![[dr. bob]](/dr-bob-sm.gif)
Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 39 to 63 of 131. Go back in thread:
Posted by linkadge on August 9, 2007, at 8:42:19
In reply to Re: beta carbolines to reverse benzo cognitive pro » FredPotter, posted by Quintal on August 8, 2007, at 15:58:10
I'd have to see more than one study suggesting that long term benzo use causes depression, and that it wasn't associated with something like a nutrient deficiancy, and that it wasn't reversable upon withdrawl.
As for the Nardil comment, I think it is the way the drug affects sleep cycles not the drug itself. Any drug which dramatically reduced REM sleep in such a way would be sure to have an effect on learning and memory.
Anyhow, its also worth questioning if benzos are just creating temprorary depression or long term depression after the drug is withdrawn. The former is not a big deal.
Also it would be worth studying which benzos were supposed to have lead to depression, because depressive reactions are not always a class effect.
Linkadge
Posted by linkadge on August 9, 2007, at 9:00:13
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by Quintal on August 8, 2007, at 17:11:02
>But they're no panacea and they have cause much >suffering to the people who became involuntarily >addicted to them, and they've also claimed lives >in the form of suicide resulting from benzo->induced depression.
Depression and suicide are two entirely different things. According to the most recent studies, a suicide victom shows very specific abnormalties aside from the average depressed person. I don't think it is fair to say that a drug that induces depression is completely responsable for a suicide.
>The SSRIs are pretty much a crap shoot as a >monotherapy for all but the mildest conditions, >as most of us here know.
While the SSRI's don't work for everybody, I don't think there is any solid data to suggest that severe depression responds significantly more poorly to SSRIs than to other drugs. Sure, TCA's and MAOI's can sometimes help resistant patients, but there need not be a correlation between depresison sevarity and treatment resisance. There are plenty of severe depressions that have responded to current treatments including SSRI's.
>Don't we all want safer, more effective >anxiolytics? I'm thinking, for example, of the >synthetic flavonoid 6,3'-dinitroflavone that's >said to have fewer adverse effects on learning >and memory than classical benzos.
Yes, but just because it is natural doesn't mean it can't have bad side effects of its own. I had a hell of a withdrawl from valerian. Valerian withdrawl can actually cause cardiac failure. While I prefer chamomile, I can get depressed if I drink too much, and I also have withdrawl if I stop it abruptly. Only time would verify if this flavanoid is truly as devoid of cognative symptoms as is stated.
>Yes, remedies like beta carbolines might be >helpful for reversing some of the side effects, >but it's odd that we have a thread of people >approving of a remedy for a problem they deny >exists.
People have the right to deny it exists, because it honestly may not. It is totally state dependant. Just like there are those of us (God bless their hearts) who don't get SSRI sexual dysfunction. The brain is a mystery, its not possable to say that one drug will affect a person the same way as another.
For instance, a person who is high in estrogen, which desensitizes GABA-A, may have much less effect of a standard dose of valium than somebody who has high progesterone (sensitizes GABA-A).
With the right dose, and the right amount of receptor activation, side effects might be greatly diminished.
>Benzos couldn't be used effectively in a medical >setting unless they caused consistent sedative >and amnesic effects, and they certainly do.Well, seing as they are not approved for inducing amnesia, I can totally see why they could be effective without causing amnesia. You are saying that you read people's minds based on a few studies and some personal experience. The highest concentration of benzodiazapine receptors is in the amydala. For a person who's cognition is hampered by an overactive amydala, who knows how the cognition might actually improve when the amydala is tamed down. Its just like how Dilantin is used as a nootropic. For some people, it apparently improves cognition.
>If equally effective anxiolytics were available >that did not cause cognitive impairment and >amnesia I'm pretty sure we'd all jump at the >chance to take them, and consign the benzos to >retirement in operating theaters and dentists >chairs.
I hope better drugs are developed too.
Linakdge
Posted by Quintal on August 9, 2007, at 10:33:56
In reply to Re: beta carbolines to reverse benzo cognitive pro » Quintal, posted by linkadge on August 9, 2007, at 8:42:19
Benzodiazepines can cause depression with long-term use. This is a well known fact and proven by many studies as well as clinical experience. Heather Ashton has done some excellent work on the subject, have you read it?
Benzodiazepines seem to cause a *progressive* deterioration in mental performance and mood over time, usually several years. So somebody could be relatively unaffected at the beginning, yet over time their cognitive functioning declines and their mood darkens. This happens gradually so it may be attributed to other factors in a person's life. Benzos also lose their anxiolytic efficacy as tolerance develops and after a while fear creeps in from every corner until it's everywhere (agoraphobia/GAD). This too is a well known and documented phenomenon. Interesting, link, that you feel so passionately about the temporary worsening of depression induced by SSRIs, but with benzos, to you this is an acceptable side effect. I often wonder what your views would be like now if you were given benzos as a teenager, not SSRIs, and suffered as a consequence.
Your comments on Nardil. Again, I question their relevance because interference with REM sleep is often said to be one of the central antidepressant mechanisms, not only of MAOIs but SSRIs and some other antidepressants too. So if that were remedied then there is a risk the antidepressant response would vanish too. Therefore if Nardil cognitive impairment was down to REM it would seem that the cognitive impairment is central to the antidepressant (and possibly anxiolytic) response.
This study concludes:
"The main result of this study is that a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability. These data are in line with the knowledge of a lack of efficacy of benzodiazepines in depressive and most anxiety disorders, despite long term treatment. They also confirm the current guidelines which recommend prescribing serotoninergic antidepressants, and not benzodiazepines, when long term treatments are needed for severe and chronic affective disorders."
__________________________________________________1: Encephale. 2007 Jan-Feb;33(1):32-8.
[Anxiety and depressive disorders in 4,425 long term benzodiazepine users in general practice]
Pélissolo A, Maniere F, Boutges B, Allouche M, Richard-Berthe C, Corruble E.
Service de Psychiatrie Adulte et CNRS UMR 7593, AP-HP, Hôpital Pitié-Salpêtrière, 47, boulevard de l'Hôpital, 75013 Paris.
Consumption rates of anxiolytic drugs, and especially of benzodiazepines, remain very high in France compared to other Western countries, whereas clinical guidelines limit their indications to short term treatments and only for some precise anxiety disorders. Recent epidemiologic surveys in the community indicated that more than 15% of people used once or more an anxiolytic drug in the past year. The issue of chronic treatments is particularly crucial because of their poor benefit/risk ratio in most anxiety disorders (limited efficacy, cognitive side effects, withdrawal and dependence problems). To address this important public health issue, and knowing that, in France, benzodiazepines are prescribed mainly by general physicians, our aims were to explore psychiatric diagnoses in GP's patients with chronic use of anxiolytic benzodiazepines. We included 4 425 patients consuming such drugs regularly for six months or more, and assessed their anxiety and depression symptoms through various clinical scales (Hospital Anxiety and Depressive scale - HAD, Clinical Global Impression scale - CGI, Sheehan Disability Scale - SDS, Cognitive Dependence to Benzodiazepines scale - CDB) and with the Mini International Neuropsychiatric Interview for DSM IV criteria. Only 2.2% of the subjects had neither anxious nor depressive symptoms as indicated by low scores on both subscores (less than 8) of the HAD scale, used as a screener. Nearly three quarters of the 4,257 subjects (73.2%), had CGI scores of at least 5 (markedly ill to extremely ill). Social and familial disability was also high in more than 40% of the sample (marked to extreme disruption according to SDS scores). About half of the sample had CDB scores suggesting a benzodiazepine dependence. According to the MINI, 85.1% of the patients had at least one current DSM IV diagnosis of affective disorder. The most frequent diagnoses were major depressive episode (60%), generalized anxiety disorder (61.2%), and panic disorder (22.5%). An anxiety and depressive comorbidity wad found in 41.9% of the subjects. Some methodological limitations must be taken into account in the discussion of our results, and especially the fact that the included patients were not supposed to be totally representative of all patients consuming anxiolytic benzodiazepines in general practice. However, the size of our sample is sufficiently large to limit possible biases in patient selection. The main result of this study is that a great majority of the patients had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability. These data are in line with the knowledge of a lack of efficacy of benzodiazepines in depressive and most anxiety disorders, despite long term treatment. They also confirm the current guidelines which recommend prescribing serotoninergic antidepressants, and not benzodiazepines, when long term treatments are needed for severe and chronic affective disorders. This epidemiologic study leads to the conclusion that a specific and attentive diagnostic assessment should be done in all patients receiving benzodiazepines for more than three months, in order to purpose in many cases other long term therapeutic strategies.
PMID: 17457292 [PubMed - indexed for MEDLINE]
--------------------------------------------------2: Psychopharmacology (Berl). 2006 Nov;188(4):472-81. Epub 2006 Aug 17.Click here to read Links
Effects of the amnesic drug lorazepam on complete and partial information retrieval and monitoring accuracy.
Izaute M, Bacon E.Laboratoire de Psychologie Sociale et Cognitive (LAPSCO-UMR 6024 CNRS), Universite Blaise Pascal, 34 Avenue Carnot, 63037, Clermont-Ferrand Cedex, France. Marie.Izaute@srvpsy.univ-bpclermont.fr
RATIONALE: In Koriat's accessibility model (Koriat, Psychol Rev, 100:609-639, 1993; Koriat, J Exp Psychol Gen, 124:311-333, 1995), when a person fails to recall a required target, he or she can nevertheless provide some partial information about the target. Moreover, individuals are able to provide feeling-of-knowing (FOK) judgments about the availability of the target in memory. The cues for the FOK evaluations reside in the products of the retrieval process itself. It was shown that the benzodiazepine lorazepam drug induces some impairment of memory. OBJECTIVES: The effects of the amnesic benzodiazepine lorazepam on the total and partial recall of recently learned material and on FOK ratings were investigated in healthy volunteers. METHODS: Twenty-eight healthy volunteers participated in the study: 14 of these received a capsule containing lorazepam (0.038 mg/kg) and 14 a placebo capsule. The material to be learned consisted of four-letter nonsense tetragrams with each letter providing partial information with regard to the four-letter target (Koriat, Psychol Rev, 100:609-639, 1993). RESULTS: The number of incorrect letters reported was higher for the lorazepam than for the placebo condition. The FOK magnitude was higher for the placebo participants than for the lorazepam participants. The predictive value of FOK for recognition was preserved by the drug. CONCLUSION: When studying four-letter nonsense letter strings, lorazepam participants present an impairment of episodic short-term memory and the drug has an effect on FOK estimates but not on the predictive accuracy of the FOK. The accessibility hypothesis of FOK was confirmed in this study and seems to retain some validity even under the effect of an amnesic drug.
PMID: 16915380 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Psychopharmacology (Berl). 2004 Mar;172(3):309-15. Epub 2003 Nov 28.Click here to read Links
Benzodiazepines and semantic memory: effects of lorazepam on the Moses illusion.
Izaute M, Paire-Ficout L, Bacon E.Laboratoire de Psychologie Sociale de la Cognition (LAPSCO-UMR 6024 CNRS), Universite Blaise Pascal, 34 Avenue Carnot, 63037 Clermont-Ferrand Cedex, France. Marie.Izaute@srvpsy.univ-bpclermont.fr
RATIONALE: When asked "How many animals of each kind did Moses take on the ark?", people fail to notice the distortion introduced by the impostor "Moses" and respond "two". It has been argued that the effect must be due to the existence of a partial-match process. In most situations, the form of a question is not likely to closely match the memory representation it queries. Thus, for the partial match hypothesis people ignore some semantic distortions. In the same vein, it has been shown that the benzodiazepine lorazepam drug induces some impairments of semantic memory as participants under lorazepam provide more incorrect recalls than placebo do with general information questions. OBJECTIVES: The aim of this study was to investigate the effects of the benzodiazepine lorazepam on the Moses illusion paradigm. METHOD: The effects of lorazepam (0.038 mg/kg) and of a placebo were investigated in 28 healthy volunteers. Twenty-two illusory questions were presented along with 72 normal general information questions. RESULTS: Lorazepam impaired the ability to detect the Moses illusion. Moreover, lorazepam participants appeared less biased to consider a question distorted than placebo participants. CONCLUSIONS: The temporary and reversible semantic memory impairments experienced by participants when falling into the Moses illusion are more frequent under lorazepam. The amnesic drug lorazepam may impair semantic processing as well as the strategic control of memory.
PMID: 14647957 [PubMed - indexed for MEDLINE]
--------------------------------------------------3: Psychopharmacology (Berl). 1995 Nov;122(2):187-93.Links
Encoding, remembering and awareness in lorazepam-induced amnesia.
Curran HV, Barrow S, Weingartner H, Lader M, Bernik M.Clinical Health Psychology, University College London, UK.
The effects of lorazepam (1,2 mg) and placebo on encoding, remembering and awareness were assessed in a study with 54 healthy volunteers. All subjects studied stimulus materials in a levels of processing (L-o-p) task. Half the subjects were assessed on an explicit memory task of word recognition and the other half were given an implicit memory task of word-stem completion. Following the implicit task, awareness of retrieval was further investigated by questions and by subjects' recollective experience in recognising the actual words they had completed from stems. L-o-p effects and marked lorazepam-induced impairments were found in the implicit task of word-stem completion although the interaction between L-o-p and drug effects emerged only as a trend in the data. Lorazepam-induced impairments on stem-completion may then be explained at least in part as being due to contamination by explicit retrieval processes, but we cannot rule out the possible role of drug effects on perceptual processes at encoding. Results from responses to "awareness" questions and from analysis of subsequent recollective experience indicated that subjects were not aware of using explicit retrieval during the implicit task. Results also replicated previous findings showing that both lorazepam and L-o-p independently affect performance in an explicit memory task of word recognition. Thus drug-induced deficits at encoding persist regardless of the level at which information is initially processed.
PMID: 8848535 [PubMed - indexed for MEDLINE]
--------------------------------------------------4: Psychopharmacology (Berl). 1996 Nov;128(2):139-49.Click here to read Links
Effects of oxazepam and lorazepam on implicit and explicit memory: evidence for possible influences of time course.
Stewart SH, Rioux GF, Connolly JF, Dunphy SC, Teehan MD.Department of Psychology, Dalhousie University, Halifax, Nova Scotia, Canada.
The effects of oxazepam (30 mg), lorazepam (2 mg), and placebo on implicit and explicit memory were studied in two testing cycles, 100 and 170 min after drug administration. Thirty healthy volunteers were randomly assigned to one of three groups (placebo, oxazepam, or lorazepam) in a double-blind, independent groups design. Drug groups were equivalent prior to drug administration on a variety of cognitive measures. Following drug administration, both oxazepam and lorazepam equally impaired performance on a cued-recall explicit memory task relative to placebo, at both testing cycles. Relative to placebo, lorazepam markedly impaired priming on a word-stem completion implicit memory task, at both testing cycles. Consistent with previous work, oxazepam failed to produce impairments in priming on the word-stem completion task at 100 min post-drug administration. However, oxazepam was found significantly to impair priming on this latter task relative to placebo, at close to theoretical peak plasma concentration (i.e., 170 min post-drug administration). Explanations for the observed detrimental effect of oxazepam on implicit memory task performance are considered, including: possible time-dependent effects related to the relative rate of absorption of these two benzodiazepines (BZs); and potential contamination of the implicit memory task by explicit memory strategies during the second testing cycle.
PMID: 8956375 [PubMed - indexed for MEDLINE]
--------------------------------------------------5: Psychopharmacology (Berl). 1999 Dec;147(3):266-73.Click here to read Links
Lorazepam impairs both visual and auditory perceptual priming.
Vidailhet P, Danion JM, Chemin C, Kazès M.INSERM Unité 405, Département de Psychiatrie d'Adultes, Hôpitaux Universitaires de Strasbourg, France.
RATIONALE: Lorazepam has been repeatedly shown to impair both explicit memory and perceptual priming, a form of implicit memory, in the visual domain. However, the effects of this benzodiazepine on priming in other perceptual domains, such as auditory priming, have never been explored. OBJECTIVE: The present study investigated whether the deleterious effects of lorazepam on perceptual priming are restricted to the visual domain, or if they could be extended to the auditory domain. METHODS: Thirty-two healthy volunteers were randomly assigned to two parallel groups, placebo and lorazepam 0.038 mg/kg. The drug was administered orally, following a double-blind procedure. In the same subjects, perceptual priming was assessed in the auditory and visual domains using similar word-stem completion tasks, and explicit memory was explored using a free-recall task. RESULTS: Lorazepam markedly reduced free-recall performance for visually and auditorily presented words. Lorazepam equally impaired visual and auditory priming. In the auditory word-stem completion task, prior presentation of a word facilitated perception of its stem in the placebo group. This facilitation effect was not observed in the lorazepam group. The lorazepam-induced impairment of priming was not due to sedation or explicit contamination. CONCLUSION: These results indicate that the deleterious effects of lorazepam on priming are not restricted to the visual modality, but extend to the auditory modality.
PMID: 10639684 [PubMed - indexed for MEDLINE]
--------------------------------------------------6: Psychopharmacology (Berl). 2001 May;155(2):204-9.Click here to read Links
Lorazepam and diazepam impair true, but not false, recognition in healthy volunteers.
Huron C, Servais C, Danion JM.CNRS UMR 7593, Personnalités et Conduites Adaptatives, Hĵpital de la Pitié-Salpétrière, Paris, France.
RATIONALE: The deleterious effects of benzodiazepine on memory are well documented. However, their effects on false memories are unknown. OBJECTIVE: The aim of this study was to investigate the effects of lorazepam and diazepam on false memories and related states of awareness in healthy volunteers. METHODS: The Deese/Roediger-McDermott procedure was used in 36 healthy volunteers randomly assigned to one of three parallel groups (placebo, diazepam 0.3 mg/kg, lorazepam 0.038 mg/kg). Subjects studied lists of words semantically related to a non-presented theme word (critical lure). On a recognition memory task with both previously presented words and non presented critical lures, they were asked to give Remember, Know or Guess responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. RESULTS: The proportions of studied words correctly recognized and the proportions of Remember responses associated with true recognition were lower in the benzodiazepine groups than in the placebo group. In contrast, benzodiazepines did not significantly influence the proportions of critical lures falsely recognized or the proportions of Remember responses associated with false recognition. CONCLUSION: These results indicate that diazepam and lorazepam impair conscious recollection associated with true, but not false, memories.
PMID: 11401011 [PubMed - indexed for MEDLINE]
--------------------------------------------------7: Int Clin Psychopharmacol. 2002 Jan;17(1):19-26.Click here to read Links
Lorazepam, sedation, and conscious recollection: a dose-response study with healthy volunteers.
Huron C, Giersch A, Danion JM.Department of Psychology, Yale University, New Haven, CT, USA.
The role of sedation in the benzodiazepine-induced impairment of conscious recollection is still subject to debate. The aim of this study was to investigate further the role of sedation using the Remember-Know procedure and a physiological measure of sedation based on pupillography in addition to standard measures of sedation and attention (digit-symbol substitution task, symbol cancellation task, self-rated sedation). Twelve subjects were tested after the intake of placebo, lorazepam 0.026 mg/kg and lorazepam 0.038 mg/kg, administered in a randomized order, with a minimum interval of 8 days between each administration. On a recognition memory task, they were asked to give 'Remember', 'Know' or 'Guess' responses to items that were recognized on the basis of conscious recollection, familiarity, or guessing, respectively. Lorazepam selectively impaired recognition based on 'Remember' responses. This impairment was greater in the lorazepam 0.038 mg/kg than in the lorazepam 0.026 mg/kg groups. Measures of sedation were not correlated with the proportion of 'Remember' responses. These results suggest that sedation alone cannot account for the impairment of conscious recollection induced by lorazepam.
PMID: 11800502 [PubMed - indexed for MEDLINE]
--------------------------------------------------8: Clin Neuropharmacol. 2001 Mar-Apr;24(2):71-81.Click here to read Links
Pharmacokinetic and pharmacodynamic analysis of sedative and amnesic effects of lorazepam in healthy volunteers.
Blin O, Simon N, Jouve E, Habib M, Gayraud D, Durand A, Bruguerolle B, Pisano P.Fédération de Pharmacologie Médicale et Clinique et Pharmacocinétique, CHU Timone, Marseille, France.
This study describes for the first time the pharmacokinetic and pharmacodynamic modeling of the psychomotor and amnesic effects of a single 2-mg oral dose of lorazepam in healthy volunteers. Twelve healthy volunteers were included in this randomized, double-blinded, placebo-controlled two-way crossover study. The effect of lorazepam was examined for a battery of tests that explored mood, vigilance, psychomotor performance, and memory. The pharmacokinetic and pharmacodynamic modeling of these tests was performed using the indirect response model. Vigilance and psychomotor performance were significantly impaired. Short-term memory was not affected, but a paradoxical tendency to improvement of the score was observed 0.4 hours after drug intake. Significant impairment was observed for immediate and delayed cued verbal recall, for immediate and delayed free recall, and for picture recognition as well as for visual-verbal recall, but not for cued visual-spatial recall or priming. Globally, the different effects were greatest between 0.4 to 3 hours after dosing. However, the time course profile of the recovery period suggests a possible dissociation between the kinetics of the effects of lorazepam on vigilance, psychomotor performance, and visual episodic memory, on the one hand, and on verbal episodic memory, on the other. The pharmacokinetic and pharmacodynamic model used two compartments with first-order absorption to describe the lorazepam concentrations and an indirect response model with inhibition or stimulation of Kin to describe the effects. The mean values for calculated median effective concentration (EC50) derived from the pharmacokinetic and pharmacodynamic modeling of the different tests ranged from 11.3 to 39.8 ng/mL. According to these EC50 values, lorazepam seemed to be more potent on the delayed-recall trials than on the immediate-recall trials; similar observations were made concerning the free-recall versus cued-recall trials. The previously stated results suggest that the tests performed in this study represent sensitive measurements of the effects of lorazepam on the central nervous system. Moreover, the parameter values derived from pharmacokinetic and pharmacodynamic modeling, especially, the EC50 values, may provide sensitive indices that can be used to compare the central nervous system effects of benzodiazepines.
PMID: 11307041 [PubMed - indexed for MEDLINE]
--------------------------------------------------This is an example of how benzodiazepine GABA-A ligands can be improved to produce fewer amnesic effects:
9: Fundam Clin Pharmacol. 2001 Jun;15(3):209-16.Click here to read Links
Erratum in:
Fundam Clin Pharmacol. 2003 Oct;17(5):643.A double blind parallel group placebo controlled comparison of sedative and mnesic effects of etifoxine and lorazepam in healthy subjects [corrected].
Micallef J, Soubrouillard C, Guet F, Le Guern ME, Alquier C, Bruguerolle B, Blin O.Centre de Pharmacologie Clinique et d'Evaluations Thérapeutiques et Service de Pharmacologie Clinique, UMR-CNRS-FRE-Université de la Méditerranée, Développement et Pathologie du Mouvement, Hôpital de la Timone, 13385 Marseille cedex 5, France.
This paper describes the psychomotor and mnesic effects of single oral doses of etifoxine (50 and 100 mg) and lorazepam (2 mg) in healthy subjects. Forty-eight healthy subjects were included in this randomized double blind, placebo controlled parallel group study [corrected]. The effects of drugs were assessed by using a battery of subjective and objective tests that explored mood and vigilance (Visual Analog Scale), attention (Barrage test), psychomotor performance (Choice Reaction Time) and memory (digit span, immediate and delayed free recall of a word list). Whereas vigilance, psychomotor performance and free recall were significantly impaired by lorazepam, neither dosage of etifoxine (50 and 100 mg) produced such effects. These results suggest that 50 and 100 mg single dose of etifoxine do not induce amnesia and sedation as compared to lorazepam.
PMID: 11468032 [PubMed - indexed for MEDLIN
--------------------------------------------------10: Br J Clin Pharmacol. 1999 Oct;48(4):510-2.Click here to read Links
Pharmacokinetic-pharmacodynamic analysis of mnesic effects of lorazepam in healthy volunteers.
Blin O, Jacquet A, Callamand S, Jouve E, Habib M, Gayraud D, Durand A, Bruguerolle B, Pisano P.Fédération de Pharmacologie Médicale et Clinique et Pharmacocinétique, Marseille, France.
AIMS: To describe the pharmacokinetic-pharmacodynamic modelling of the psychomotor and mnesic effects of a single 2 mg oral dose of lorazepam in healthy volunteers. METHODS: This was a randomized double-blind, placebo-controlled two-way cross-over study. The effect of lorazepam was examined with the following tasks: choice reaction time, immediate and delayed cued recall of paired words and immediate and delayed free recall and recognition of pictures. RESULTS: The mean calculated EC50 values derived from the PK/PD modelling of the different tests ranged from 12.2 to 15.3 ng ml-1. On the basis of the statistical comparison of the EC50 values, the delayed recall trials seemed to be more impaired than the immediate recall trials; similar observations were made concerning the recognition vs recall tasks. CONCLUSIONS: The parameter values derived from PK/PD modelling, and especially the EC50 values, may provide sensitive indices that can be used, rather than the raw data derived from pharmacodynamic measurements, to compare CNS effects of benzodiazepines.
PMID: 10583020 [PubMed - indexed for MEDLINE]
__________________________________________________More later.
Q
Posted by Quintal on August 9, 2007, at 10:45:39
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by linkadge on August 9, 2007, at 9:00:13
>You are saying that you read people's minds based on a few studies and some personal experience.
!?!?!?!?! Do elaborate please, as also point to the passage where I said I could 'read people's minds' based on a few studies and personal experience. I'm certain I said no such thing. So what is this accusation based on?
Q
Posted by LlurpsieNoodle on August 9, 2007, at 11:25:06
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 9, 2007, at 10:45:39
What are some nutritional sources of beta-carbolines?
I'm thinking of taking a coffee and benzo vacation. I have a sleeping pill that is effective, and my AD seems to be doing really well. Perhaps I can channel my nervous energy into something productive.
I suspect that most everyone involved in this discussion is so brilliant that knocking a few IQ points off the top is not going to be devastating.
I have also experienced transient effects in increased intense suicidal thoughts that lasted about 2 weeks after I started cymbalta. This seems to be different in character than the depressive effects of benzodiazepines, which may cause a depressive state akin to long-term alcohol abuse.
-Ll
Posted by FredPotter on August 9, 2007, at 16:05:36
In reply to Re: beta carbolines to reverse benzo cognitive pro » FredPotter, posted by Quintal on August 8, 2007, at 20:22:58
Quintal Benzos help for at least a while so at the start of the trial the benzo group would not have shown their underlying symptoms. To me this indicates that benzos lose their efficacy. They may cause depression but these two conclusions are not separable. It's also not clear what is meant by "abuser".
Fred
Posted by FredPotter on August 9, 2007, at 16:07:53
In reply to Re: beta carbolines to reverse benzo cognitive pro » Quintal, posted by Phillipa on August 8, 2007, at 21:05:24
Yes we're talking about benzo use in general. There will always be exceptions like you and me.
Posted by FredPotter on August 9, 2007, at 16:18:59
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 9, 2007, at 10:33:56
I was given my first benzo (Librium) at age 17 and I'm now 61, after taking them most of my life. I'm thoroughly happy and fulfilled, for which I may have to thank Nardil. I don't think benzos do much now though. They do however still seem to work for flat-out panic, which I haven't had for a long time though
Posted by Quintal on August 9, 2007, at 16:38:41
In reply to Re: beta carbolines to reverse benzo cognitive pro » Quintal, posted by FredPotter on August 9, 2007, at 16:18:59
I was given my first benzo, 4mg Ativan, at 19 and I'm now 25. I'm pleased to hear that you're happy and fulfilled. Everybody deserves to be. I wonder why you got to the point of needing a drug like Nardil though if benzos were so effective? I think we're fairly typical in that few people can take the same psychiatric drug at the same dose and achieve the same effect indefinitely. I disagree with your opinions on the Vietnam study, I think it was fair and the conclusions they reached were reasonable. I hope Nardil keeps you well and functioning for as long as you need it.
Q
Posted by FredPotter on August 9, 2007, at 20:44:32
In reply to Re: beta carbolines to reverse benzo cognitive pro » FredPotter, posted by Quintal on August 9, 2007, at 16:38:41
>I wonder why you got to the point of needing a drug like Nardil though if benzos were so effective
It hardly needs saying but Nardil is an antidepressant and benzos anxiolytics
Posted by Phillipa on August 9, 2007, at 21:00:47
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 9, 2007, at 10:33:56
Guess I'm a freak of nature. Love Phillipa
Posted by Quintal on August 9, 2007, at 21:13:13
In reply to Re: beta carbolines to reverse benzo cognitive pro » Quintal, posted by FredPotter on August 9, 2007, at 20:44:32
Nardil is a powerful anxiolytic. Most people take it for that reason. I remember you saying you started Nardil to control your anxiety.
Q
Posted by Quintal on August 9, 2007, at 21:18:51
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by linkadge on August 9, 2007, at 9:00:13
>People have the right to deny it exists, because it honestly may not.
Look at the title you chose for this thread.
>Yes, but just because it is natural doesn't mean it can't have bad side effects of its own.
6,3'-dinitroflavone isn't natural, it's a synthetic compound derived from a natural flavonoid.
>I had a hell of a withdrawl from valerian. Valerian withdrawl can actually cause cardiac failure. While I prefer chamomile, I can get depressed if I drink too much, and I also have withdrawl if I stop it abruptly.
If this is true, then it bodes badly for you with the much stronger synthetic benzodiazepine receptor agonists. It's illogical that the small amounts of low-bioavailability benzodiazepine-like compounds found in valerian and chamomile tea would produce stronger withdrawal effects than than larger doses of the more potent synthetic benzodiazepines. I know you didn't say that, but it stands to reason that someone who suffers such strong reactions to Valerian and chamomile would fare much worse with Klonopin and Valium under the same circumstances. Perhaps it's a blessing that your doctor, as the guidelines recommend, has restricted you to short courses of low-dose benzos so far. If you'd been taking them for years at high doses I feel sure your experiences would have been different.
>For instance, a person who is high in estrogen, which desensitizes GABA-A, may have much less effect of a standard dose of valium than somebody who has high progesterone (sensitizes GABA-A).
How is this relevant? I'm not intimidated.
>Well, seing as they are not approved for inducing amnesia......
Lorazepam is indicated for peri-operative amnesia in the UK. I don't have any US drug references to hand but I know lorazepam is certainly used, and recommended, as a pre-medication to induce amnesia during medical procedures in the US though, regardless of whether it is licensed for this purpose.
>The highest concentration of benzodiazapine receptors is in the amydala. For a person who's cognition is hampered by an overactive amydala, who knows how the cognition might actually improve when the amydala is tamed down. Its just like how Dilantin is used as a nootropic. For some people, it apparently improves cognition
Same again. None of this changes the fact that therapeutic doses of benzos cause significant amnesia and cognitive impairment.
Q
Posted by linkadge on August 10, 2007, at 9:20:49
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 9, 2007, at 10:33:56
>Benzodiazepines can cause depression with long->term use. This is a well known fact and proven >by many studies as well as clinical experience. >Heather Ashton has done some excellent work on >the subject, have you read it?
The operative word is *can*. Some studies have found that benzodiazapines can augment the effects of antidepressants, and/or have their own antidepressant effect.
See:
http://biopsychiatry.com/clonazepam-depadj.htm
>Benzodiazepines seem to cause a *progressive* >deterioration in mental performance and mood >over time, usually several years. So somebody >could be relatively unaffected at the beginning, >yet over time their cognitive functioning >declines and their mood darkens.I have read some studies allong these lines but I have also read studies that do not support this.
Dr. Paul Cheny uses clonazepam for CFS. His theory, which is supported by some research, is that by restoring "action potentials", clonazepam can be be neuroprotective. He sites some studies suggesting that long term use of clonazepam apparently led to lower rates of Alzheimers. He has a book, I believe, which details his work.
See:
http://www.immunesupport.com/library/showarticle.cfm?ID=3154
>This happens gradually so it may be attributed >to other factors in a person's life. Benzos also >lose their anxiolytic efficacy as tolerance >develops and after a while fear creeps in from >every corner until it's everywhere >(agoraphobia/GAD).Actually thats not necessarily true, and unnecessarily dramatic. Benzodiazapines can provide long term relief for certain types of anxiety disorders. Some researchers have noted that while tollerance builds to the sedative and hypnotic effects, tollerance to the antianxiety does not always develop. I had sucessfully treated pure GAD for about two years on benzodiazapines alone. I had depression from the beginning, but did not notice any specific worsening.
>This too is a well known and documented >phenomenon.
Again, a possable phenomon.
>Interesting, link, that you feel so >>passionately about the temporary worsening of >>depression induced by SSRIs, but with benzos, >to >you this is an acceptable side effect.
I just feel passionately that people should know about possable side effects. While I don't feel its is right that side effects fail to be mentioned, I also don't think it is right to suggest that possable side effects extend to all users.
>I often wonder what your views would be like now >if you were given benzos as a teenager, not >SSRIs, and suffered as a consequence.
Well, actually I was given a benzo as a teenager, and still graduated high school with honors. I was given awards for the highest highschool marks in a few subject areas as well as completing my grade 10 RCM piano on benzodiazapines.
While I know people have had problems with them, I personally think they are *much* safer than SSRI's.
>Your comments on Nardil. Again, I question their >relevance because interference with REM sleep is >often said to be one of the central >antidepressant mechanisms, not only of MAOIs but >SSRIs and some other antidepressants too. So if >that were remedied then there is a risk the >antidepressant response would vanish too.
So what? REM sleep is where the brain regains ballence allong the cholinergic axis. While SSRI's will diminish REM sleep to some extent the MAOI's are known to almost abolish REM sleep for a much longer period than with SSRI's or TCA's. Clomipramine comes close to the MAOI's in terms of REM supression. Although, it is a dumb drug too!
>Therefore if Nardil cognitive impairment was >down to REM it would seem that the cognitive >impairment is central to the antidepressant (and >possibly anxiolytic) response.
Bingo. Many have noted that there is a direct correlation between the efficacy of an antidepressant and its propensity to cause cognitive problems. MAOI's, lithium, ECT, Nortryptaline, Clomipramine, Amitryptaline...some of the most effective antidepressants (clinically).
Linakdge
Posted by linkadge on August 10, 2007, at 9:26:54
In reply to Re: beta carbolines to reverse benzo cognitive pro » FredPotter, posted by Quintal on August 9, 2007, at 16:38:41
There is a very high comobidity between depressive disorders and anxiety disorders.
Sometimes one can predominate for a while, so treating it with a benzo might mask depressive symptoms for a while.
Linkadge
Posted by linkadge on August 10, 2007, at 9:53:14
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 9, 2007, at 21:18:51
>People have the right to deny it exists, because it honestly may not.
>Look at the title you chose for this thread.
I need to elaborate. When I say it may not exist I mean on an individual basis. I personally don't have too bad cognition on benzo's. My reason for this post was simply a pharmachological question based on what I had learned about the beta carbolines. Some people do complain of cognative problems so I was just wondering. This doesn't mean everybody has the problem.
>6,3'-dinitroflavone isn't natural, it's a >synthetic compound derived from a natural >flavonoid.Synthetic or natural, I doubt it is side effect free.
>If this is true, then it bodes badly for you >with the much stronger synthetic benzodiazepine >receptor agonists. It's illogical that the small >amounts of low-bioavailability benzodiazepine->like compounds found in valerian and chamomile >tea would produce stronger withdrawal effects >than than larger doses of the more potent >synthetic benzodiazepines.
You are working under the assumption that the only mechanism of activity is benzodiazapine receptor agonism. I had worse withdrawl from SJW than I did from SSRI's, even though SJW has less effect on the serotonin transporter than an SSRI.
>I know you didn't say that, but it stands to >reason that someone who suffers such strong >reactions to Valerian and chamomile would fare >much worse with Klonopin and Valium under the >same circumstances.
Probably, but it depends. Valerian has effects of adenosine, 5-ht1a, gaba reuptake, gaba-a, bdz, and serotonin transport.
>Perhaps it's a blessing that your doctor, as the >guidelines recommend, has restricted you to >short courses of low-dose benzos so far.I am permitted to take upto 1mg of clonazepam on a daily basis.
>If you'd been taking them for years at high >doses I feel sure your experiences would have >been different.
Have you been taking them for years? Unfortunately, "I feel dumber", isn't really a thorough scientific assesment. A few studies can only really "suggest" things. If you are about to jump on the bandwagon of some synthetic anxiolytic under the guise that a few animal studies suggest it is safe(r), than other pharmacuticals, you may want to wait a little while.
>How is this relevant? I'm not intimidated.
Well, I don't know what you mean by intimidate. I was simply stating that the individual allosteric regulation of gaba-a receptors may be of particular importance to the sensitivity an individual has to benzodiazapines.
>Same again. None of this changes the fact that >therapeutic doses of benzos cause significant >amnesia and cognitive impairment.
Again, you may want to use the word "can". Otherwise I will have completed a awefull number of cognitivly demanding tasts with significant amnesia and cognative impairment. Well, I guess thats a complimenent.
Linkadge
Posted by Quintal on August 10, 2007, at 13:04:15
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by linkadge on August 10, 2007, at 9:53:14
>I personally don't have too bad cognition on benzo's.
I feel the operant word here is 'too'.
>Have you been taking them for years?
I took benzos for about five years. I've been off them for over a year.
>Unfortunately, "I feel dumber", isn't really a thorough scientific assesment.
I'm not sure where that statement came from, but I'm sure I didn't say it. There are a huge number objective scientific studies from a wide variety of sources demonstrating amnesia and cognitive impairment at therapeutic doses of benzodiazepines. The fact that you can find a handful to the contrary based on some esoteric mechanism or medical condition doesn't alter the conclusions of the overwhelming body of scientific evidence. You can't prove a negative.
>A few studies can only really "suggest" things.
A *lot* of studies support the fact that benzodiazepines cause significant amnesia and cognitive impairment at therapeutic doses. When a finding is easily replicated by independant researchers around the word this forms evidence. Collecting these studies is easy as apple-gathering in the fall, they being so plentiful. To find studies to the contrary you need to go cherry-picking.
>If you are about to jump on the bandwagon of some synthetic anxiolytic under the guise that a few animal studies suggest it is safe(r), than other pharmacuticals, you may want to wait a little while.
I'm jumping on no bandwagons link. I'm inclined to ask you to read that statement, reflect on it a while, then review my post further up this thread containing the amnesia studies.
>Again, you may want to use the word "can". Otherwise I will have completed a awefull number of cognitivly demanding tasts with significant amnesia and cognative impairment.
I disagree with this. I too went to college and got decent grades, top of my class in biology, passed my driving test etc. Still, I was significantly impaired compared to my unmedicated state.
Q
Posted by Quintal on August 10, 2007, at 14:41:52
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 10, 2007, at 13:04:15
I can't be the only one that's getting sick and tired of this thread. As a concession to peace I'm willing to concede this:
The overwhelming majority of studies show significant cognitive impairment at typical therapeutic doses of benzodiazepines in the majority of volunteers. However, there is evidence that a minority of individuals, by dint of either leviathan brain or quirk of metabolism, or possibly some other unknown mechanism, can consume small-to-moderate doses of benzodiazepines with little adverse effect on learning and memory.
Q
Posted by linkadge on August 10, 2007, at 14:59:20
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 10, 2007, at 13:04:15
>I feel the operant word here is 'too'.
Alright, ha ha. I major in math and physics; bad spelling/grammer is a prerequisite.
>I'm not sure where that statement came from, but >I'm sure I didn't say it. There are a huge >number objective scientific studies from a wide >variety of sources demonstrating amnesia and >cognitive impairment at therapeutic doses of >benzodiazepines.
Yes, but only a small number of them are assesing the potential for such side effects to be long term / permanant. The only side effects are somewhat proven to occur in some patients are short term cognative problems which really don't concern me.
The assertion that benzodiazapines cause permanant brain damage is intrinsically a very challenging one to establish. Comorbidity, comedication, multiple substance use / alchohol use. Secondary effects such as masking of vitamin deficiancies. Asessment times (ie sufficiant time would need to be given for a complete withdrawl).
A more accurate assesment would compare long term benzodiazapine users with drug naive age matched individuals with an anxiety disorder. Ie. to asess the effect of an anxiety disorder itself on cognition. The effect of a stressfull lifestyle would also need to be accounted for. Stressfull lifestyles are linked to cognative decline!
As a side example, studies designed to asess the effect of long term neuroleptic use on cognition are generally difficult seeing as neuroleptic naive age matched (disease duration matched) schizophrenics also generally show cognative disturbance. (There is a progressive loss of grey matter in schizophrenia with or without treatment)
>The fact that you can find a handful to the >contrary based on some esoteric mechanism or >medical condition doesn't alter the conclusions >of the overwhelming body of scientific evidence. >You can't prove a negative.
I still don't see what you are getting at. The notion that long term benzo use leads to permanant cognative decline is a relativly recent one. Only time will help to clarify the incidence / validity of such preliminary claims.
>A *lot* of studies support the fact that >benzodiazepines cause significant amnesia and >cognitive impairment at therapeutic doses. When >a finding is easily replicated by independant >researchers around the word this forms evidence. >Collecting these studies is easy as apple->gathering in the fall, they being so plentiful. >To find studies to the contrary you need to go >cherry-picking.
Hundreds of studies have established the possability that SSRIs can cause sexual side effects. That doesn't mean everybody gets them.
I don't see what you are trying to say(?).>I'm jumping on no bandwagons link. I'm inclined >to ask you to read that statement, reflect on it >a while, then review my post further up this >thread containing the amnesia studies.
I don't even think we are arguing the same thing here. I agreed with you in the beginning that benzodiazapines *can* cause cognative side effects or else I woudn't have started this thread!!?
>I disagree with this. I too went to college and >got decent grades, top of my class in biology, >passed my driving test etc. Still, I was >significantly impaired compared to my >unmedicated state.
Thats great. You cannot proove however, that every individual who takes a benzodiazapine looses cognative capacity. Infact just the existence of one study suggesting that benzdiazapine use can improve cognative performance makes it impossable to prove a totality.
The doses of benzodiazapine I use to help anxiety, are in the magnitude of those used in this study.
Linakdge
Posted by Quintal on August 10, 2007, at 15:40:17
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by linkadge on August 10, 2007, at 14:59:20
>Yes, but only a small number of them are assesing the potential for such side effects to be long term / permanant. The only side effects are somewhat proven to occur in some patients are short term cognative problems which really don't concern me.
Well they concern me, and their existence is confirmed by these studies. The evidence shows that cognitive problems last as long as treatment continues, and that the risk of depression increases with length of treatment, so this is a concern for anyone taking benzodiazepines long-term.
>The assertion that benzodiazapines cause permanant brain damage is intrinsically a very challenging one to establish.
Linkadge, I said no such thing. There is no evidence as yet that benzodiazepines cause permanent brain damage. Heather Ashton herself confirms this. At worst, there are functional changes at receptors that may cause lingering withdrawal symptoms in a minority of individuals. In my own case the withdrawal symptoms disappeared within the first month, full psychological adjustment to living without benzos took longer of course. The cognitive and memory problems were resolved within a week of quitting.
>I still don't see what you are getting at.
I'm saying that the overwhelming body of evidence demonstrates significant cognitive and memory impairment at typical therapeutic doses of benzodiazepines in the majority of subjects. For some people this is a serious problem, others a nuisance, and a small minority seem to be unaffected. When questioned many benzodiazepine users claim to be unaffected, but objective studies of their performance show otherwise. It should be borne in mind that people under the influence of alcohol (and many other drugs) tend to dangerously overestimate their performance and competence, even to the point of denying any impairment at all. The evidence shows a similar effect with benzodiazepines.
>The notion that long term benzo use leads to permanant cognative decline is a relativly recent one. Only time will help to clarify the incidence / validity of such preliminary claims.
See above.
>Hundreds of studies have established the possability that SSRIs can cause sexual side effects. That doesn't mean everybody gets them.
Again, how is this relevant to a discussion of benzodiazepines? I think I've made considerable effort already to be fair in saying a small minority seem to be unaffected by the amnesic and cognitive blunting effects of small doses of benzodiazepines. However, the overwhelming body of evidence demonstrates significant cognitive and memory impairment at typical therapeutic doses of benzodiazepines in the majority of subjects.
>I agreed with you in the beginning that benzodiazapines *can* cause cognative side effects or else I woudn't have started this thread!!?
Yes, that would be logical. However, I think you've spent the majority of this thread trying to prove the contrary.
>You cannot proove however, that every individual who takes a benzodiazapine looses cognative capacity.
I have said no such thing.
>Infact just the existence of one study suggesting that benzdiazapine use can improve cognative performance makes it impossable to prove a totality.
I am not trying to prove a totality. I *am* saying the overwhelming body of evidence demonstrates significant cognitive and memory impairment at typical therapeutic doses of benzodiazepines in the majority of subjects.
Q
Posted by cactus on August 10, 2007, at 16:47:27
In reply to Re: beta carbolines to reverse benzo cognitive pro » linkadge, posted by Quintal on August 10, 2007, at 15:40:17
All I know is that if I get a little drowsy from my benzo's I'll have a coffee and I'm fine
Posted by Quintal on August 10, 2007, at 17:10:52
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by cactus on August 10, 2007, at 16:47:27
I did more or less the same thing cactus. Actually, we haven't even got round to looking at the original study on beta-carbolines yet have we? Could you dig it out for us please link? I think Ms. Noodle asked a question on this subject further up the thread.
Q
Posted by cactus on August 10, 2007, at 17:28:05
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by Quintal on August 10, 2007, at 17:10:52
> I did more or less the same thing cactus. Actually, we haven't even got round to looking at the original study on beta-carbolines yet have we? Could you dig it out for us please link? I think Ms. Noodle asked a question on this subject further up the thread.
>
> QThanks qunital, I'm having a coffee right now, well it is 8:30 in the morning on a cold wet winters day.
Posted by cactus on August 10, 2007, at 17:29:44
In reply to Re: beta carbolines to reverse benzo cognitive pro, posted by Quintal on August 10, 2007, at 17:10:52
and I just took my zoloft and rivotril
Posted by Quintal on August 10, 2007, at 17:59:59
In reply to Re: beta carbolines to reverse benzo cognitive pro » Quintal, posted by cactus on August 10, 2007, at 17:28:05
I think all of us on this thread click on our notification updates with a feeling of trepidation and foreboding, so it was a welcome surprise to see your posts cactus. Strange to think of you hanging upside down there beneath my feet, sipping your coffee and quaffing your Rivotril as I type. All of us spinning round on a giant ball, itself just a tiny speck of dust, hurtling through an endless vacuum. Winter in the middle of summer indeed. But enough of my philosophical musings.
Guarana was quite effective at reversing benzo-induced sedation. I'm not sure if it contains beta-carbolines, mainly caffeine and other xanthines if I remember correctly. Gotu Kola also had some beneficial effects.
Q
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