Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Wider implications for our understanding of "mental illness"
- Woody Caan (3 December 2004)
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Cellular metabolism and CNS dysfunction yet AGAIN
- Ken M. Jacobie (4 December 2004)
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CANNABIS PSYCHOSIS DEBATE: NEW FACE ON RECOGNISED FACTS.
- Albert M. E. Coleman (4 December 2004)
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Cannabis and copper and zinc upsets increase the risk of psychosis?
- Ellen C G Grant (5 December 2004)
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Parallels in cannaboid, thyroid and transplantation madness.
- Richard G Fiddian-Green (7 December 2004)
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cannabis increasing odds of developing psychosis
- Andrew Campbell (7 December 2004)
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Predisposition to psychosis
- Adam Jacobs (10 December 2004)
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Imputation Sequences in Cannabis Study
- Stefan Kruszewski, M.D. (12 December 2004)
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Re: Predisposition to psychosis
- Cécile Henquet, Lydia Krabbendam, Janneke Spauwen, Charles Kaplan, Roselind Lieb, Hans-Ulrich Wittchen and Jim van Os (14 December 2004)
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Where is the random assignment?
- Andrew S Fox (17 December 2004)
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Re: Where is the random assignment?
- Woody Caan (17 December 2004)
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Overstatement of risk
- Michael Harvey (2 January 2005)
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Some remarks on the excellent paper...
- Antonio lopez zanon, Mary G. Alport (25 January 2005)
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Causality not demonstrated
- Peter L Nelson, Ph.D. (27 January 2005)
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Doubling of schizophrenia incidence questions assumptions of previous rapid response
- Dr Hans-Christian Raabe MD MRCP MRCGP (5 March 2005)
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Evidence-based statements
- Stevie M Gamble (7 March 2005)
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Woody Caan, Professor of public health APU, Chelmsford, Essex CM1 1SQ.
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Thank you, BMJ, for publishing this rigorous prospective study of cannabis use among young people in Munich [1]. Kraeplin and Lange's classic description of psychotic features of cumulative cocaine use (Kokainismus) came from the same city, and they would be proud of the contribution from 'Kraepelinstrasse' today. Our retrospective study of cannabis users who presented with psychotic symptoms, within a broader clinical population [2] generally failed to convince health planners that cumulative exposure to drugs, especially in at-risk groups of young people, added to the overall burden of disease. Systematic research on acute cannabis effects in psychiatric settings has a long history [3] but within the lifecourse there may be critical stages of development where young people are most vulnerable to drug-related harm. The challenge is to use research knowledge, to identify young people with "predisposition to psychosis" [1] in a non-stigmatising way, to strengthen their mental wellbeing as they mature, until they are enabled to become "mentally and emotionally resilient" [4]. This resilience may depend not just on individual growth, but on the wider social capital in the community that can nurture and value each teenager. However, the more we learn about the complex frontiers between individual differences, chemical and social environments, genetic inheritance and mental wellbeing, the more our understanding of "mental illness" itself will have to grow [5]. 1 Henquet C, Krabbendam L, Spauwen J, Kaplan C, Lieb R, Wittchen H-U, van Os J. Prospective cohort study of cannabis use, predisposition for psychosis and psychotic symptoms in young people. BMJ 2004; doi:10.1136/bmj.38267.664086.63 2 Mathers DC, Ghodse AH, Caan AW, Scott SA. Cannabis use in a large sample of acute psychiatric admissions. British Journal of Addiction 1991; 86: 779-784. 3 Deschamps A. Ether, Cocaine, Hachisch, Peyotl et Demence Precoce. Paris: Vega, 1932. 4 Caan W. National service framework for children. BMJ 2004; 329: 1239. 5 Claridge G. Origins of Mental Illness: temperament, deviance and disorder. Cambridge MA: Malor, 1996. Competing interests: Past chair of the School Health Research Group. |
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Ken M. Jacobie, Massage Therapist Private Practice - Latham, NY 12110
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I am curious why data regarding serum and dietary homocysteine, folate, docosahexaenoic acid, eicosapentaenoic acid, pyridoxal 5 phosphate, methionine and others were not controlled for in this study. The dearth of published data on the topic of cannabis and altered cognitive function fails to provide any concept of MECHANISM for cognitive decline let alone psychosis, schizophrenia or depression. However little argument should be found suggesting that cannabinoids do in fact modify the cellular metabolism of the CNS. Serum and dietary homocysteine, folate, docosahexaenoic acid, eicosapentaenoic acid, pyridoxal 5 phosphate, methionine and several other compounds are known to influence phospholipid membranes, neurotransmitter production, monoaminergic neurotransmission and neurogenesis and other areas which are known pathophysiological factors in psychosis, schizophrenia and depression. If a subject is not nutritionally replete how is it possible for the CNS to meet the cellular changes that cannabinoids are known/anticipated to produce? It has been my experience that doctors and researchers have almost no nutrition education and certainly no understanding of even basic nutritional biochemistry(late 20th century nutrition). This as they formulate a hypothetical framework it is devoid of the modifying effect LARGE areas of scientific knowledge. As an example: Hyperhomocysteinemia has been associated with poor memory recall[Am J Clin Nutr 2001;73:927-33] and blood homocysteine concentrations are inversely correlated with some cognitive-function tests.[Arch Neurol 1998;55:1449-55, Am J Clin Nutr 1996;63:306-14, Acta Psychiatr Scand 1992;86:386-90,Int J Geriatr Psychiatr 1998;13:235-9. Circulating homocysteine concentrations reflect B-vitamin status, and B-vitamin deficiency might lead to hypomethylation of chemicals that are crucial to brain function(B-6(pyridoxal 5 phosphate) as a co-enzyme is instrumental in the production of the putative neurotransmitters, dopamine, norepinephrine, serotonin, GABA and taurine as well as the sphingolipids and polyamines. [Annals of New York Academy of Sciences Vol. 585 1990: Vitamin B-6 page 128] The hypothesis that cannabis is a causative in CNS illness is interesting in light of the fact that none of the studies seem to have controlled for the rational confounders I have mentioned above. Additionally there is data (including international numerous patents held by various parties including the US Government: EP1071419A1) suggesting that cannabinoids are actually antioxidants and neuroprotectants. [J. Neurosci. 1999;19 (8): 2987, JPET 2000;293 (3): 807, PNAS 1998; 95 (14): 8268. Considering that the first evidence of the medicinal use of cannabis is found in the book Pên-ts’ao Ching, attributed to the Emperor Shen-nung of about 2000 B.C. I wonder if perhaps it's more recent changes in dietary repleteness that might be triggering the pathophysiological changes in the CNS of heavy pot smokers... or for that matter anyone that suffers from psychiatric illnesses... A bit of non-peer review please take is as such... Be well, Ken Jacobie, LMT Competing interests: None declared |
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Albert M. E. Coleman, Associate specialist psychiatrist. Greenarces CMHT, WSHSS NHS Care trust, Homefield road. Worthing, BN11 2DH. W. Sussex.
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Editor- The debate of the probable causal relational between cannabis use and mental illness has been around for a while. This more so, as in the larger society opinions continue to be mixed as to whether cannabis should be classified as a harmless drug or not. The results of the study by Hanquet et al, 1 adds on to the available evidence in the medical literature 2. That some people choose to ignore this is another story. If history of medicine teaches us anything at all, the possible harmful effects of cannabis to humans was of concern even in medieval times, prompting an 8th century ordinance in Egypt prohibiting the use of hemp drugs, otherwise punishable by extraction of a tooth if the ordinance was contravened! 3 A probable biological explanation of the cannabis psychosis link can be explained by the fact that in rat brains cannaboid rececptors have been found to collocate with dopamine D1 receptors.4 This collocation could suggest a possible modulation of dopaminergic receptors as possible mechanism of cannabis induced psychosis, considering the role of dopamine in the pathogenesis of psychosis in general. An indirect tissue evidence of the probable cannabis psychosis link is the demonstrated toxic effect of 9-tetrahydrocannabinol on mammalian nonmyelinated nerve fibers.5 This last point may sound far fetched, except that nerve fibres constitute the substrates of various neural circuitries involved in brain function. I tend to believe based on clinical evidence and available data that the cannabis psychosis linkage may be real. 1. Hanquet Cecile, Krakbendam Lydia, Spanwen Janneke, Kaplan Charles et al. Prospective cohort study of cannabis use, predisposition for psychosis and psychotic symptoms in young people. BMJ 2004;0: bmj. 38267.664086.63v1. 2.Arseneault Louise, Cannon Mary, Witton John, Murray Robin M (2004). Causal association between cannabis and psychosis: examination of the evidence. British Journal of Psychiatry. 184, 119-117. 3.Naha GG. Hasish in Islam 9th to 18th century. Bull N Y Acad Med. 1982 Dec; 58(9): 814-31. 4. Herkenham M. Cannabinoid receptor localization in brain: relationship to the motor and reward system. Ann N Y Acad Sci 1992; 654: 19-32. 5. Byck R, Ritchie JM. 9- Tetrahydrocannabinol: effects on mammalian nonmyelina nerve fibers. Science. 1973 Apr 6; 180(81): 84-5. Competing interests: None declared |
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Ellen C G Grant, physician and medical gynaecologist 20 Coombe Ridings, Kingston-upon-Thames, KT2 7JU, UK
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A clue why the risk of cannabis-psychosis is four times more likely in young people with predisposing factors, may be found in the results of animal studies of the interactions with copper and zinc and cannabis.1 Copper potentiated the barbiturate hypnosis-potentiating activity of cannabis.2 Single doses of copper partially inhibited tolerance to barbiturate hypnosis-potentiation activity and markedly delayed the development of tolerance to hypothermic activity of cannabis for one to two weeks. Many patients prone to mental instability have difficulty in maintaining a normal copper/zinc balance. Zinc deficiency is extremely common and is increased with smoking tobacco and drinking alcohol. Men have lower zinc levels than women and need extra zinc during growth. Menstruating females have higher copper levels than males. If women also use progesterone contraceptives or menopausal hormones, high monoamine oxidase levels and even higher than usual copper levels increase the risk of mental illnesses and suicide attempts.3,4 Infections also increase copper levels. Copper stores may become depleted and copper deficiency impairs Cu/Zn superoxide dismutase activities. These important homeostatic imbalances increase adverse reactions to foods and chemicals. Zinc and copper deficiency or high copper levels can also block essential fatty acid pathways, causing both omega-6 and omega-3 deficiencies, and also vitamin B group deficiencies, which further increase the risk of psychosis. Monitored nutritional supplementation with 1mg doses of copper in the morning and 30 mg doses of zinc in the evening for two or three weeks can give a rapid improvement in many conditions. In particular, the resolution of mental or neurological illnesses can be very dramatic. 1 Henquet C, Krabbendam L, Spauwen J, et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people BMJ 2004; 0: bmj.38267.664086.63v1 2 Singh PP, Das PK. Studies on the interactions of copper and cannabis. Psychopharmacology (Berl). 1978 ;56 : 309-16. 3 Grant ECG. The Pill, Hormone Replacement Therapy, Vascular and Mood Over-reactivity, and Mineral Imbalance J Nutr Environ Med 1998; 8: 105- 116. 4 Price EH. Increased Risk of Mental Illness and Suicide in Oral Contraceptive and Hormone Replacement Therapy Studies 1998; 8: 121-127. Competing interests: None declared |
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Richard G Fiddian-Green, FRCS, FACS c/o Hrhold, Maitland and Co, 44 Dover street, London W1
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Disorders of thyroid function, which may be associated with disorders of iodine metabolism, are very instructive in so far as the putative effects of an energy supply/demand imbalance or energy deficit upon mood and behavioural disturbances with cannabis use are concerned. In the case of thyrotoxicosis temperature is increased, because of the uncoupling effect of thyroxine, and with it oxygen consumption and basal metabolic rate, the Q10 effect. The ATP turnover rate is increased proportionately but as the temperature and BMR rise to abnormally high levels an energy supply/demand mismatch may develop because utilisation outstrips the rate of ATP resynthesis. This may occur because the proportion of being energy supplied by anaerobic glycolyis exceeds the cardiovascular capacity to deliver the necessary nutrient (1). The development of a energy supply/demand mismatch may be sudden and dramatic. In such an event the thyroid crisis or storm, as it is known, may manifest as diarrhoea, dyspnoea, palpitations, fever, shock, and even apnoea, coma or cardiac arrest (2,3). An energy deficit or dysoxia is undoubtedly present in these circumstancs (4). Some believe this was Mozart's last disease (5). In hypothyroidism the reverse occurs, the metabolic effect being similar to that caused by closing the mitochondrial permeability transition pore with cylosporin A. "There was no specific psychiatric clinical picture [in patients with untreated thyrotoxicosis]but affective psychoses were commonest [in the 18 cases studied]- seven depression, seven mania. The other diagnoses were two schizophreniform, one paranoid, and one delirium. Initially, neuroleptic medication was used in all but one patient, and during long- term follow-up (median 11 years) more than half our series had remained well with no further psychiatric problems.... Two patients were not mentally ill when thyrotoxicosis was diagnosed, but suffered major mood swings when thyroid hormone levels were falling" (6). "The hypothyroid patient may present with depression, an organic mental disorder, apathy and/or frank psychosis (usually with paranoid symptoms)"(7). The condition is commonly called myxoedma madness. In some cases mania develops following the administration of thyroxine. "The patients experiencing mania showed concurrent psychopathology at the time of replacement therapy, frequently had a past history of personal or familial psychiatric disorder and were given dosages in the high range of normal"(8). The mania may in effect be a manifestation of a minor thyroid crisis or storm precipitated by an excess of thyroxine. "The incidence of psychoses [following renal tranplantation (RT) and immunosuppressive therapy likely to have included some degree of closing of the permeability transition pore with cylosporin] was 7.5/1000 person- years (PY) after RT compared with 7.2/1000 PY for all patients on chronic dialysis and 9.6/1000 PY for dialysis patients aged 65 yr or younger. Among RT recipients, graft loss (Adjusted hazard ratios (AHR), 2.97; 95% CI, 2.19 to 4.02), allograft rejection, and cadaveric donation were independently associated with psychosis, which was associated with an increased risk of both death (AHR, 2.09; 95% CI, 1.71 to 2.56; P < 0.001) and graft loss (AHR, 1.79; 95% CI, 1.15 to 2.78; P = 0.01). Graft loss due to noncompliance was significantly more common after psychosis (9.0% versus 3.7% in patients not hospitalized for psychosis; P < 0.001)"(9). Some commit suicide (10). Perhaps the condition should be called transplantation madness. In the pulmonary transformed cell line A549 Delta(9)- tetrahydrocannabinol (THC) deplete ATP levels in a dose dependent manner and may even cell cell death (11). "Studies using JC-1, a fluorescent probe for mitochondrial membrane potential revealed diminished mitochondrial function at THC concentrations as low as 0.5 microg/ml. At concentrations of 2.5 or 10 microg/ml of THC, a decrease in mitochondrial membrane potential was observed as early as 1 h after THC exposure. Mitochondrial function remained diminished for at least 30 h after THC exposure. Flow cytometry studies on cells exposed to particulate smoke extracts indicate that JC-1 red fluorescence was fivefold lower in cells exposed to marijuana smoke extract relative to cells exposed to tobacco smoke extract. Comparison with a variety of mitochondrial inhibitors demonstrates that THC produced effects similar to that of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, suggesting uncoupling of electron transport. Loss of red JC-1 fluorescence by THC was suppressed by cyclosporin A, suggesting mediation by the mitochondrial permeability transition pore". Generation of reactive oxygen species (ROS) is 10-fold higher in renal allografts in acute rejection relative to control kidneys on day 9 (P <0.01) and is associated with histologic signs of acute rejection (12). NADPH oxidase [which generates the superoxide radical] activity is increased significantly in the renal allografts in acute rejection. Delta9 -Tetrahydrocannabinol (delta9-THC), the active ingredient of marihuana, has also been found to be a highly effective inhibitor in vitro of the NADH-oxidase activity of rat brain and heart mitochondria (13). NADH- oxidase, which reduces oxygen to hydrogen peroxide, is inhibited by the immunosuppresant deoxycorticosterone suggesting its activity may be mediated by an inhibition of ROS release. . The activity of electron-transfer complex I (NADH oxidase and NADH- cytochrome c oxidoreductase) and the energy-dependent reduction of NAD+ by succinate are unaltered by oxidative stress in isolated rat liver mitochondria. Exposure to free radicals also had an uncoupling effect at all three coupling sites. Cyclosporin A completely prevents the mitochondrial damage i.e uncoupling induced by oxygen free radicals (14). The mitochonrial regulation of cellular energtics is complex. Two models have been considered in accounting for the activity of complex I (NADH oxidase and NADH-cytochrome c oxidoreductase) in the electron transport chain, one in which each enzyme may be rate-controlling and another in which the whole metabolic pathway behaves as a single supercomplex and inhibition of any one of its components elicits the same flux control (15). In the absence of other components of the oxidative phosphorylation apparatus (i.e. ATP synthase, membrane potential, carriers), the existence of a supercomplex would elicit a flux control coefficient near unity for each respiratory complex, and the sum of all coefficients would be well above unity. A brain acutely exposed to delta(9)-tetrahydrocannabinol would appear, therefore, to behave like a kidney in acute rejection or a patient with a minor or even major thyroid storm. The effects may be the product of a acute energy deficit induced by an abnormally large degree of uncoupling the degree of which might be attenuated or even reversed by cyclosporin A. In the longer term, however, an chronic energy defict may develop for different reasons, one similar to that seen in myxoedema and transplantation madness. In these circumstances the therapeutic objective might have to be reversed and the degree of uncoupling present increased. A striking feature of the mood and behvioural changes induced by the metabolic disturbances in thyroid diseases is that they appear to cover the entire spectrum of psychiatic phenomenology. The implication is that subclassifications of the phenomenology into different psychoses and disorders may by unwarranted and therefore pathophysiologially, diagnostically and therapeutically misleading. It is highly likely that the entire spectrum of mood and behavioural changes occur in sync with abnormal or "chaotic" changes in the frequency and amplitude of synchronised metabolic variations (16). The frequency and amplitude being abnormally increased with the acute effects of delta(9)- tetrahydrocannabinol and decreased with the chronic effects in the same way that the voltages are decreased on an EKG in a patient with myxoedma. If then cannaboid, thyroid and transplanatation madness are real entitites what of pharmaceutical or simply error (17) madness? 1. Successful evolutionary adaptation to environmental stress? Richard G Fiddian-Green Heart Online, 14 Jul 2004 eLetter re: D A Lawlor, G Davey Smith, R Mitchell, and S Ebrahim Temperature at birth, coronary heart disease, and insulin resistance: cross sectional analyses of the British women’s heart and health study Heart 2004; 90: 381-388 2. Pruijm MT, Pereira AM. [Thyrotoxic crisis in a patient with Graves' disease] Ned Tijdschr Geneeskd. 2004 Aug 21;148(34):1691-4. 3. Hirvonen EA, Niskanen LK, Niskanen MM. Thyroid storm prior to induction of anaesthesia. Anaesthesia. 2004 Oct;59(10):1020-2. 4. Fiddian-Green RG. Gastric intramucosal pH, tissue oxygenation and acid-base balance. Br J Anaesth. 1995 May;74(5):591-606. 5. Lindstedt G. Thyrotoxic crisis--the last disease of Mozart? Lakartidningen. 2004 Aug 19;101(34):2585. 6. Brownlie BE, Rae AM, Walshe JW, Wells JE Psychoses associated with thyrotoxicosis - 'thyrotoxic psychosis.' A report of 18 cases, with statistical analysis of incidence. Eur J Endocrinol. 2000 May;142(5):438-44. 7. McGaffee J, Barnes MA, Lippmann S Psychiatric presentations of hypothyroidism. Am Fam Physician. 1981 May;23(5):129-33. 8. Josephson AM, Mackenzie TB Thyroid-induced mania in hypothyroid patients. Br J Psychiatry. 1980 Sep;137:222-8. 9. Abbott KC, Agodoa LY, O'Malley PG. Hospitalized psychoses after renal transplantation in the United States: incidence, risk factors, and prognosis. J Am Soc Nephrol. 2003 Jun;14(6):1628-35. 10. Shimmura H, Tanabe K, Tokumoto T, Ishida H, Ishikawa N, Miyamoto N, Shimizu T, Shirakawa H, Setoguchi K, Teraoka S, Toma H. Analysis of cause of death with a functioning graft: a single-center experience. Transplant Proc. 2004 Sep;36(7):2026-9. 11. Sarafian TA, Kouyoumjian S, Khoshaghideh F, Tashkin DP, Roth MD. Delta 9-tetrahydrocannabinol disrupts mitochondrial function and cell energetics. Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L298-306. 12. Sun K, Kiss E, Bedke J, Stojanovic T, Li Y, Gwinner W, Grone HJ Role of xanthine oxidoreductase in experimental acute renal-allograft rejection. Transplantation. 2004 Jun 15;77(11):1683-92. 13. Bartova A, Birmingham MK Effect of delta9-tetrahydrocannabinol on mitochondrial NADH-oxidase activity. J Biol Chem. 1976 Aug 25;251(16):5002-6. 14. Takeyama N, Matsuo N, Tanaka T. Oxidative damage to mitochondria is mediated by the Ca(2+)-dependent inner-membrane permeability transition. Biochem J. 1993 Sep 15;294 ( Pt 3):719-25. 15. Bianchi C, Genova ML, Parenti Castelli G, Lenaz G. The mitochondrial respiratory chain is partially organized in a supercomplex assembly: kinetic evidence using flux control analysis. J Biol Chem. 2004 Aug 27;279(35):36562-9. 16. SUD: product of an abnormally increased amplitude of synchronised metabolic variations? Richard G Fiddian-Green (16 November 2004) eLetter re: A M A Shehab, R J MacFadyen, M McLaren, R Tavendale, J J F Belch, and A D Struthers Sudden unexpected death in heart failure may be preceded by short term, intraindividual increases in inflammation and in autonomic dysfunction: a pilot study Heart 2004; 90: 1263-1268 17. Error reporting: should it be confined to pharmaceuticals? Richard G Fiddian-Green (26 November 2004) eLetter re: Amy Jo Ehman Mandatory error reporting in Saskatchewan CMAJ 2004; 171: 1158-a Competing interests: Yes |
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Andrew Campbell, Psychiatrist 36 Marlborough St Drummoyne NSW Australia
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This finding is the tip of the iceberg. My clinical work over the past 5 years indicates that about 80% of men in New South Wales under 40 years of age and experiencing chronic psychosis were smoking cannabis on a daily basis in their adolescence. The earlier the cannabis use the earlier the subsequent onset of psychosis but the onset was delayed by several years. Use of other known psychosis inducing drugs such as amphetamines and LSD resulted in an earlier onset of a longterm psychosis. Many people who began regular high potency cannabis use at age 18 did not develop a psychosis until age 25 or later and so will not be identified in this study. People who were genetically predisposed to psychosis and used cannabis (<1% of the people I reviewed) generally became acutely hypervigillant and so did not use the drug again but developed a psychotic illness some years later. Cannabis addiction and withdrawal states are a real phenomena but tend to be diagnosed as an affective disorder. I have yet to see anyone develop a longterm psychosis who began smoking cannabis after the age of 21. Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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All studies of the association between psychosis and cannabis use are faced with a serious problem in trying to untangle cause and effect. Henquet et al’s method of adjustment for prospectively measured predisposition to psychosis strikes me as an ingenious attempt to solve this problem. Their method is, however, crucially dependent on whether their predisposition measure is genuinely a reliable predictor of future psychosis. If the odds ratio for the association between baseline predisposition to psychosis and subsequent psychotic symptoms is large, then their conclusions will be more convincing than if the odds ratio is close to one. I could not find the odds ratio reported in their paper: I assume that it was omitted owing to lack of space, so perhaps Henquet et al would be kind enough to report that important extra information as a rapid response? Table 4 suggests that psychosis at follow up is indeed more common among those with a predisposition at baseline, which is certainly encouraging, but it would be instructive to see the odds ratio and its confidence interval. On a related matter, I must take issue with Henquet et al’s conclusion that they have refuted the hypothesis that predisposition to psychosis is a predictor of cannabis use. Although the odds ratio for this association was not significantly greater than one, and thus did not confirm the hypothesis, it was greater than one nonetheless, and the upper end of the confidence interval included a doubling of the odds of cannabis use for those with a predisposition to psychosis at baseline. It therefore seems to be overstating the case to say that the hypothesis is refuted. Competing interests: None declared |
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Stefan Kruszewski, M.D., Addiction Psychiatrist Harrisburg, Pennsylvania USA
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I have several questions for the authors of the recently-published paper in BMJ entitled, 'Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people.'(1) Before I enumerate my questions, I would like to assure the authors that I am asking them out of ignorance and for no other reason than my attempt to understand the methodology and statistical analysis of their work. Here is what I do not understand: 1. The authors stated (page 2) that they used sensitivity analyses to examine whether differential attrition in the sample as a whole could have biased the findings... by multiple imputation of missing values of cannabis use at baseline, ..." It is my understanding that this was done to explain why there was an approximately 19.3% attrition rate (Of the original cohort of 3,021, 584 patients were lost to follow-up) in the study. I would appreciate if the authors would explain how the imputation of missing values gave them confidence that their 19.3% attrition rate did not bias their conclusions? 2. My second question is related to my first. I do not understand how (at the end of page 2) "Based on 1000 imputation sequences...(where the authors)..stochastically imputed missing values of cannabis use at baseline and psychotic symptoms...at four year follow-up in the whole sample.." gave confidence to their conclusions about the estimated average additive interaction between predisposition for psychosis at baseline and cannabis use at baseline? How is that possible? The relationship between cannabis usage in early life and subsequent predisposition to psychopathology---or any human pathology (or the lack thereof)---remains a vitally important area of research. I appreciate the authors’ research. (1)C Henquet et al. Prospective cohort study of cannabis use, predisposition for psychosis, and psychotic symptoms in young people.BMJ 2004; 0: bmj.38267.664086.63v1 Competing interests: None declared |
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Cécile Henquet, research psychologist Department of Psychiatry and Neuropsychology, Maastricht University, Lydia Krabbendam, Janneke Spauwen, Charles Kaplan, Roselind Lieb, Hans-Ulrich Wittchen and Jim van Os
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Jacobs argues that our method depends on the predictive value of our baseline predisposition measure on psychosis outcome. This is not correct, however, as predisposition as a component cause for schizophrenia does not necessarily have to show a main effect on the outcome of psychotic symptoms. In fact, if there is complete interaction between two component causes, neither will have a main effect but their interaction will. However, in specific response to Jacobs, we report that in our sample predisposition at baseline did predict the cumulative incidence of psychotic symptoms at follow up (unadjusted odds ratio 2.38, 95% confidence interval 1.75 to 3.22). After adjustment for age, sex, socioeconomic status, urbanicity, childhood trauma, cannabis use, use of other drugs, nicotine use, alcohol use and predisposition to psychosis at follow up, this association remained both large and significant (adjusted odds ratio 1.76, 95% confidence interval 1.20 to 2.60). Jacobs furthermore states that we seem to be overestimating our results by saying that the self medication hypothesis can be refuted. In taking this issue, Jacobs points out that although the association between baseline predisposition to psychosis and cannabis use at follow up was not significant, it was greater than unity nonetheless. We agree that these results indicate that self medication may explain a limited part of the association between cannabis use and the emergence of psychosis, but they do not support the hypothesis that this is the sole explanation for the association between cannabis and psychosis as it is reported and discussed in many studies. Competing interests: None declared |
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Andrew S Fox, Associate Research Specialist University of Wisconsin-Madison, Madison, WI, 53703, USA
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The authors claim that "Cannabis use moderately increases the risk of psychotic symptoms in young people". While this is a compelling argument, this is not demonstrated by their study. There are two major points. The authors need to consider a major confounding factor in their study, which is that the participants with a predisposition toward psychoses may be more likely to take the risk to try cannabis and/or enjoy it. The groups in this study were not randomly assigned, and the authors fail to acknowledge competing explanations. This is an example of where science fails to appropriately inform the public. While researchers who read this paper will certainly recognize the unsubstantiated claim, untrained readers may not. Future work should be held to this higher standard. Competing interests: None declared |
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Woody Caan, Professor of public health APU, Chelmsford CM1 1SQ, UK
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Dr. Fox and other readers may have been steeped in Cochrane criteria for randomised controlled trials. In Public Health studies of exposure to potential health hazards, it is rarely ethical or practical to perform RCTs, for example to expose some adolescents to cannabis and others to a suitably equivalent placebo hazard. In community research well-described "natural experiments" often have to do, instead. The US Centers for Disease Control have developed standards called TREND for rigorous, non- randomised designs [1]. If one substitutes the word 'exposure' for 'intervention', then the community study of Henquet et al. meets most of the TREND gold standards. [1] Caetano R. Standards for reporting non-randomized evaluations of behavioral and public health interventions: the TREND statement. Addiction 2004; 99: 1075-1080. Competing interests: None declared |
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Michael Harvey, Clinical Haematologist Haematology Department, Liverpool Hospital, Australia
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This is an interesting and worthwhile paper, however I think that the conclusion of "moderately increased risk" is overstated. This is unfortunate, given that the press will only quote the conclusions, and potentially will make more difficult the ability to mount trials exploring the therapeutic benefits of cannabinoids in cancer therapy. The increased risk in the majority of patients without a predisposition to psychosis is only 5.6% (table 4). The significantly increased risk of 24% only applied to the small part of the study population with a propensity to psychosis. As far as I could determine this increased risk applied to use both at the onset of the study and during the study period. I couldn't derive the answer to the question of the odds ratio of developing psychosis if someone is not using at baseline and takes marijuana up, which is the practical issue. The paper convincingly debunks the self-medication hypothesis which is interesting and worthwhile. Competing interests: None declared |
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Antonio lopez zanon, psychiatric clinic Madrid. 28003. Spain, Mary G. Alport
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Dear Sir/Madam, We would like to make some observations on this article in the light of our extensive clinical experience (approximately fifty five thousand acute psychiatric patients, in the course of thirty five years). Our work was first carried out on a psychiatric ward (70 beds) between 1959 and 1992. From 1959 to 1963, we worked with patients who had exclusively consumed cannabis, and since 1968 our cases have been politox users. After Weitbrecht’s contribution (1957, 1959), we became especially interested in this syndrome and have isolated (Natural History of cannabis patient evolution) some particular syndromes which seem to us to be more interesting than mere symptoms: • Cannabic Ivresse
We would also like to comment on language disturbance in cannabis users. These patients have a perturbation of language “sur mesure” (syntactic construction, categorical conceptions) and their language is degraded to a protopathic level. We attribute academic failure at school to this language/thinking disturbance. (Wittgenstein) Finally, we wish to point out that in Psychiatry the symptomatic and syndromic expression is never specific, but only typical. (Weitbrecht) Prof. Dr. Antonio López Zanón.
Mary G. Allport
Bibliography: Sobre las drogas y los drogadictos (a través de su ejemplo – tipo: los consumidores de cannabis) A. López Zanón, I. López San Roman, P. Blanco. Edipo, S.A., 2004. Competing interests: None declared |
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Peter L Nelson, Ph.D., Social Science Consultant Ballina, NSW 2478, Australia
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Although this is an excellent piece of longitudinal research, it should be remembered that regression models do not reveal causal connections amongst variables -- only associations. On the issue of schizophrenia and cannabis use, there has been a great deal of discussion in the scientific literature as well as in the popular press. However, it is widely ignored that, in spite of the statistically dramatic increase in cannabis use in the developed world over the past 30+ years, the rate of schizophrenia in the population has remained much the same -- slightly more than 1 percent. If there was an unambiguous causal relationship between cannabis use and the development of psychosis (primarily schizophrenia), then we would have seen a statistically significant increase in the rate of schizophrenia in the general population. We have not. No doubt cannabis use in adolescence is a danger to psychosocial development and that there is some kind of synergy between cannabis use and worsening mental states in those afflicted with psychotic disorders. However, if as researchers we are not very clear about the meaning and limits of our research, we will encourage the kind of drug 'hysteria' seen in countries like the USA, where a social justice crisis has developed through inappropriate use of the criminal justice system as a means of curtailing the 'evil' of drugs. Competing interests: None declared |
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Dr Hans-Christian Raabe MD MRCP MRCGP, Fellow, Environmental Health Environmental Health Clinic, Toronto, Ontario, Canada
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Doubling of schizophrenia incidence questions assumptions by Dr Nelson 'Causality not demonstrated' Dr Nelson claims that ‘it is widely ignored that, in spite of the statistically dramatic increase in cannabis use in the developed world over the past 30+ years, the rate [you mean prevalence, I suspect] of schizophrenia in the population has remained much the same -- slightly more than 1 percent’. He continues: ‘If there was an unambiguous causal relationship between cannabis use and the development of psychosis (primarily schizophrenia), then we would have seen a statistically significant increase in the rate [I presume you mean incidence] of schizophrenia in the general population. We have not.’ This statement is incorrect. A recent review by Boydell, van Os et al (Incidence of schizophrenia in south-east London between 1965 and 1997. Br J Psych. 2003: 182; 45-49.) finds that over the past 35 years, there has been a doubling in the incidence of schizophrenia in South-East London. In the 1965-1968 cohort, there has been a schizophrenia incidence of 6.8 per 100,000 population which had more than doubled to 15.3 per 100,000 in the 1995-1997 cohort. The increase in incidence was greatest in those under the age of 35, which would be in keeping with the much higher use of cannabis among under 35 year olds. We cannot at this time be confident that this increase is due to the increase in cannabis consumption over the past decades but cannabis could be a significant contributing factor in the increased incidence. Competing interests: None declared |
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Stevie M Gamble, retired HMIT EC2Y 8BL
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Henquet et al state 'It is generally accepted that cannabis use is strongly associated with psychosis' Really? In the absence of any proffered evidence to support this, I conducted a straw poll. People were presented with this statement and asked whether they agreed strongly, agreed weakly, disagreed strongly, disagreed weakly, or had no view. Responses were as follows: 100% asked for a definition of 'generally accepted', 100% asked for a definition of 'cannabis', 100% asked for a definition of 'use', 100% asked for a definition of 'strongly associated' and 100% asked for a definition of 'psychosis'. Actually, 100% also asked if I was feeling alright but that's not strictly relevant. It should be noted, however, that the group sampled comprised of serving or former members of Her Majesty's Inspectors of Taxes, and were therefore rigorously selected for, and rigorously trained in, evidence- based thinking. Thus it is possible that the group intolerance of warm and fuzzy waffle (WFW) might lead to the rejection of any generalised statement. I therefore included a question to test this; responses were as follows: 100% agreed strongly that 'It is a truth universally acknowledged, that a single man in possession of a good fortune, must be in want of a wife.' Stevie M Gamble Competing interests: None declared |
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