors (MOR), which are primary
targets for traditional opioid analgesics. With a
binding affinity of approximately 0.233 μM,
mitragynine can activate MOR to produce
analgesic effects but with limited efficacy
compared to full agonists like morphine. This
partial agonism allows mitragynine to provide
pain relief while significantly reducing the side
effects typically associated with opioid receptor
activation, including respiratory depression and
high potential for addiction. The decreased
ability to fully activate MOR is linked to a
reduced risk of tolerance development, meaning
that patients are less likely to need increasing
doses over time to achieve the same level of
pain relief. Additionally, the partial agonism at
MOR may result in lower risks of gastrointestinal
side effects, such as constipation, which is a
common issue with traditional opioids [9
,10,11].
Kappa-Opioid Receptor (KOR) Antagonist: In
contrast to its partial agonism at MOR,
mitragynine functions as an antagonist at
kappa-opioid receptors (KOR). KOR activation
is often associated with dysphoria,
hallucinations, and a reduction in reward-
seeking behaviors. By antagonizing KOR,
mitragynine reduces these adverse effects,
potentially providing mood-stabilizing effects
and lessening dysphoric reactions. KOR
antagonism also contributes to pain relief, as
KOR can play a role in modulating pain
perception, especially in conditions where stress
and mood are exacerbated by pain. This dual
MOR agonism and KOR antagonism may offer
a balanced analgesic effect while avoiding some
of the psychological side effects of KOR
agonists [12
].
Competitive Antagonist at Serotonin Receptors
(5-HT2A): Mitragynine acts as a competitive
antagonist at the 5-HT2A serotonin receptor,
which modulates the release of various
neurotransmitters involved in mood, cognition,
and pain perception. By blocking 5-HT2A
receptors, mitragynine can reduce serotonin-
related neurotransmission, which may help in
stabilizing mood and controlling pain perception,
particularly in individuals with anxiety or
depression-related pain. This antagonism is also
thought to reduce anxiety and prevent
overstimulation of neural pathways, contributing
to an improved quality of life for those with
chronic pain [9
,10].
Partial Agonist at 5-HT1A: As a partial agonist at
the 5-HT1A receptor, mitragynine can enhance
serotonin signaling to some extent, particularly
in ways that are anxiolytic and mood-enhancing.
The 5-HT1A receptor is linked to improved
mood and anxiety reduction, both of which are
beneficial in chronic pain management, as pain
can be exacerbated by psychological stress and
anxiety. By partially activating this receptor,
mitragynine may improve the psychological
state of individuals suffering from chronic pain,
which indirectly aids in pain management by
reducing pain perception linked to stress and
anxiety [9
,10].
Binding to 5-HT2B and 5-HT2C Receptors:
Mitragynine has weaker interactions with 5-
HT2B and 5-HT2C serotonin receptors, binding
with a Ki of approximately 1260 nM. While these
interactions are less pronounced than its actions
on other receptors, they may have subtle
modulatory effects on mood and cognition.
Since 5-HT2B and 5-HT2C receptors are
involved in the regulation of mood and appetite,
the slight binding affinity could contribute to
mitigating symptoms like irritability or loss of
appetite in individuals with chronic pain,
although the impact is likely minor compared to
its effects on other receptors [9
,10].
Alpha-2 Adrenergic Receptor Agonist: Acting as
an agonist at alpha-2 adrenergic receptors,
mitragynine engages mechanisms similar to
clonidine, a drug used to manage opioid
withdrawal symptoms. Alpha-2 agonism can
reduce norepinephrine release, which calms the
sympathetic nervous system and provides a
sense of relaxation and reduced arousal. This
agonism is particularly useful for managing
symptoms of opioid withdrawal, including
cravings, irritability, and heightened pain
sensitivity. The activity at alpha-2 receptors may
also contribute to the overall analgesic effect of
mitragynine by reducing sympathetic responses
that can intensify pain perception in stressful
situations [9
,13].
Dopamine D2 Receptor Affinity: Mitragynine’s
affinity for dopamine D2 receptors suggests
potential antipsychotic effects, which may
alleviate symptoms of psychosis in vulnerable
individuals. By interacting with D2 receptors,
mitragynine could theoretically reduce excessive
dopamine activity, which is linked to conditions
such as schizophrenia and bipolar disorder. For
chronic pain patients, this dopaminergic
modulation might help in managing pain
perception and emotional responses, as well as
in mitigating the negative psychological
symptoms sometimes associated with chronic
pain, such as anhedonia and low motivation
[14
].
β-Arrestin Activity: Unlike traditional opioids,
mitragynine does not recruit β-arrestin 2 at the
mu-opioid receptor, which is significant because
β-arrestin 2 recruitment is linked to several
adverse effects of opioids, including respiratory
depression, constipation, and tolerance [15
].
The absence of β-arrestin 2 recruitment in
mitragynine’s mechanism suggests a potentially
safer side effect profile, offering effective pain
relief without the heightened risks associated
with conventional opioids. This property is a
crucial factor in its unique pharmacological
safety, making it a promising candidate for
further research in pain management settings.
Cannabinoid Receptor Modulation: Mitragynine
also interacts with cannabinoid receptors,
particularly CB1 and CB2, which play roles in
modulating pain and inflammation. Research
indicates that mitragynine’s analgesic effects,
particularly in neuropathic pain, may be
mediated through these cannabinoid pathways.
For instance, in models of chemotherapy-
induced peripheral neuropathy, the analgesic
effect of mitragynine was lessened when
cannabinoid receptors were blocked, suggesting
that these receptors are instrumental in its effect
on neuropathic pain. This cannabinoid receptor
interaction provides a unique avenue for pain
relief, especially in complex pain conditions
involving both central and peripheral
mechanisms [16
].
TRPV1 Modulation: Recent studies have shown
that mitragynine may modulate the Transient
Receptor Potential Vanilloid 1 receptor (1), a
non-opioid pathway involved in sensing noxious
stimuli, such as heat and inflammation. By
affecting TRPV1 receptors, mitragynine can
potentially reduce pain signaling in inflammatory
and neuropathic pain conditions. TRPV1
modulation is particularly relevant for pain states
where peripheral sensitization occurs, as
blocking or modulating these receptors
decreases the activation of pain pathways. This
pathway represents an additional analgesic
mechanism that can complement its opioid-like
effects [17
].
The absence of significant Delta-Opioid
Receptor (DOR) activity in both mitragynine and
corynoxeine indicates that their analgesic and
neuroprotective effects are mediated through
other pathways [12
]. DORs are involved in
modulating pain, mood, and neuroprotection,
but DOR agonists are associated with the risk of
convulsions and other adverse effects.
2.2. Pharmacokinetics
Mitragynine, the principal indole alkaloid in
Mitragyna speciosa (kratom), exhibits distinctive
pharmacokinetic properties that are crucial to its
therapeutic applications. It is a lipophilic weak
base (pKa ~8.1) with high plasma protein
binding (85–95%) and undergoes extensive
hepatic metabolism through both phase I
(oxidation, demethylation) and phase II
(glucuronidation, sulfation) pathways.
The pharmacokinetics of mitragynine
demonstrate dose-dependent variations, with
key parameters providing insights into its
behavior. After a single dose, the Cmax ranged
from 17.1 ng/mL (6.65 mg dose) to 125 ng/mL
(53.2 mg dose), while at steady-state
(Cmax,ss), it ranged from 21.4 ng/mL to 143
ng/mL. The Tmax remained consistent across
both single and multiple doses, ranging from 1.0
to 1.7 h. The elimination half-life (t1/2) increased
significantly with dose, ranging from 8.5 h at the
lowest dose to 43.4 h at the highest dose for
single dosing, and from 25.7 to 67.9 h at steady
state. Systemic exposure, measured as
AUC0–∞, increased proportionally with dose,
ranging from 52.8 h·ng/mL to 908 h·ng/mL after
a single dose, while steady-state AUC
(AUC0–τ,ss) ranged from 85.1 h·ng/mL to 958
h·ng/mL. Clearance (CL) decreased with
increasing doses, ranging from 278 L/h at lower
doses to 94 L/h at higher doses, indicating
nonlinear pharmacokinetics. The volume of
distribution (Vd) also increased with dose, from
1349 L to 3788 L for single doses and from
2980 L to 6020 L at steady-state, reflecting
extensive tissue distribution [18
]. These findings
highlight the importance of dose adjustments to
account for significant changes in clearance and
half-life at higher doses.
A significant factor influencing the
pharmacokinetics of mitragynine is the variability
between administering pure mitragynine versus
raw kratom products. Raw kratom contains a
complex mixture of alkaloids and bioactive
compounds that can alter absorption,
metabolism, and clearance, resulting in greater
variability in pharmacokinetic parameters. For
instance, other alkaloids in raw kratom may
competitively inhibit or enhance mitragynine
metabolism, affecting Cmax, Tmax, and t1/2.
Furthermore, no standardization of kratom
formulations or dosing exists, making it
challenging to establish predictable therapeutic
outcomes or mitigate potential adverse effects.
The pharmacokinetics of corynoxeine exhibit
notable differences between normal
physiological conditions and CUMS-induced
depression models, which are essential to
consider for therapeutic applications. In normal
rats, the maximum plasma concentration
(Cmax) of corynoxeine was 407.48 ± 10.87
ng/mL, with a time to reach Cmax (Tmax) of
1.67 ± 0.24 h. In contrast, CUMS-induced
depression rats demonstrated a lower Cmax of
306.83 ± 18.72 ng/mL and a delayed Tmax of
2.33 ± 0.47 h, indicating reduced absorption
under pathological conditions. The elimination
half-life (t1/2) was slightly longer in CUMS-
induced depression rats (2.68 ± 0.30 h)
compared to normal rats (2.40 ± 0.12 h), while
the clearance rate (CL) was faster in the
depression model (18.06 ± 1.36 L/h/kg versus
14.48 ± 0.61 L/h/kg in normal rats), suggesting a
reduced systemic exposure to the compound
[14
].
Additionally, the volume of distribution (Vd) was
significantly higher in CUMS-induced
depression rats (69.15 ± 3.25 L/kg) compared to
normal rats (50.09 ± 2.11 L/kg), implying greater
tissue penetration in the pathological state. The
area under the concentration–time curve (AUC),
representing overall drug exposure, was
reduced in CUMS-induced rats, with AUC0-t
values of 1202.97 ± 39.79 ng·h/mL versus
1495.62 ± 55.23 ng·h/mL in normal rats and
AUC0-∞ values of 1614.48 ± 119.62 ng·h/mL
versus 1914.65 ± 95.66 ng·h/mL, respectively
[14
]. These findings highlight a significant
impact of depression on corynoxeine’s
pharmacokinetics, including reduced absorption,
faster clearance, and greater distribution into
tissues.
The altered pharmacokinetic parameters in the
depression model underscore the influence of
pathological conditions on the behavior of
corynoxeine within the body. These differences
emphasize the need for tailored dosing
regimens in clinical applications to ensure
therapeutic efficacy and safety in patients with
underlying conditions. Understanding these
variations provides a foundation for optimizing
the use of these compounds in different
physiological and pathological contexts.
Furthermore, these disparities underscore the
necessity of further research to optimize
standardization, characterize dose–response
relationships, and establish regulatory
frameworks for the safe and effective clinical
use of mitragynine and kratom products.
3. Discussion
3.1. Summary of Findings
Mitragynine and corynoxeine exhibit significant
potential in effectively managing and treating
various types of pain through their multifaceted
mechanisms of action. When addressing pain
management, there is a large basis of
pharmacotherapy because of the vastly diverse
pathophysiology. While these compounds hold
significant potential in neuropathic pain
(chemotherapy-induced peripheral neuropathy
(CIPN), diabetic neuropathy, postherpetic
neuralgia), inflammatory pain, nociceptive pain
(post-surgical, musculoskeletal), visceral pain
(IBS, endometriosis), and central pain
syndromes (MS, spinal cord injury), cancer pain
is the most notable for effective management.
Cancer pain presents a unique challenge in pain
management due to its complex and
multifaceted nature, often involving a
combination of nociceptive, neuropathic, and
inflammatory components. Traditional opioids
like morphine have long been the mainstay for
cancer pain management; however, their use is
associated with significant drawbacks, including
the risk of tolerance, dependence, respiratory
depression, and constipation. Furthermore,
recent studies have suggested that morphine
and other opioids may promote tumor growth
and metastasis by enhancing angiogenesis and
suppressing immune function [19,20]. This
potentially adverse effect on cancer progression
highlights the need for alternative analgesics
that do not compromise cancer treatment
outcomes.
Mitragynine and corynoxeine offer promising
alternatives to traditional opioids for cancer pain
management. Mitragynine, a partial agonist at
mu-opioid receptors, provides effective
analgesia while reducing the risk of severe side
effects associated with full opioid agonists [16
].
Its lack of beta-arrestin 2 recruitment minimizes
the risks of respiratory depression, constipation,
and tolerance development. Additionally,
mitragynine’s partial agonist activity at 5-HT1A
receptors and antagonist activity at 5-HT2A
receptors may offer mood-enhancing and
anxiolytic benefits, which are crucial for the
overall well-being of cancer patients [10
,21].
Corynoxeine, with its potent anti-inflammatory
and neuroprotective properties, can further
enhance pain relief in cancer patients. Its ability
to reduce inflammation and protect neurons
from damage is particularly beneficial in
managing pain caused by tumor growth and
metastasis [8
,22]. Corynoxeine’s vasorelaxant
effects, mediated through calcium channel
blocking and adrenergic receptor antagonism,
can help alleviate pain associated with tumor-
induced vascular tension and improve blood
flow to affected tissues [6
,22].
Moreover, neither mitragynine nor corynoxeine
has been shown to promote tumor growth,
making them safer options for cancer patients
compared to traditional opioids [23
,24]. By
offering effective analgesia without the risk of
enhancing tumor progression, these compounds
represent a significant advancement in the
management of cancer pain. The combined
pharmacological actions of mitragynine and
corynoxeine, including their opioid receptor
modulation, anti-inflammatory effects, and
neuroprotective properties, position them as
superior alternatives to traditional opioids like
morphine for cancer pain management. Their
potential to provide comprehensive pain relief
while minimizing adverse effects and supporting
overall patient health underscores their
importance in the evolving landscape of cancer
pain therapeutics.
3.2. β-Arrestin Activity
G-protein-coupled receptors such as the opioid
receptors are transmembrane receptors that are
capable of recruiting proteins β-arrestins to
initiate separate cellular signal transduction
pathways [12
]. One of the most promising
aspects of the major alkaloids found
in Mitragyna speciosa is their lack of beta-
arrestin 2 recruitment. Traditional opioids like
morphine and fentanyl not only activate G-
protein signaling pathways to provide pain relief
but also recruit beta-arrestin 2. This recruitment
is associated with many adverse effects, such
as respiratory depression, constipation, and the
development of tolerance and dependence.
Beta-arrestin 2 mediates these effects by
desensitizing the receptors, internalizing them,
and initiating altern
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