Ketamine & Cannabinoids
Ketamine, a dissociative anesthetic, operates primarily through antagonism of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor integral to excitatory neurotransmission and synaptic plasticity. By binding within the receptor's ion channel, ketamine inhibits calcium influx, thereby dampening excitatory neuronal activity. This blockade is not uniform; ketamine exhibits a preference for NMDA receptors on GABAergic interneurons, leading to reduced inhibitory control and a subsequent surge in glutamate release. This glutamatergic burst activates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, initiating downstream signaling cascades involving brain-derived neurotrophic factor (BDNF) and the mammalian target of rapamycin (mTOR) pathway, which are associated with synaptogenesis and antidepressant effects.
Additionally, ketamine's metabolites, such as hydroxynorketamine, may contribute to its pharmacological profile through mechanisms independent of NMDA receptor antagonism, including modulation of nicotinic receptors and enhancement of AMPA receptor activity.
Synthetic cannabinoids (SCs) are a diverse class of compounds designed to mimic the effects of Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of cannabis. SCs exhibit high affinity and efficacy at cannabinoid receptors, particularly CB1 receptors, which are abundantly expressed in the central nervous system. Activation of CB1 receptors by SCs leads to inhibition of adenylate cyclase, modulation of ion channels, and suppression of neurotransmitter release, including glutamate, GABA, and dopamine.
Unlike THC, many SCs are full agonists at CB1 receptors, resulting in more pronounced and unpredictable effects. Some SCs also interact with other receptor systems, such as serotonin and NMDA receptors, contributing to their complex pharmacological and toxicological profiles.
The concurrent use of ketamine and synthetic cannabinoids poses significant risks due to their overlapping and potentially synergistic effects on neurotransmission. Both substances modulate glutamatergic signaling. This bidirectional modulation can lead to dysregulated excitatory neurotransmission, increasing the risk of neurotoxicity, cognitive impairment, and psychiatric disturbances.
Furthermore, both agents can induce psychotomimetic effects, and their combination may exacerbate symptoms such as hallucinations, paranoia, and dissociation.
Cardiovascular effects, including hypertension and tachycardia, may also be amplified, posing additional health risks.
Clinical data on the combined use of ketamine and synthetic cannabinoids are limited; however, case reports and observational studies have documented severe adverse events associated with their co-administration. These include acute psychosis, seizures, and cardiovascular complications.
We have not come across confirmed data on fatal conditions associated with this combination. At the same time, there are no signs of worthwhile positive recreational effects that could cover the risks.
All things considered, we recommend avoiding this combination.
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