Tag Archives: glutamate

schizophrenia

Cannabidiol may treat psychosis while tetrahydrocannabinol can induce schizophrenia in those susceptible  

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

There is a well-known correlation of use of cannabis whether it is medical or recreational to the onset of schizophrenia. It unclear if this could be to a direct correlation and disinhibition of the genetic component or the behavior of using it is a prodrome leading up to schizophrenia. This review seeks to elucidate the mechanisms in the correlation of the use of cannabis and onset of schizophrenia.

Mechanisms related to the underlying genetic composition

Schizophrenia may be linked when some of the normal pathways become disrupted with an introduction of THC.  There are 4 genes that were described after a lifetime use of cannabis including KCNT2 which were THC responsive, NCAM1 and CADM2 are significant in functioning in post-synapse. With THC in the system, there are more post-synaptic density genes (1).

Mechanisms related to other neurotransmitter pathways influenced by cannabinoids

In one study, because of the alarming rate of potent synthetic cannabis used recreationally which was found to leave long-lasting schizophrenia disorder in recreational users, this has accelerated research into the pathophysiology. Because cannabinoids work on the CB1 receptor, it is likely that it plays a modulatory role on the other neurotransmitters that can give rise to schizophrenia including dopaminergic, glutamatergic and serotonergic pathways. These pathways are well-established as playing a role in a pro-psychotic state. High efficacy synthetic cannabinoids which are manufactured for recreational purposes are highly more potent compared to natural organic cannabinoids and there is an alarming increase in the correlation of schizophrenia in these users (2).

In one study it is thought to be due to the hypofunctioning of the glutamate system which is directly affected by THC. Exposure to tetrahydrocannabinol appears to reduce the activity at the level of the glutamate receptor as well as deregulate genes for synaptic function(1).

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Susceptibility is related to the development of schizophrenia

In one animal model, the set-up tried to mimic a more real state seen where not all adolescents exposed to synthetic cannabinoids react by developing schizophrenia, there are some studies where all animals develop schizophrenia with exposure. In this animal model, they provided a model that resembles the human model more closely and found that exposure to synthetic cannabinoids in schizophrenia-prone animals caused hyperfunctioning of dopaminergic pathways compared to the control group who were not susceptible at the same dosages. There may be underlying genetic or environmental factors that cause certain individuals to become more prone (2).

THC can cause anxiety and behavioral disorders but can be prevented with CBD

In one animal study, it was found in a rat study that THC can induce anxiety and behavioral disorders. With THC  administration object recognition was impaired in adolescent rates. The studies support effect on the developing brain in relation to cognitive impairment in the animal model. In addition, when rats were exposed to THC there was increased marble burying behavior which in scientific research is thought to signify anxiety or obsessive-compulsive type behavior usually ameliorated with serotonin reuptake inhibitors or benzodiazepines(4).

It was found, however, that a combination of CBD and THC or cannabidiol alone was administered, these behaviors were not produced or produced only minimally. The thought is that CBD is an allosteric competitive inhibitor at the CB1 receptor so that one sees less of the toxic undesirable effects of THC if administered alone (4).

Cannabinoids have a similar profile to atypical anti-psychotics and may be a possible adjunctive treatment in the treatment of psychotic events (5).

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In summary

There is historical evidence that exposure to THC can give rise to schizophrenia in those individuals that are susceptible accounting for the fact that it does not happen to everybody exposed to it. This is related to its influence on serotonergic, dopaminergic and glutamate pathways. THC can induce anxiety, repetitive behaviors which are ameliorated by CBD. CBD may be a useful adjunctive treatment for psychotic disorders. However, the elucidated mechanisms are based on scientific research based on animal models which may not translate into humans.

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References

  1. Guennewig, et al, “THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorder,” Transl. Psychiatry, 2018, Apr., 8(1):89.
  2. Fantegrossi, et al, “Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin and glutamate systems, Drug Metab. Review, 2018, Jan, 50(1)
  3. Aguilar, et al, “Adolescent synthetic cannabinoid exposure produces enduring changes in dopamine neuron activity in the rodent model of schizophrenia,” Int. J. Neurpsychopharmacol., 2018, Apr., 31 (4):393-403.
  4. Murphy, et al, “Chronic adolescent delta9-tetrahydrocannabinol treatment of male mice leads to long-term cognitive behavioral dysfunction which is prevented by concurrent cannabidiol treatment,” Cannabis Cannabinoid Res., 2017, 2(1):235-246.
  5. Deiana, et al, “Medical use of cannabis: a new light for schizophrenia?” Drug Test Analysis, 2013, Jan., (5)1:46-51
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Epilepsy

Ketogenic diet and its variants, modified Atkins diet and medium-chain triglyceride ketogenic diet and control of seizures

Virginia Thornley, M.D, Neurologist, Epileptologist

March 6, 2018

Introduction

In the past decade, different modifications of the ketogenic diet have evolved given the high intolerance to the side effects of the classic ketogenic diet and poor adherence to the strict regimen. Other variants have had similar effects in achieving control of seizures. The ketogenic diet remains a viable treatment option in patients medically refractory to conventional agents and should not be discounted as part of the armamentarium of the epileptologist or neurologist who treats patients with seizures.

 

 

Studies and classic ketogenic diet

In one small trial of febrile related seizures, 7 children with medically refractory febrile infection-related epilepsy syndrome (FIRES)were followed, 6 had less frequent and less severe seizures. On average, 4 antiepileptic agents were weaned (1). FIRES is a febrile related convulsion syndrome that starts during childhood where febrile seizures are thought to induce a cytokine reaction that occurs post-infectiously(2). In one remarkable study of 77 patients with refractory status epilepticus, only one patient had a shortened acute phase in response to ketogenic diet, 2 to anesthesia and 1 in response to IVIG, all other treatment modalities including conventional IV medications failed to shorten the acute phase (6).

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In several case reports of pediatric patients in status epilepticus, the ketogenic diet was used to stop the continuous seizures. In 10 patients in one case series, all 10 pediatric patients were in continuous status epilepticus. 4 patients had focal partial status epilepticus while 6 had generalized status epilepticus. The patients had a mean duration of seizures of 18 days. The mean time for achievement of ketosis was 7 days of which 9/10 patients stopped having continuous seizures during that timeframe(4).

Modified Atkins diet and seizure control

In one study of 14 patients, the modified Atkins diet seemed to be better tolerated than the ketogenic diet. The diet was well-tolerated by 86%. 7 (50%)remained on the diet after 6 months and 36% had a 50% reduction in seizures 21% were seizure free. Strong ketosis appeared to be key in controlling the seizures (5).

Medium chain triglyceride ketogenic diet 

In another variation, the medium-chain triglyceride ketogenic diet, ketones have been challenged as the substrate for control of seizures. It has been shown that medium-chain fatty acids can work through the AMPA receptors where the excitatory neurotransmitter glutamate binds, as the mechanism for controlling seizures and by changing the bioenergetics of the mitochondria (3).

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References:

  1. Gofshteyn, et al, “Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome in acute and chronic phases,” Journal of Child Neurology, 2017, Jan.,32(1):35-40.
  2. Gaspard, et al “New onset refractory epilepticus (NORSE) and febrile infection-related epilepsy syndromes (FIRES): state of the art and perspective,” Epilepsia, 2018, Feb., doi:10:1111/epi. 14022 (Epub ahead of print)
  3. Augustin, et al, “mechanism of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorder,” Lancet Neurology, 2018, Jan., 17(1):84-93.
  4. Appavu, et al, “Ketogenic diet treatment for pediatric super-refractory status epilepticus,” Seizure, 2016, Oct., 41:62-65.
  5. Kang, et al, “Use of modified Atkins diet in intractable childhood epilepsy,” Epilepsia, 2007, Jan. 48(1):182-186.
  6. Kramer, et al, “Febrile infection-related epilepsy syndrome(FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children,” Epilepsia, 2011, Nov., 52 (11):1956-1967.

 

 

 

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Epilepsy, pain

Cannabidiol: Is there any scientific evidence? Review of some of the novel mechanisms of action in analgesic, anti-epileptic, anti-inflammatory, anti-tumorigenic and anxiolytic effects 

Virginia Thornley, M.D., General Neurologist and Epileptologist

@VThornleyMD

February 16, 2018

Introduction

Cannabidiol (CBD) is the little known medical component without the euphoria used for medical indications such as analgesic, anti-inflammatory, anti-epileptic and anxiolytic effects. In the pathway for endocannabinoids, cannabinoid exerts its therapeutic effects by binding to the CBD1 receptor found in the brains and the nerves exerting their analgesic effects. CBD does not have the same euphoriant effect as THC its counterpart which is better known to the public with much stigma. CBD will need to be 100 times more potent to have the same euphoria as THC making it relatively safe to give without the intoxicating effects. THC or delta-tetrahydrocannabidiol is the main psychoactive component in the marijuana plant, the one finds in the street drugs which has caused such a stigma shadowing the beneficial effects of the plant. Cannabidiol is also thought to work on the 5HT1 receptor giving its anxiolytic properties. This review seeks to understand some of the laboratory research that study the underlying mechanisms for its beneficial actions.

Cannabidiol works on CBD1 receptor and is thought to have an analgesic and anti-inflammatory role in diseases. In many states, it still outlawed to have in possession but growing clinical evidence shows that it can be used in pain syndromes. In the state of Florida there are 10 conditions recognized that can be treated with CBD. It is most commonly used in pain from stage IV metastatic cancer. Cannabidiol has been found to have anti-inflammatory, anti-tumorigenic, analgesic, anti-epileptic and anxiolytic properties.

Analgesic effects

CB1 receptors are found to be expressed in anterior horn cells. The CB2 receptors possibly reduce pain by acting on the neutrophil accumulation and mast cell degranulation which can reduce pain both of these processes increase inflammatory algesia(1).Analgesia has been demonstrated with cannabinoids in visceral inflammation and pain due to peripheral neuropathies, important areas of therapeutic considerations.

Anti-seizure effects

Some of the vast scientific research for cannabinoid is found in the animal models for epilepsy. Cannabinoids exert effects on CB1 and CB2 receptors in the hippocampus where it has a weak affinity(5). CBD1 receptors affect transmission in the synapses through the voltage-gated calcium and potassium channels. There are studies on the effects of CBD in refractory types of epilepsy such as Dravet’s syndrome one of the SCN1a genetic disorders affecting the sodium channel manifesting as severe myoclonic epilepsy. Mechanisms of CBD include increasing excitation of the inhibitory effect of the hippocampus where seizures are propagated.  At low doses, it helps with autism and impaired cognition.  It may exert its effect by working against GPR55(7), TRPV1 in addition to voltage-gated voltage-gated potassium and sodium channels. Another study supports the role that cannabinoids may play in shifting the inhibition of glutamatergic effects and GABAergic effects in the hippocampus mediated by CB1 receptors. In the rat model, it was suggested that seizures can upset the balance of these glutamate and GABA systems (4). 15 minutes after an induced seizure, there is increased 2-arachidonylycerol which is a CB1 agonist suggesting cannabinoids act as a negative feedback loop for seizures(4). In addition, it was found there are more CB1 receptors in the hippocampi with induced seizures compared to control suggesting plasticity of the brain with a compensatory increase in CB1 receptors in response to increased seizures(4). CB2 receptors are related to the immune system and are limited in the CNS. Cannabinoids affect calcium homeostasis and may provide its neuroprotective effects. Growing evidence shows case series, case reports and anecdotal reports on patients having fewer seizures on cannabidiol. Large case-controlled clinical randomized trials are needed.

Anti-tumor effects

There appears to be increased cancel cell death, reduced viability and reduced numbers of metastatic cells. In one study, it is found to reduce epidermal growth factor-induced multiplication and chemotaxis of cells in breast cancer. In mouse models, it inhibits macrophage recruitment in tumor-related cells.n It can potentially inhibit metastasis and proliferation and may provide a novel therapeutic option in breast cancer(2).

Anxiolytic effects

It works on the 5HT1 receptor by altering effects on this receptor the exact mechanism is unknown accounting for anxiolytic properties(6).

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Anti-psychotic effects

CBD may alter the effects of THC and reduce its psychoactive properties (6).

 

Alternative treatment in opioid use

CBD might also work in place of opioids with the growing epidemic of chronic pain and overuse of opioids, CBD may be an alternative analgesic for chronic pain without the effect of tolerance or sedating properties. CBD was found to reduce the reward effects of morphine and does not have the same properties of tolerance. CBD does not have the same euphoria and THC and works on pain(6).

In summary, it is an exciting time for research in the use of cannabinoids. There are innumerable basic science research studies demonstrating the therapeutic effects at the cellular level. Large randomized clinical trials are still needed to gain information in using cannabinoids in humans.

Introduction/Disclaimer

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References

1. Rice, AS, et al, “Endocannabinoids and pain: peripheral and spinal analgesia in inflammation and neuropathy, ” Prostaglandins, Leukotrienes and Essential Fatty Acids, 2002, Feb., 66(2-3)246-256.

2. Elbaz, E. et al, ” Modulation of tumor microenvironment and inhibition of EGF/EGFR pathway: novel mechanisms of Cannabidiol on breast cancer,”Molecular Oncology, 2015, Apr., 9(4):906-919.

3. Welty, W.E., et al, “Cannabinoids: the promises and pitfalls,” Epilepsy Currents, 2014, Sep.-Oct., 14(5):250-252.

4. Wallace, MJ, et al, ” The endogenous Cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy, ” The Journal of Pharmacology and Experimental Therapeutics, 2003, Oct., 307(1):129-137.

5. Gaston, T. et. al, “Pharmacology of cannabinoids in the treatment of epilepsy, ” Epilepsy Behavior, 2017, May, 70:313-318.

6. Volkow, Nora, “The biology and potential therapeutic effects of cannabidiol,” National Institute on Drug Abuse Senate Caucus on International Narcotics Control, 2015, June.

7. Kaplan, et.al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome, “Proceedings of the National Academy of Science, 2017, Oct.

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