Andrew C. Kruegel's research while affiliated with Columbia University and other places

Publications (16)

Article
Background and purpose: Mitragynine, the major alkaloid in Mitragyna speciosa (kratom), is a partial agonist at the mu-opioid receptor (MOR). CYP3A-dependent oxidation of mitragynine, results in the metabolite 7-OH mitragynine, a more efficacious MOR agonist. While both mitragynine and 7-OH mitragynine can induce anti-nociception in mice, recent e...
Preprint
Substance use and related mental health epidemics are causing increasing suffering and death in diverse communities. Despite extensive efforts focused on developing pharmacotherapies for treating substance use disorders, currently approved medications do not reverse the persistent neurocircuitry and psychological changes that underlie addiction sta...
Article
Full-text available
Mitragynine (MG) is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We have developed a synthetic method for selective functionalization of the unexplored C11 positio...
Preprint
p>Mitragynine is the most abundant alkaloid component of the psychoactive plant material “kratom”, which according to numerous anecdotal reports shows efficacy in self-medication for pain syndromes, depression, anxiety, and substance use disorders. We developed a new synthetic method for selective functionalization of the unexplored C11 position of...
Article
Full-text available
Kratom (Mitragyna speciosa) is a tree-like plant indigenous to Southeast Asia. Its leaves, and the teas brewed from them have long been used by people in that region to stave off fatigue and to manage pain and opioid withdrawal. Evidence suggests kratom is being increasingly used by people in the United States and Europe for the self-management of...
Article
Mitragyna speciosa, more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability, have...
Preprint
p> Mitragynina speciosa , more commonly known as kratom, is a plant native to Southeast Asia, the leaves of which have been used traditionally as a stimulant, analgesic, and treatment for opioid addiction. Recently, growing use of the plant in the United States and concerns that kratom represents an uncontrolled drug with potential abuse liability,...
Article
The leaves of Mitragyna speciosa (commonly known as kratom), a tree endogenous to parts of Southeast Asia, have been used traditionally for their stimulant, mood-elevating, and analgesic effects and have recently attracted significant attention due to increased use in Western cultures as an alternative medicine. The plant's active alkaloid constitu...
Article
Full-text available
Depression is a debilitating chronic illness that affects around 350 million people worldwide. Current treatments, such as selective serotonin reuptake inhibitors (SSRIs), are not ideal because only a fraction of patients achieve remission. Tianeptine is an effective antidepressant with a previously unknown mechanism of action. We recently reported...
Article
Mu-opioid receptor agonists represent mainstays of pain management. However, the therapeutic use of these agents is associated with serious side effects, including potentially lethal respiratory depression. Accordingly, there is a longstanding interest in the development of new opioid analgesics with improved therapeutic profiles. The alkaloids of...
Article
Modulation of growth factor signaling pathways in the brain represents a new experimental approach to treating neuropsychiatric disorders such as depression, anxiety, and addiction. Neurotrophins and growth factors exert synaptic, neuronal, and circuit level effects on a wide temporal range, which suggests a possibility of rapid and lasting therape...
Article
The iboga alkaloids have attracted considerable attention in both the scientific community and popular media due to their reported ability to reverse or markedly diminish cravings for, and self-administration of, the major drugs of abuse. We have developed three new intramolecular C-H functionalization procedures leading to the core seven-membered...
Article
Full-text available
Current pharmacological treatments of depression and related disorders suffer from major problems, such as a low rate of response, slow onset of therapeutic effects, loss of efficacy over time and serious side effects. Therefore, there is an urgent need to explore new therapeutic approaches that address these issues. Interestingly, the atypical ant...

Citations

... It is currently believed that the µOR dependent oral analgesic actions of kratom are derived from the metabolism of mitragynine to 7-hydroxy mitragynine (7OH) 8 . Recent reports have also shown that MP is a minor metabolite of mitrgynine 9,10 . Previously, we synthesized and systematically examined the pharmacological behaviors of a series of mitragynine-based natural products and analogs that included mitragynine, 7OH, and MP both in vitro and in vivo. ...
... All rights reserved ibogaine. One is peer reviewed (Cameron et al., 2021), and the other awaiting peer review (Havel et al., 2021). Due to the low toxicity and lack of hallucinogenic properties of these new molecules, they represent potential non-hallucinogenic derrivatives of hallucinogenic parent molecules with therapeutic effect. ...
... Further, we assess the locomotor effect, constipation, and conditioned-place preference induced by kratom, mitragynine, and its opioid-active metabolites, in order to better clarify the interaction of these compounds in mediating the side effect profile of the kratom plant. extracted from kratom leaves as described before by Varadi et al. 7 The alkaloid derivatives, namely, 7-hydroxymitragynine (7OH), 34 9-hydroxy corynantheidine (9OH), glucuronyl 9hydroxycorynantheidine (9G), 3-dehydromitragynine (3DM), 35 and mitragynine pseudoindoxyl (MP), 7 were found as the major metabolites of mitragynine ( Figure 1B, discussed in a later section) in mice dosed per os (po). The syntheses of 7-hydroxymitragynine, 9-hydroxycorynantheidine (9OH), and MP were accomplished by following our previously reported procedure. ...
... 7 Broyan and colleagues cited a paper 8 with an estimated "KUD prevalence" of 0.8%, which was derived from a different assessment method (the Drug Abuse Screening Test-10), meaning KUD was not evaluated; interpretations of those findings are debated. 9,10 Our own surveys of kratom-using adults using modified DSM checklists showed higher rates of past-year KUD (12.0% and 29.5%, respectively). 5,6 DSM-based assessments also permit reporting important caveats: among people meeting KUD criteria, symptom counts were predominantly mild-moderate and driven by tolerance and withdrawal rather than impairments of daily functioning. ...
... Kratom's DEA status is largely due to insufficient data for appropriate scheduling and concerns about the public-health risks of banning licitly marketed kratom. 2,3 We advocate for operationalized clinical definitions of KUD and accuracy reporting KUD prevalence KUD is not a formally recognized diagnosis, so descriptions need to detail its conceptualization and measurement. The term KUD (used by Broyan and colleagues) evokes the diagnostic system of the DSM-5, 4 in which substance use disorders (SUDs) are diagnosed by the presence of 2-11 criteria. ...
... Current research indicates that mitragynine is metabolized by CYP enzymes to 7-hydroxymitragynine which may account for some of the analgesic effects. 32 Another metabolic pathway for activation of mitragynine is metabolism via an esterase to a pseudoindoxyl which has also shown activity at opioid receptors. 33 ...
... 18 Such data cannot be extrapolated to humans via simple linear transformations, 19 and extrapolation in this instance is further complicated because 7-HMG is only one of many kratom alkaloids. 20 Presently, assessment of human dose-effect relationships for kratom is probably best done with human data. ...
... Although several alternative mechanisms have been proposed over the years, Gassaway et al. (2014) discovered that tianeptine acts as a low-affinity but high-efficacy mu opioid receptor (MOR) agonist. Subsequent experiments in rats suggested that tianeptine's agonist activity at MOR is necessary for its antidepressant and other behavioral effects such as antinociception (Samuels et al. 2017). However, the degree to which tianeptine produces opioid-like abuse potential and other common opioid side effects remains unclear. ...
... 23 Aside from academic endeavors, mitragynine and other kratom indole alkaloids served as precursors for patented opioid agonist compounds that may at some point be developed into drugs. 24 Various in vitro and in vivo studies of mitragynine have clarified its action at opioid receptors over the past decade and identified it as a biased partial agonist at the μ-opioid receptor lacking recruitment of β-arrestin 2. [25][26][27] Furthermore, mitragynine is a competitive κ-opioid and δ-opioid receptor antagonist. In all cases, the effects of mitragynine can be reversed with administration of a competitive non-selective opioid receptor antagonist such as naloxone or naltrexone. ...
... In this conte the development of small molecules, brain-permeable and capable of inducing GDNF pression in the CNS, has attracted interest [11][12][13]. Previous reports in the literat showed that N-indolylethyl-substituted isoquinuclidines with disconnected heteroar and isoquinuclidine systems of the iboga skeleton act as potent GDNF-releasers in the glioma cell line [14,15]. This cell line is commonly used as an astrocyte model [16,17] t is able to express GDNF in response to different stimuli, including a variety of small m ecules [13,[18][19][20][21][22][23]. ...