IL-GWIDA TAJBA DROGA

INTRODUZZJONI

Jista ngħixu kuntenti qatt wara? Forsi. Interess wieħed fil- ġenetikament pre-programmati istati ta 'sublimity fasslet fil Il imperattiva hedonistic huwa mtaffi mill-għarfien li wieħed huwa probabbli li jkun ta 'madwar li jgawdu minnhom. Dan kollu tajjeb ħafna jghidulek tagħna dixxendenti se jesperjenzaw kull mument ta 'ħajjithom bħala Epifanija maġika. Għal primitives emozzjonali u l-maħbubin tagħna fil-preżent, ħafna mumenti tal-ħajja ġġib xejn tat-tip . Fil sekli li ġejjin, emozzjonali tagħna benesseri jista 'tabilħaqq jaqbżu kull ħaġa li bniedem wirt wetware tista' anki jikkontempla. Dritt issa, madankollu, kwalunkwe futur wara l-Darwinian Era tal -ġenna l-inġinerija jistgħu jidhru mod awfully bogħod. Soċjetà ġenerali illum għandu iddisprat sottożviluppati kunċett ta 'saħħa mentali.

Hemm b'mod ċar rabta kawżali b'saħħitha bejn il-kapaċità bijoloġika prima li l-esperjenza kuntentizza u sa liema punt il-ħajja jinħass li jkun utli. Treatises filosofija Għoli moħħom għandhom jikkumplikaw iżda mhux jikkonfondi l-primat tal- pjaċir l-uġigħ assi. Allura wieħed ħafna metodu prattiku ta 'ħajja arrikkiment jikkonsisti kimikament inġinerija kuntenti imħuħ għal kulħadd fil-hawn-u-issa. Iżda kif jista 'dan l-aħjar jsir?

Kull strateġija li ma iwaqqa tagħna inerenti treadmill hedonic ta inibitorji mekkaniżmi ta 'reazzjoni fil- CNS se jonqsu. Riformi politiċi u soċjo-ekonomiċi joffru fl-aħjar stopgap lame. Lill-naturalista xjentifika, rotot kollha lejn l-hena għandu b'mod definittiv bijoloġika - "kultura" u "talk-terapija" simili għandhom jiġu kodifikati neurochemically jeżerċitaw kwalunkwe effett fuq il-psyche. Xi wħud minn dawn ir-rotot għall-kuntentizza jinvolvu l-devjazzjonijiet ambjentali tradizzjonali. Huma wisq tekniċi, diversa u għalxejn li jindirizzaw hawn. Jekk il-kwalità tal-ħajja tagħna huwa li jissaħħu b'mod sinifikanti fit-tul, allura l-predisposti ġenetikament set-punt ta 'termostats emozzjonali tagħna jiġi kkalibrati mill-ġdid . Il-telqa ridden norma tipikament adattivi fl-ambjent antenati umanità għandhom jiġu mormija. Għalhekk, filwaqt li qed nistennew sakemm raħs tal-linja ġene-terapija biex jippromwovu mentali super-saħħa tista 'ssir l-istandard, huwa min jikkunsidrah minflok kif ordinarja kmieni Seklu 21 Homo sapiens tista sostenibbli timmassimizza emozzjonali-benessri biss ma tal-lum farmakoloġija li jistrieħu fuq. Mhux inqas importanti, kif huwa possibbli li jgħaqqdu toqgħod kontinwament " aħjar minn ukoll "ma jżommu sens wieħed ta 'soċjali u responsabbiltà etika għal oħra nies u l-forom tal-ħajja ?

Estrazzjoni affidabbli informazzjoni dwar dan is-suġġett huwa straordinarjament diffiċli għall lajċi u l-professjonisti simili. Il-layman huwa aktar probabbli li jingħata propaganda ħafna slanted. Fatt bla verniċ jista 'jħawwad allegatament uneducated u funzjonalment moħħ tiegħu diminuttiv. Karriera l-xjentisti, min-naħa l-oħra, huma bedeviled minn problema differenti. Aċċess għall-fondi, laboratorji, materja prima, pubblikazzjoni ġurnal, il preferment professjonali, u l-liċenzji li twettaq provi sperimentali huwa dipendenti fuq riċerkaturi twassil riżultati tagħhom paymasters jixtiequ jisimgħu. Il-diżinċentivi għall intellettwali integrità tista bilkemm tkun akbar; u huma cloaked b'tali fama moħbija Bħala. illustrazzjoni , huwa min jikkontempla 1 esaġerat xenarju . Kif tista 'droga hena eterna-- droga li (implausibly!) xi ħadd xellug li ppruvaw darba jgħixu kuntenti-dejjem wara - ssib ruħha deskritti fil-letteratura?

"X Sustanza jikkaġuna, irriversibbli ħsara serja strutturali newrotrasmettitur subsistema y. Konsegwenzi tagħha jinkludu burdata-kongruwenti delużjonijiet konjittivi, trattament reżistenti ewforija, u psikożi affettivi tossiċi. "

Eeek! M'hemmx għalfejn ngħidu, l-ebda adult responsabbli ikun mess madwar ma 'newrotossina potenti taħt din id-deskrizzjoni.

Riċerkaturi eċċellenti Diversi jilagħbu l-logħba mir-regoli. Huma jżommu opinjonijiet heterodox tagħhom infushom. Oħrajn isibu bħal dissonance konjittivi wisq pjaċevoli. Allura dawn gradwalment internalizzati l-irwol puritanical u tendenza li proża xjentifika warped mistenni minnhom. [Billi ittorturati mhux umani annimali sperimentali , per eżempju, blandly jiksbu "użata" u "sagrifikati", ċerti mediċini soċjalment tabù dejjem jiksbu "abbużat" b '"droga l-Drogati"] Min-naħa l-oħra, uħud mill-aktar oriġinali u produttivi imħuħ fil-qasam tal Psikofarmakoloġija - testijiet pre-eminentement Alexander Shulgin - ġiet diġà msikkta. Karrieri Ħafna aktar kienu intellettwalment strangled fit-twelid jew mibgħuta lill-oblivion professjonali. Il-periklu ta avvelenament-bjar ta 'informazzjoni, għal kwalunkwe mottivi, huwa sempliċi. Meta ż-żgħażagħ jiskopru dawn ikunu ġew gideb jew mqarrqa, fuq kannabis per eżempju, dawn se pardonably jassumu li dawn ikunu ġew gideb jew mqarrqa fuq il-perikli ta 'l-oħra illegals wisq. U dan, fi kliem ħafif, tkun eċċessivament raxx.

Aktar reċentement, l-Internet ta 'kuljum tagħti up inkontrollabbli għargħar marea ta' ideat ġodda biex jiġġieldu misinformazzjoni uffiċjali. Uħud mill-letteratura fuq l-internet, per eżempju Erowid , huwa l-ewwel rata. Fl-aqwa tiegħu, Wikipedija tpoġġi pubblikazzjonijiet stampati għall-mistħija. Sfortunatament, ħafna web ppubblikat materjal ma jkunx għan ħafna iktar fil-kontenut jew l-istil mill-ġurnali professjonali li tikkomplementa. Mediku ghostwriting , mhux rikonoxxut kunflitti ta 'interess u bias pubblikazzjoni huma endemiċi għal 'peer-riveduti ġurnali akkademiċi ", imma rigorożità metodoloġika hija skarsa fil-kontro-kultura xjentifika wisq. Jitfassal sistema tiegħu stess ta 'filtrazzjoni u l-kwalità ta' kontroll biex drown l-istorbju huwa sfida kompitu għal kulħadd.

XI sqaqien mejta

Wieħed spettakolari inkompetenti rotta għal ħajja ta 'ferħ tinvolvi teħid psychostimulants insostenibbli bħal kokaina jew il- amfetamini . Fi żmien qasir, l-attivazzjoni tagħhom tas-sistema nervuża simpatetika tendenza li jeleva, burdata motivazzjoni u l-enerġija. Utenti għandhom tendenza li jitkellmu ħafna. L-awto-kunfidenza hija msaħħa: dawn huma 'drogi enerġija ". Saħħa fiżika u akutezza mentali huma variably miżjuda. Billi jimblokka kokaina il newronali ri-assorbiment tal- catecholamine newrotrażmettituri noradrenaline u dopamine , amfetamina jqajjem, fi grad wisq akbar rilaxx sinattika tagħhom. Amfetamina iħoss partiċelli, idum aktar u l-ispejjeż inqas.

Fi kwalunkwe każ, stmerrija libertarian li l-Istat tippreżumi li tissuġġetta ċ-ċittadini tagħha totalitarji stil f'moħħu-kontroll m'għandux jaħbi l-fatt li għall-aktar skopijiet dawn mhumiex drogi utli. Dan huwa għaliex is-sistema nervuża ċentrali jappoġġja web ta 'xulxin inibitorji feedback l-mekkaniżmi. Bi tweġiba għal żieda ta 'terminu qasir ta' burdata-medjatur Monoamini fil-synapses, il-ġeni u riċetturi newronali jerġgħu jirregolaw . Allura fl-aħjar ebda reali fit-tul benefiċċju derivat mill-użu ta 'komposti bħal dawn. La kokaina u lanqas amfetamina jagħti l-attivazzjoni sostnut ta 'intraċellulari sinjal transduction kaskati meħtieġa biex iqarrqu-treadmill hedonic u iżżommna mexjin tassew kuntenti.

Xi nies tkompli tieħu psychostimulants każwali għas-snin mingħajr dannu serju. Madankollu r-riskji potenzjali ta 'ħsara fiżiċi, psikoloġiċi u soċjali morda-effetti huma għoljin. L-użu tagħhom lil hinn narkolessija u forsi ADHD huwa l-aħjar skoraġġuta.

Il-"dipressanti" opjojdi huma kemmxejn aktar beninni . Huma analġeżiċi effettivi. L-opjojdi jistgħu wkoll ikunu ferm pja `evoli . . Fl-antikità klassika, Aristotli - ċertament mhux dejjem l-awtorità iktar waħda adattata dwar kwistjonijiet mediċi - uġigħ klassifikata bħala emozzjoni Opju kien tradizzjonali rimedju għad-dipressjoni Melancholic; effikaċja tiegħu huwa probabbilment superjuri għal Prozac , għalkemm provi komparattivi kliniċi kkontrollati huma nieqsa. Fil "mudelli ta 'annimali", l-opjojdi reverse -imġiba batuti, tgħallmu djufija u neuroendocrine tweġibiet assoċjati mad-dipressjoni klinika. B'kuntrast, antagonisti opjojdi bħal ma 'hu naloxone taggravahom. Li jħawdu kwistjonijiet aktar, li jsofru minn depressjoni tipikament jaqsmu sensittività ogħla għall-uġigħ, u moderni " antidipressanti "tista infushom jaġixxu bħala" fiżika " analġeżiċi . Bil-maqlub, mu agonisti riċettaturi opjojdi-joffru kemm unsurpassed uġigħ eżenzjoni u straordinarji emozzjonali-benessri, u delta -opjojdi agonisti u enkephalinase inibituri jistgħu jiffunzjonaw bħala antidipressanti. Hemm b'mod ċar intima rabta bejn "fiżika" u "emozzjonali" uġigħ. Bi sfida metaphysics duwalista, opjojdi għandhom tendenza li tkun tajba fuq banishing tnejn.

Kontemporanji medika orthodoxy jikklassifika droga indotta bliss bħala "negattiv effett sekondarju" ta 'opjojdi analġeżiċi - anke fil-terminalment morda. Madankollu nistgħu kollha do ma jkollhom nattivi tagħna endorphin sistemi arrikkit. Aktar tard dan is-seklu u lilhinn minnha, il-apposta sit selettivi suċċessuri drogi opjojdi tal-lum jista 'jkollhom rwol kruċjali fil-promozzjoni emozzjonali super-saħħa. Per eżempju, wieħed mill-skoperti tar-riċerka l-aktar eċċitanti fis-snin riċenti kien il-sintesi ta ' JDTic . JDTic jeżerċita sostnut kontra l-ansjetà u burdata-jdawwlu effett: hija l-ewwel attiv b'mod orali selettiv antagonist opjojdi kappa. Kappa huwa l-"ikrah" riċettur opjojdi li endoġenu ligand huwa dynorphin . Is-sistema riċettur dynorphin / kappa-opjojdi huwa implikat fl-Istati spjaċevoli tal-moħħ ikkawżat minn mhux ikkontrollat ​​kronika stress . Użu ripetut ta 'kokaina, eroina, etil alkoħol u drogi oħrajn euphoriant jinduċi kumpens up-regolamentazzjoni tas-sistema riċettur dynorphin / kappa-opjojdi wisq, li jikkawżaw, ansjetà anhedonia u disforja. Billi opjojdi mu agonist riċettur jinduċi ewforija minn rilaxx ta 'dopamine titjib fil-accumbens nukleu, attivazzjoni ta' riċetturi kappa opjojdi jimpedixxi r-rilaxx ta 'dopamine mill-terminals mesolimbic. Dan in-nuqqas huwa suġġettivament spjaċevoli għaliex is-sistema ta 'dopamine mesolimbic jirregola ton hedonic u l-kapaċità li l-esperjenza (u jantiċipaw) kuntentizza. Dopamine wkoll jimmodula l-limitu ta 'perċezzjoni ta' uġigħ. Mill-2011, provi kliniċi kontrollati ta ' JDTic jew analogi tiegħu (eż. zyklophin ) fil-bnedmin għadhom tibda. Iżda jirriżulta mhux umani "mudelli ta 'annimali" huma inkoraġġanti. F'Lulju 2011, konferenza ewwel fid-dinja ddedikata għall-opjojdi kappa u antagonisti, Terapewtika Kappa , saret Seattle.Unfortunately, l-opjojdi fil-lum użu mill-bniedem huma difettuż. Meħuda fi dożaġġ fiss, huma jitilfu xi effett euphoriant u analġeżiku tagħhom bħala tolleranza settijiet; drogi opjojdi huma fiżjoloġikament vizzju. Dożi eċċessivi jista 'jikkawża dipressjoni respiratorja ; b'kuntrast, uġigħ fiżiku huwa stimulant potenti respiratorja. Meta jittieħed rikreattiv, l-opjojdi jispira irtirar dreamily kuntent mill-problemi tad-dinja. L-użu tagħhom jnaqqas mixja tagħna għall-attività kostruttiv bħala konsumaturi tal-lum suq globali kompetittiv. Aktar insidjuż, il-konsum żejjed ta 'narkotiċi jinibixxi ir-rilaxx ta 'opjojdi endoġeni normalment kkaġunati mill-interazzjoni soċjali ma' ħbieb u familja . Billi jitnaqqsu l-effetti tax-xenqa għall-kumpanija tal-bniedem, is-sostituti Addict 1 forma ta 'dipendenza opjojdi għall-ieħor. Għalhekk junkies huma normalment "egoist".

Ir-riskji fiżiċi ta 'użu opjojdi m'għandhomx jiġu esaġerati. Ħafna mill-problemi li l-utenti jsofru finalment jieħdu inqas minn għażla tagħhom ta 'droga innifsu milli mill-istat illegali ta' drogi fis-soċjetà prohibitionist. Issa, anki jekk id-drogi opjojdi kienu legali u mogħtija bogħod fil-pakketti taċ-ċereali, id-drogi bħal dawn ma tkunx tagħmel għażla tajba ta 'burdata-booster - jew għallinqas mhux fil-preżenti tagħhom, crudely mhux speċifiku iskuża. Kappa agonisti riċettaturi, per eżempju, ħsara dopamina funzjoni. Huma għandhom effetti dys phoric u psychotomimetic: 1 tista 'ukoll tixrob l-alkoħol etiliku spiced ma meths . Il- ġenna l-inġiniera ta 'posterità żgur li se weed adulterants bħal dawn mill tagħhom elixirs għal kollox.

B'kuntrast għal opjojdi tal-lum, marijuana mhuwiex normalment vizzju fis-sens tradizzjonali tal-kelma. Xorta tista 'tkun drawwa li jiffurmaw. Marijuana għandha euphoriant, proprjetajiet psychedelic u sedattivi. Esperimenti ma 'stoned firien jissuġġerixxu li l-użu tal-kannabis inaqqas l-ammont ta 'corticotrophin-rilaxx fattur ( CRF ) fil- amygdala . Sekrezzjoni eċċessiva ta 'CRF huwa assoċjat ma' anormalitajiet fil- fus HPLA u dipressjoni. Iż-żieda rebound ta 'CRF ta' waqfien mill-kannabis-użu jikkorrelata ma vulnerabilità akbar biex l-istress u l-irtirar ta 'reazzjoni , probabbilment wieħed raġuni tajba biex ma tiqafx fl-ewwel istanza. Stress indotta endocannabinoid defiċit fil-moħħ jistgħu jikkawżaw depressjoni melancholic fil-utenti u mhux utenti simili. Rispons jiffunzjonax għal stress , marbuta ma 'assi HPLA kronikament attiva żżejjed, il-kawżi l-ansjetà u dipressjoni; CRH tat-tip 1 antagonisti tar-riċettur bħal antalarmin qed jiġu investigati kif ansjolitiċi potenzjali u anti-dipressanti. Il- fond għeruq ta 'telqa tagħna jinsabu midfuna fil-passat evoluzzjonarju.

L-ingredjent psikoattiva primarja marijuana hija THC , tetraidrokannabinol. Tipjip jew tiekol marijuana u cocktail kumpless ta 'komposti jistgħu rarament jikkawżaw episodji ta' depersonalizzazzjoni , derealisation u l-psikosi. Kultant jista 'jinduċi paranojja, b'mod partikolari fil difensuri tal-Gwerra Kontra Drogi. Aktar komuni, marijuana biss tħalli l-utent pleasantly u mingħajr ħsara stoned . Huwa gost . , Ngħas uġigħ eżenzjoni u ewforja huma reazzjonijiet tipiċi. Kannabinojde CB (1) agonisti riċettaturi huma antidipressanti potenzjali. Tabilħaqq cannabinoids jista 'jkun neuroprotective kontra l-effetti ta 'stress. Bil-maqlub, cannabinoid BĊ agonisti riċettaturi (1) ant / agonisti invers, bħall-ġdid KE-liċenzjat dieta droga rimonabant ( Acomplia ), jistgħu jikkawżaw dipressjoni u ansjetà. Tabilħaqq l-ewwel moħħ derivata sustanza tinstab li jeħilx ma 'riċetturi kannabis tagħna kien christened "anandamide", derivattiv tal-kelma Sanskrit għall interna contentment . Getting għolja tista 'għalhekk sservi bħala pastime rikreazzjoni innoċenti f'dinja uncaring.

Madankollu marijuana mhix wonderdrug. Funzjoni konjittiva fil-utent huwa spiss indebolita, għalkemm moderat u riversibbli . Marijuana jinterferixxi mal-memorja-formazzjoni billi jfixklu fit-tul fil-potenzjazzjoni hippocampus . Waħda mill-funzjonijiet ta 'endoġeni cannabinoids fil-moħħ huwa li jippromwovi selettiv għal żmien qasir amneżija . Jinsa mhuwiex, kif wieħed jista 'jissoponi, proċess purament passiv. Mż-żewġ naħat, l-għażla deliberatament li jixrob 1 amnesija aġent għal perjodi twal ftit huwa ideali ħajja istrateġija. Huwa speċjalment difettuż minħabba l-ċentralità ta ' memorja għall-bniedem awto-identità. Xi artisti u Bohemians professjonali, huwa veru, apparentament ma jsibu ħaxix tipjip żieda mal ħsieb kreattiv. Għall-persuni ta 'temperament aktar philistine, min-naħa l-oħra, huwa diffiċli li tara tali droga bħala għodda ewlenija għall-ħajja affermazzjoni jew l-iżvilupp ta' l-ispeċi umana. Dan in-nuqqas ma, wieħed suppost bilkemm bżonn li jiżdiedu, jissuġġerixxu utenti marijuana għandhom jiġu ppersegwitati u kkriminalizzati. Tabilħaqq il-THC kompost marijuana jista 'effettivament ikun superjuri għall-prodotti kummerċjalment liċenzjati fil jimblokka l-formazzjoni ta 'plakek amilojde mind-tħassir tal-memorja-qerda marda ta 'Alzheimer .

Il-drogi differenti aħna psychedelics tikketta - lysergamides bħal -LSD-25 , tryptamines bħall DMT u psilocybin , u phenethylamines bħal Mescaline -huma xi kultant exhilarating. Fl -aħjar , huma ħajja trasformazzjoni u ruħ-tarrikkixxi. Huma jistgħu ċertament tkun f'moħħu-tqaċċit. Teħid psychedelics kbar jistgħu jiġġeneraw esperjenzi wisq outlandish għal qafas kunċettwali tagħna normali biex jakkomodaw. Aħna lanqas biss ismijiet għall-modi ġodda stramba ta ', perċezzjoni selfhood u introspezzjoni mogħdijiet bijokimiċi tagħhom jiżvela. Sfortunatament, waħda tħares posizzjoni mżerżqa wara l-gidjien, jimlew formoli dawk tat-taxxa jew iwettqu dawk ir-responsabbiltajiet soċjali filwaqt tgerbib fuq LSD . Psychedelics huma tipikament wisq stramba, eżotiku u ineffable fl-effetti tagħhom biex jintegraw fis-bqija ta 'dawk il-ħajja. Billi jintasab ħafna minna fil-"ordinarja" sensi qawmien, id-DNA egoist stumbled fuq trick cunning sabiex jgħin vetturi tagħha jħallu aktar kopji ta 'nnifisha. Aghar minn hekk, il-psychedelics mhumiex primarjament euphoriants. Huma dont jistimulaw direttament l-divertiment-ċentri u jiggarantixxu l-utent vjaġġ tajba. Kemm il-serotonin-u catecholamine bħall-grillu familji psychedelia prinċipalment permezz rwol tagħhom bħala agonisti parzjali ta 'l- 5-HT2A riċetturi fis-sistema nervuża ċentrali; 5-HT2 heteroreceptors jeżerċitaw effett inibitorju toniku fuq il- striatal newroni dopaminerġiċi. Dawn l-aġenti arenta għażla affidabbli ta 'klinika jew ta' rikreazzjoni burdata-aġent li jdawwal, kemm jekk fil-qasir jew fit-tul. Depressives, il neurotics u l-erwieħ mnikkta oħra fit-tfittxija ta 'kjarifika huma aktar probabbli li jgħaddu nightmarish skerz-outs. Derealisation psikotiċi mhuwiex ta 'illuminazzjoni - jew gost. Il-posizzjoni mżerżqa moħħ mediċina naïve jagħmlu għażla informata minn qabel jekk biex jesploraw istati radikalment mibdula. Għal jaspiraw psychonauts posizzjoni mżerżqa jafu, minn qabel, in-natura vera ta 'dak li jista' jkun għażla - jew nieqsa.

Fl-aħħarnett, meta l-benesseri huwa tagħna ġenetikament hardwired u invincible, psychedelia jista 'jintuża b'sigurtà esplorati. L -istudju ta 'koxjenza tista' ssir sperimentali dixxiplina. Is-sinteżi ta 'ġejjieni disinjatur l-psychedelics jista jinħeles 1 rivoluzzjoni intellettwali mingħajr preċedent. Sa dakinhar, id-drogi psychedelic huma wisq imprevedibbli - u dlam, tagħna Darwinian imħuħ huma wisq valenata - b'mod responsabbli sabiex jippromwovu l-użu tagħhom.

Apparentement b'kuntrast, l- empathogen "tgħanniqa-droga" ecstasy (methylenedioxymethamphetamine; MDMA ) toffri esperjenza quċċata wonderfully sħun, sensuous, loving, u empathetic għall-utent għall-ewwel darba - "trasmessi mill-mument qasir ta 'sanità" [ Dr Claudio Naranjo ] . MDMA ttejjeb ir-rilaxx ta 'serotonin u ta 'dopamine fit-terminali sinapsi; jinibixxi tagħhom serotonin. MDMA jistimula pro-soċjali oxytocin rilaxx permezz ta 'attivazzjoni ta' l-serotonin 5-HT1A riċetturi. Bħala konsegwenza,, nuqqas ta 'fiduċja suspett u jealousy jevapora. Dawn huma sostitwiti minn sens trankwilla 'l-imħabba universali. Il sensorium tibqa ċara. Emozzjoni huwa intensifikat. Ħafna rikreazzjoni droga użu tendenza li tkun awto-ċċentrata. Użu tad-droga huwa spiss marka bħala egoist. Madankollu hawnhekk hija "peniċillina ta 'l-ruħ" li twiegħed li iwaqqa DNA mmexxija tendenza tagħna għall-awto-aggrandizement.

Diżappuntanti, kemm jekk minħabba l-enżimi ta 'induzzjoni jew kawżi oħrajn mhux kompletament mifhuma, ħafna utenti qatt ma kollox qbid mill-ġdid maġija ta 'vjaġġi ewwel ftit. Barra minn hekk, ecstasy huwa newrotossiku għall serotonerġiċi axons. Dan jista 'saħansitra jkun ta' ħsara fuq is-terapewtiċi dożi. Peress li l-proċess ta 'rkupru inċert newrali settijiet, utenti l-kbar b'mod partikolari jistgħu jesperjenzaw l-sottili fit-maħruġ l barra treġġigħ lura ta 'l-effetti tajba li inizjalment jgawdu mill-droga. Teħid ta 'wara l-vjaġġ selettiv serotonin re-uptake inhibitor (SSRI) bħal fluoxetine ( Prozac ) 2-6 sigħat afterward huwa profilattiku kontra l-serotonin jistgħu jitkejlu wara E dip inkella esperjenzaw xi 48 siegħa wara. Madankollu tieħu SSRIs fuq bażi regolari prinċipalment tikser l-benefiċċji diġà attenwati ta 'użu ecstasy fit-tul. Fi kwalunkwe każ, it-tul ta 'l-esperjenza E quċċata hija sempliċi 90 minuta. Allura filwaqt ecstasy bilkemm jammonta għal strateġija fuq skala sħiħa għall-ħajja jew. Ecstasy ma, min-naħa l-oħra, tagħti foretaste exquisite ta 'l- sbieħ forom ta 'koxjenza li finalment tistenna lilna.

Ieħor ħjiel tantalizing u deliciously sensuous tal-Sublime huwa offrut - rarament u imprevedibbli - billi l-gamma-hydroxybutyrate ( GHB ). GHB normalment tieħu l-forma ta ', ċara mingħajr riħa u daqsxejn mielħa b'togħma likwidu. Fil-moħħ, il-molekula GHB huwa wkoll prekursur endoġenu u l-metabolit ta 'l-newrotrasmettitur inibitorju GABA . GHB huwa mhux tossiku, imma m'għandux jitħallat ma ' l-alkoħol jew depressanti oħra. Huwa metabolizzat malajr għal dijossidu tal-karbonju u ilma . GHB ma wieqaf kurva doża-reazzjoni ifisser l-utenti naïve ir-riskju serju ta 'torqod. Meta użat ħafif fil rekrejazzjonali aktar milli dożi stuporific jew anestetiku, GHB huwa kompost touchy-feely li tipikament iwassal laxkar fil-fond muskolari, sens ta serenità, u sentimenti ta 'sħana emozzjonali. Spiss dan itejjeb ftuħ emozzjonali u x-xewqa biex jissoċjalizzaw. Sensittività mess u l-apprezzament tal-mużika huwa arrikkit. Ħafna notevolment, l-utent jista moderat imqajjem aggornata wara irqad restful fond: GHB jidher temporanjament jinibixxu dopamine-rilaxx filwaqt li tiżdied il-ħażna, li jwassal għall-burdata tjiebet u inċiżiv tiffoka mentali ta 'wara "dopamine-rebound". GHB taġixxi kemm bħala disinhibitor u aphrodisiac. Intensità ta ' orga hija akbar. Għalhekk GHB huwa potenzjalment utli biex iserrħu l-psychopathologies 'ripressjoni prudery u sesswali. Sfortunatament, il-valur terapewtiku tiegħu ġie eclipsed mill demonization tagħha fil-massa-midja. Stejjer ta 'VIRGIN chaste tidwir fis-sess crazed nymphomaniacs jagħmlu kopja kbira u l-mediċina xjentifika foqra. Barra minn hekk GHB kultant konfużi mal-amnesija "data tal-kolza" benzodiazepine, flunitrazepam - ​​aħjar magħruf bħala l-qawwi u li jaġixxu malajr sedattiv ipnotiku-"tinsa pillola", Rohypnol. Inxtara fit-toroq, GHB jistgħu jiġu konfużi ma 'kull xorta ta' sustanzi oħra wisq.

Madanakollu anke GHB pur ebda Elixir magic. Mhux kulħadd jħobb. Effetti psikoloġiċi GHB huma imprevedibbli u ftit li xejn jiftiehem. Hija għandha indiċi terapewtiku relattivament baxx. Dardir, sturdament, INCO-koordinazzjoni huma komuni; reazzjoni ħin naqas. GHB normalment ma jippromwovu fond kbir ta 'ħsieb. Istatus tagħha stess bħala "irqad kważi ideali jinduċu-sustanza" jagħmilha ta 'użu limitat għal dawk li jaspiraw minflok li jkunu aktar intensiv imqajjem . In-nuqqas ta 'kwalunkwe dixxernibbli korp joqgħod biex isostnu d-panics morali perjodiċi użu tiegħu jinduċi jista' jippermetti rijabilitazzjoni parzjali. Madankollu GHB tevoka - fl-aħjar - biss debboli, parodija trasmessi mill-ħajja tul Nirvana kimiċi fuq offerta lill tagħna transhuman suċċessuri.

Alkoħol etiliku - l-tradizzjonali data tal-kolza droga ta 'għażla - u, ħafna insidjuż ta' kollha, sigaretti huma l-massa qattiela verament sinister. A rapport ippubblikat fil The Lancet Marzu 2007 kklassifikati alkoħol u tabakk bħala aktar perikolużi għas-saħħa tal-bniedem minn LSD . Kumulattiv tal-bniedem tagħhom mewt toll sal-lum huwa ta 'madwar 100 miljun u tixbit. A WHO rapport ippubblikat fi Frar 2008 proġettat li l-abbuż tat-tabakk jistgħu joqtlu biljun ruħ mill-2100 sena. Ma 'dak Poker-ffaċċjati Alice Wonderland-Fil-loġika popolari fost il-gvernijiet sleazier tad-dinja, mhux biss jagħmlu l-awtoritajiet jippreservaw l-istatus legali tal-bejgħ tas-sigaretti hawn fir-Renju Unit għal raġunijiet ta' żamma libertà personali. Il-marketing għaljin slickly u glamorisation tal tabakk prodotti lill-vittmi potenzjali hija sanzjonata għal raġunijiet simili wisq. Dovremmo ikunu kif ixxukkjat bil-promozzjoni tat-tabakk bħala aħna'd ċertament tħossok jekk minflok il-billboards ħeġġeġ gidjien li jippruvaw eroina għaliex dan huwa jibred. Madankollu familjarità razez apatija morali. Iż-żgħażagħ huma tipikament hooked qabel ma jkunu fi kwalunkwe pożizzjoni li jagħmlu għażla informata ta 'velenu preferut tagħhom - jew saħansitra li jastjeni għal kollox. Sadanittant drive esportazzjoni istat appoġġjati miri-foqra fil-pajjiżi vulnerabbli tat-Tielet Dinja. Bil-cynicism li kważi tallaba twemmin, wieħed ċċelebrat British ex-Prim Ministru aċċetta tixħima miljun dollaru minn membru ewlieni tal-mediċina l-kartelli għal servizzi tagħha. Home Secretary parti Tagħha mbagħad mogħtija ruħu mill-demm baqtar jitlob xaqq 'l isfel fuq ħŜiena tal-mediċina li jimbuttaw (!). Huwa kompla biex iżidu l-pieni ħorox huma diġà disponibbli għall-utenti personali ta ' kannabis .

Sakemm jiftiehmu gvernijiet tagħna mal-kartelli tad-drogi tat-tabakk li jaqsmu l-biljuni ta 'dollari ta' dħul fiskali mulcted mill-nikotina l-ivvizzjati - hekk li b'hekk iżżomm taxxi diretti viżibbli isfel u lilhom infushom b'mod viżibbli fil-kariga - jidher ftit tama ta 'approċċ aktar intelliġenti għall psikoattiva drogi kollha kemm hi.

Brighteners maħmuġin burdata

Il rikonoxxuti b'mod komuni legali u illegali tad-drogi rikreazzjoni joffru prospetti foqra ta bijoloġiku sostnut burdata-titjib. Allura dak dwar il-grupp eteroġenu ta 'komposti uninvitingly ttikkettjati bħala ansjolitiċi u antidipressanti ? Have huma potenzjalment xejn sinifikanti li jżidu l-kwalità aktar nies tal-ħajja? Duttrina medika Uffiċjali jgħid ebda . Allegatament, dawk li jbatu biss minn disturbi klinikament 'sanzjonati psikjatriċi se jibbenefikaw minn dawn l-aġenti - għalkemm fl-aħħar snin għandu fl-aħħar formalment rikonoxxut li disturbi depressivi huma taħt dijanjostikata u taħt l-trattati anke mill-bidu 21 seklu huwa l-istandards abjectly foqra ta' aċċettabbli ħażin li . Ħafna mill-umanità, madankollu, għadu ma jinstallax xi waħda mill-kaxxi uffiċjali djanjostiċi. Allura tista "creep djanjostika" trijonf fuq minimalism terapewtiċi u jtejbu l-kwalità tal-ħajja tagħna? Iva. Għandu l-għan ta farmakoterapija jkun limitat kemm l-aspirazzjoni Freud fuq psikoterapija: "biex jittrasformaw miżerja hysterical fis unhappiness komuni"? No.First, il-preliminari boring imma kruċjali. L-aħjar nutriment u aerobika eżerċizzju se jżidu l-effikaċja ta 'l-potenzjali tal-ħajja l-jtejbu touted hawn. Provvista rikka ta 'kimiċi prekursuri (eż. l-triptofan , ir-rata-pass li jillimita fil-produzzjoni ta 'serotonin ) jistgħu wkoll inaqqsu dożaġġi tagħhom tad-droga effettivi. Billi jagħżlu li jieklu idealized " ġebel-età "dieta rikka fil-ġewż organiċi, żrieragħ, frott u ħaxix, u naqqsu b'mod drastiku l-konsum wieħed ta 'xaħam saturat (laħam aħmar, ikel moqli), zokkor (ħelu eċċ) u żjut idroġenati (misjuba fl- marġerina u żjut veġetali raffinati), allura linja bażi wieħed ta 'benessri - jew għallinqas relattiva ħażin li - jistgħu jiġu sostenibbli titneħħa. Hemm evidenza dejjem tiżdied wisq li omega-3 fatty acid b'ħafna dieta jew supplimentazzjoni huwa protettivi kontra d-dipressjoni u disturbi psikjatriċi oħra. Aċidu Foliku tkabbir huwa rakkomandabbli ukoll. Viżitaturi li HedWeb probabilment ma jistennew li jkunu assedjati mill priedki fuq il- benefiċċji ta 'eżerċizzju aktar milli l-ikel faddism. Madankollu regolari u moderat vigoruż sforz fiżiku rilaxxi endoġeni opjojdi , itejjeb il-funzjoni ta 'serotonin, jistimula fatturi tat-tkabbir tan-nervituri, tippromwovi proliferazzjoni taċ-ċelluli fil- hippocampus , u twassal għal vivaċi, aħjar ossiġenati moħħ.

Alas, nadif għajxien u l-ħsibijiet sustanzjuż tipikament mhumiex biżżejjed. Għandna bżonn aktar b'saħħitha mediċina biex jiffjorixxu. Ewwel daqqa t'għajn, madankollu, l-istandard, Statali razzjon kimiċi mazz arent brillanti.

Il-kalmanti hekk imsejħa minuri, benzodiazepines bħal u l-iqsar li jaġixxu sedattiv ipnotiku- temazepam (Restoril), huma utli iżda xorta dreadfully mhux raffinat kontra l-ansjetà aġenti. Benzodiazepines Diversi huma ta ' naturali oriġini: diazepam, per eżempju, jistgħu jinstabu fil- patata . Benzodiazepines jaħdmu primarjament fuq il- GABA kumplessi riċettur (gamma aċidu aminobutyric). Funzjonijiet GABA bħala l-newrotrasmettitur inibitorju prinċipali fis-sistema nervuża ċentrali. GABA huwa magħmul mill-newrotrasmettitur stimulant prinċipali, glutamate . Il-progress tal-bijoloġija molekulari u neurogenetics fil tħallil-kumplessità fiendish ta riċettur GABA fuq sotto-tipi għandhom eventwalment jippermetti komposti aktar immirati li għandhom jiġu żviluppati. Idealment, dawn il-mediċini aktar selettivi u sit speċifiku se ma jkollhomx ir-proprjetajiet sedattivi, amnesija u ipnotiku ta 'marki tal-lum. Attivazzjoni ta 'GABA (A) riċetturi li fihom l- alfa 1 subunit huwa responsabbli għall benzodiazepine indotta sedazzjoni u l-iżbilanċi tal-memorja. Huwa ttamat li għadhom kemm ġew sintetizzati agonisti selettivi għall- 2-alpha GABA (A) sottotip tar-riċettur jistgħu finalment iwasslu droga antianxiety mhux sedattivi. Investigattiv Merck tal L838, 417 huwa wieħed kandidat. Provi tal-bniedem huma eagerly mistenni. L-ewwel mhux benzodiazepine, mediċini non-sedating/amnesiac tal-klassi tagħha li jilħqu s-suq tista 'tkun ocinaplon DOV Farmaċewtiku. Ocinaplon huwa GABA alpha-2 modulatur. Jeżerċita l-anti-ansjetà effett tagħha f'dożi (allegatament) sostanzjalment aktar baxx minn dożi li jwasslu sedazzjoni jitkejlu, amnesija, ir-rilassament tal-muskoli u incoordination. Ocinaplon huwa fi provi kliniċi ta 'fażi III għall-ansjetà (sajf 2005;? Temporanjament () sospiż Awwissu 2005). Fil-frattemp, benzodiazepines attwalment liċenzjati għandhom tendenza li jinduċi dipendenza, ħsara memorja u l-prestazzjoni psikomotorili, matt sensi u sħaba l-intellett. Il-grazzja iffrankar ta 'benzodiazepines huwa l tolleranza dgħajfa ta' effett anxiolytic tagħhom. Madankollu hemm mhux ċans ħafna ta 'radikali ħajja arrikkiment hawn, għal issa mill-inqas.

Buspirone (Buspar) jistgħu jidhru aktar promettenti. Hija taġixxi biex desensitise l autoreceptor inibitorja 5-HT1A sottotip ta 'riċettur ta' serotonin, ir-rilaxx ta 'serotonin u b'hekk jimmodula u (xi drabi) promozzjoni ta' tidwil tas burdata. Għalhekk buspirone jistgħu jkunu utli stati depressivi ix-xwiek. Metabolit attiv tiegħu 1-PP huwa anxiolytic 5-HT1A agonista parzjali wisq. Buspirone jonqosha l-effetti intellett-tidnis tal oħra kliniċi u alkoħolika anti-ansjetà aġenti. Mhuwiex rilassant tal-muskoli. Huwa biss kemmxejn sedattivi. Madankollu effetti dgħajfa u ekwivoka buspirone dwar sotto-tipi ta 'funzjoni ta' dopamine, filwaqt li utli kummerċjalment għall-finijiet ta touting nuqqas tagħha ta '"abbuż-potenzjal", ifisser buspirone ma tantx hu eċċitanti jew popolari. B'mod kruċjali, kuntrarjament għall-benżodijażepini, mhuwiex droga li jaġixxu malajr. Diversi ġimgħat ta 'użu jistgħu jgħaddi qabel tagħha dubjużi benefiċċji psikoloġiċi jinħassu. Riċerkaturi tama li aktar ġodda 5-HT1A agonisti fil-pipeline se tkun aktar effettiva. Alas kull qligħ terapewtiku x'aktarx li jkun żgħir ħafna. F'Ġunju 2004, l-AID iddeterminat li Organon tal gepirone (Ariza) kien "ma approvabbli". Fi Frar 2007, GlaxoSmithKline u Fabre-Kramer Farmaċewtiċi ħabbret ftehim dinji esklussiv għall-iżvilupp u l-kummerċjalizzazzjoni gepirone ER. Reviżjoni AID tal-użu tiegħu għal mard depressiv maġġuri hija antiċipata fl-2009.

Oxytocin huwa naturali kontra l-ansjetà aġent: il-" ormon cuddle ". Diversi kumpaniji tad-droga, b'mod partikolari Wyeth, qed jinvestigaw analogi sintetiċi tiegħu għall-privattiva. Msaħħa oxytocin rilaxx jikkontribwixxi għall-akuta pro-azzjoni soċjali tal MDMA (ecstasy). Oxytocin jibni fiduċja billi tnaqqas l-attività fil- biża 'proċessar ċirkwiti tal- amygdala . Jittieħdu barra mis-tikketta, oxytocin jistgħu jittieħdu man-nifs bħala sprej fl-imnieħer għall-ġlieda kontra ksenofobija soċjali. Huwa jnaqqas shyness u normali ansjetà soċjali. Aktar kontroversjali, oxytocin jistgħu jiġu applikati bħala mingħajr riħa korp ta 'sprej li jimmanipulaw it-tweġibiet ta 'nies oħra: "fiduċja fi flixkun". Peptide soċjali Natura huwa wkoll essenzjali biex par-twaħħil. Fil-ġejjieni, ħakma tas-sistema oxytocin jistgħu jippermettu magħna biex jikkontrollaw grad tagħna ta 'fedeltà u t-twaħħil ma' xulxin ħafna aktar effettiv vows żwieġ minn. L-implikazzjonijiet soċjoloġiċi ta 'l-użu mifrux u l-abbuż ta' "soċjali Viagra" tkun wiesgħa. Għandu jiġi enfasizzat li r-riċerka fil-arrikkiment sikur u sostenibbli tal-bniedem oxytocin funzjoni bilkemm bdiet.

Il-drogi ħażin assortiti aħna llum sejħa antidipressanti jaqgħu f'diversi kategoriji . Their delayed-onset mood-brightening effect is correlated with alterations in the concentration of catecholamines and/or serotonin in the central nervous system, long-term receptor re-regulation, activation of specific transcription factors regulating gene expression , and new nerve-cell growth in the hippocampus . In the first decade of the 21st century, older monoamine theories of depressive illness popular among researchers over the past 40 years have been eclipsed by the neurogenic hypothesis of depression and antidepressant action. The neurogenic model interprets depression, at least in its more severe forms, as a neurodegenerative disorder. Chronic uncontrolled stress causes oversecretion of gluocorticoid hormones, notably cortisol . Cortisol activates the glucocorticoid receptors that regulate metabolism, inflammation and immunity. An excess of glucocorticoid hormones reduces the rate of new brain cell -proliferation in the hippocampus. The hippocampus has the highest density of receptors for glucocorticoids in the brain. Stress-induced activation of the glucocorticoid receptors causes nerve cell death and dendritic atrophy in the hippocampus; by contrast, there is synaptic growth in the basolateral amygdala . The amygdala stores memories of emotional experiences – frequently fearful and unpleasant memories. Eventually, however, prolonged stress tends to atrophy the amygdala too. These long-term changes in brain morphology lower mood. They may result in anhedonia and depression in the genetically vulnerable. Antidepressants either diminish, prevent or (ideally) reverse stress-induced neural damage and impaired structural plasticity . How do they really work? Despite an explosive growth in neurobabble, no one knows.

Il triċikliċi , il prototypically imipramine (Tofranil), u alleati tagħhom huma qraba tal-mediċina newroleptiku chlorpromazine . Chlorpromazine hija magħrufa wkoll bħala Largactil, il-notorji "kimika cosh". Tricyclics block to varying degrees the reuptake of serotonin and noradrenaline into the nerve cell terminals from where they are released. The consequent changes in pre- and post-synaptic receptor sensitivity may lighten the spirits of 60-70% of the depressives who take them. Perhaps unsurprisingly given their parentage, the tricyclics are all dirty drugs, though some are dirtier than others. Their anti-cholinergic effects harm memory, concentration and intellectual performance. Their anti-histamine action induces drowsiness and sedation. Their adverse effect on cardiac function makes them dangerous in overdose. Most “euthymic” volunteers on whom they have been tested don't like their dulling effects of consciousness. Unlike chlorpromazine, the tricyclic antidepressants don't noticeably block the dopamine receptors. But with one notable exception , they do precious little to stimulate dopamine function either. Hence they're not much fun even for the severely depressed people who can benefit from taking them. For three decades they were the mainstay of the treatment of clinically-acknowledged depression . They contributed to the widely-held medical opinion that anything classed as an antidepressant won't help “normal” people; unless of course they were “really” depressed. Basically, tricyclics are cheap, nasty and usually best avoided.

Better, but still deeply flawed, are the selective serotonin reuptake inhibitors [ SSRIs ]. Serotonin, “the civilising neurotransmitter”, plays a vital role in mood, memory, appetite, sleep, pain perception and sexual desire. Fluoxetine (Prozac), fluvoxamine (Luvox, Faverin), paroxetine (Paxil, Seroxat), sertraline (Zoloft, Lustral), and citalopram (Cipramil, Celexa) are currently licensed and marketed. More of their tweaked and enhanced relatives are on the way from pharmaceutical companies eager for a lucrative piece of the action. In a triumph of marketing hype and creative use of patent law if not clinical need, citalopram's S-enantiomer was FDA-licensed in 2002 as “ Lexapro “. The SSRIs all differ in their half-lives, chemical structure and precise specificities. Their functional effects are broadly similar , though Prozac is the most activating , longest-lasting, least selective and most likely to provoke dose-related akathisia ; paroxetine has anticholinergic and sedating antihistaminergic effects; fluvoxamine most commonly induces nausea and has the shortest half-life; and citalopram is the most serotonin-selective. The mood-brightening, resilience-enhancing and anti-anxiety properties of the SSRIs really can make a (very) modest percentage of the population feel “better than well”. Unpredictably, other users feel worse. As a class, SSRIs (mostly) don't have the physically unpleasant and cognitively debilitating anticholinergic effects of the tricyclics . SSRIs don't demand the dietary restrictions of the MAOIs . Their dependence potential and withdrawal reaction is usually milder than the opioids.The (sometimes) beneficent properties of the SSRIs are celebrated in Peter Kramer's contemporary classic Listening to Prozac . Kramer has written a remarkably honest book. It's a discursive memoir by a therapist who is forced to admit that many of his clients seemed rapidly to fare far better on a pill than on his industrial-strength regimen of caring talk-therapy. Kramer's discussion of “cosmetic psychopharmacology” and “designer personalities”, however, enraged traditionalists. For chemical Calvinist orthodoxy finds the notion that people should have a right to choose pharmacologically who and what they want to be profoundly offensive. In Against Depression , published in May 2005, Kramer argues that depression should be eradicated altogether.

Two common problems limit the usefulness of SSRIs , at least when taken on their own. The problems stem from the indirect inhibitory effect sometimes exerted by Prozac-style drugs on dopamine function, a consequence of deliberate selective targeting of the serotonin system.

• First, SSRIs can compromise libido and sexual performance . This isn't always a disadvantage in over-excitable young males; indeed the currently unlicensed SSRI dapoxetine may shortly be marketed as an on-demand treatment for premature ejaculation. But SSRI-induced sexual dysfunction can still be a highly distressing phenomenon for older people too embarrassed to talk about it. Technical performance difficulties can sometimes be counteracted by taking the blood vessel dilators apomorphine or phentolamine ; the alpha2-adrenergic antagonist yohimbine ; a phosphodiesterase type-5 inhibitor like sildenafil (better known as the sexual rocket-fuel Viagra ), long-acting tadalafil ( Cialis ) or newly licensed vardenafil ( Levitra ); or a dopamine agonist, licit or otherwise , before bedtime action. Investigational drugs that heighten female sexual arousal (eg flibansein , or melanocortin agonists like PT-141 /bremelanotide) are another option. Indeed, unlicensed use of the world's first aphrodisiac and inhalable sex-drug may herald a cultural revolution without precedent. Yet polypharmacy is scarcely an ideal solution for existing SSRI users. One of the major signs of depression is loss of interest in sex and reduced libido. So it's questionable whether the FDA and the pharmaceutical industry should continue to promote serotonergic “antidepressants” that are anti-sexual; and collude to suppress antidepressants that are pro-sexual .
• Second, though a few subjects may feel mildly euphoric, in other users the SSRIs serve more as mood-stabilisers and mood-flatteners in their lives. By increasing the user's emotional self-sufficiency, too, SSRIs may subtly change the “balance of power” in personal relationships – for good or ill. In some cases, SSRIs may even act as thymoanaesthetisers which diminish the intensity of felt emotion; by contrast, a mood-brightening serotonin reuptake- enhancer like tianeptine ( Stablon ) may intensify emotion instead. Affective flattening may be welcome to someone in the pit of unmitigated clinical depression. It is scarcely a life-enriching property for “normal” people who lack any convenient diagnostic category which acknowledges their malaise.

A backlash against SSRIs is now gathering pace. In February 2008, a Public Library of Science meta-analysis of four commonly prescribed “second generation” antidepressants – using both published and withheld drug-company data – reported that SSRIs were scarcely more effective as antidepressants than placebos . The illustrious UK psychopharmacologist Professor David Healy delivers an even more damning verdict on contemporary psychiatry: “there is probably no other branch of medicine where the outcomes for a core disease are steadily worsening.” [p. 95; Shock Therapy by Edward Shorter and David Healy (2007)]

THE DOPAMINE CONNECTION

What's missing, crucially, is the therapeutic enrichment of hedonic tone via a combination of mu opioid pathway enhancement and prolonged stimulation of meso(cortico-)limbic dopamine function.

This is really much more fun than it sounds. Yet the socially responsible use of reward pathway enhancements/remedial therapies is a technical, bioethical and medico-legal minefield. Complications aside, the currently available experimental evidence has persuaded many – but not all – investigators that the mesolimbic dopamine system serves as the final common pathway for pleasure in the brain. Enhanced responsiveness of post-synaptic dopamine D2/D3 receptors is vital to long-term emotional well-being. Insofar as they work, all “serotonergic” and “noradrenergic” mood-brighteners eventually act on the mesolimbic dopamine pathway, albeit in differing degrees and with varying delay. Even SSRIs depend on sensitization of the mesolimbic dopamine D2 receptors for their (modest) mood-lifting effect. New anti-Parkinsonian agents, notably the neuroprotective dopamine D3 receptor subtype selective pramipexole (Mirapex), ropinirole (Requip), and cabergoline (Dostinex) owe their potential role as fast-acting pro-sexual antidepressants to their dopaminergic action. Likewise, the possible mood-brightening effect of low doses of the dopamine receptor ant agonist amisulpride (Solian), more commonly considered an antipsychotic agent, is explicable because amisulpride preferentially blocks the presynaptic dopamine D2/D3 auto receptors; dopaminergic transmission is thereby enhanced.

The full story is inevitably complex . Dopamine agonists and reuptake inhibitors are often inadequate long-term mood-brighteners by themselves. The mesolimbic dopamine system mediates reward-signalling , incentive salience and a sense of urgency and significance, not the essence of pure bliss . Dopamine isn't itself the magic pleasure-chemical, though its functional role in conjunction with glutamate and mu opioid agonists in regulating medium spiny neurons of the rostromedial shell of the nucleus accumbens is critical. Researchers into affective disorders can prematurely become over-attached to one particular neurotransmitter system, its receptor sub-types and their signal-transduction cascades. Traditionally, serotonin and noradrenaline have attracted the fiercest rival partisans in antidepressant research. “Dopaminergic” (and opioid) agents, by contrast, are suspect. They are politically incorrect since they are potentially “abusable”. Moreover it can be argued that the research and development of safe and sustainable Ecstasy -like empathogens and sociabilisers is at least as morally urgent as the license of safe and sustainable euphoriants. At any rate, enhanced mesolimbic dopamine release, exclusively or otherwise , enriches the intensity of experience; increases pleasure and libido, and potentially boosts cognitive performance . Even better, whereas some dopaminergics are potentially toxic , some dopamine-enhancing agents may have neuroprotective properties as well.

So what are the other contemporary options for chemical life-enhancement?

METHYLPHENIDATE (RITALIN); MINAPRINE (CANTOR); NOMIFENSINE (MERITAL)
A SSRI can be combined (“augmented” sounds more soothing to the official medical ear) with a dopaminergic such as methylphenidate . As Ritalin , methylphenidate is prolifically dispensed to American schoolchildren for different purposes altogether. It is sometimes abused as an instrument of social control. In spite of its structural relationship to amphetamine, methylphenidate resembles in many ways a more benign version of cocaine , yet with a much longer half-life. Methylphenidate blocks the reuptake of, but doesn't significantly release, the catecholamines noradrenaline and dopamine. If it is taken in sustained-release form or combined with an SSRI , all of which have anti- obsessive-compulsive properties too, then the likelihood of dose-escalation is minimised. In Europe and North America, students sometimes take Ritalin to gain a competitive edge in exams. However, its long-term effect on the developing brain is poorly understood.

Chewing coca leaves with a dash of powdered lime is a nutritious and energising way to sustain healthy mood . Unfortunately, it's illicit and not very good for one's teeth.

A more cautious but still interesting option might be minaprine (Cantor). Minaprine blocks the reuptake of both dopamine and serotonin. It is also in some degree cholinomimetic. Thus it may exhibit both mood-brightening and nootropic properties. Much more research is needed. Unfortunately, minaprine is now obtainable only as a “research chemical”.

Merital ( nomifensine ) showed great promise as a pleasantly stimulating dopaminergic that also potently inhibits the reuptake of noradrenaline and – to a much lesser extent – serotonin . It was marketed by its manufacturers Hoechst with the slogan “ vive la difference! ” Merital was withdrawn from licensed use after the discovery of its rare side-effect of precipitating a serious blood-disorder . For retarded melancholics, however, it was typically a very effective and well-tolerated mood-brightener with minimal side-effects . The risk/reward ratio of its carefully-monitored use may have been misjudged. Nomifensine is now obtainable only as a research chemical too.

BUPROPION (WELLBUTRIN); AMINEPTINE (SURVECTOR); TIANEPTINE (STABLON)
Bupropion (Wellbutrin) is possibly less effective than nomifensine. Yet it's useful because it lacks the adverse effects on sexual function characteristic of the SSRIs . In some subjects – particularly women – libido, arousal, and the intensity and duration of orgasm may actually increase. Bupropion weakly blocks the reuptake, but diminishes the release, of dopamine . This may account for reports of its diminished propensity to induce mania in the genetically susceptible. Bupropion's active metabolites inhibit the reuptake of noradrenaline. Radafaxine , one of these metabolites, also blocks the dopamine transporters; radafaxine may in future be marketed as a slimming drug as well as an antidepressant. Bupropion itself, branded as Zyban , may help in giving up smoking . Scandalously, bupropion isn't licensed and marketed as an antidepressant in Europe – though doctors may prescribe Zyban to non-smoking depressives “off-label”. Bupropion plus an SSRI is sometimes more effective than either agent alone. In June 2006, the FDA licensed bupropion/Wellbutrin XL as the first preventive pharmacological treatment of Seasonal Affective Disorder ( SAD ).

Amineptine (Survector) is a cleanish, (relatively) selective dopamine reuptake blocker. Higher doses promote dopamine release too. Amineptine is pro-sexual and liable occasionally to cause spontaneous orgasms . It is a mild but pleasant psychostimulant and a fast-acting mood-brightener. Unlike most other tricyclics , it doesn't impair libido or cognitive function . Unlike typical stimulants and other activating agents, it may actually improve sleep architecture. Scandalously, amineptine isn't licensed and marketed in Britain and America. For it is feared it might have “abuse-potential”. FDA pressure led to its withdrawal in Europe too. This drove amineptine onto the pharmaceutical grey market , discomfiting doctors and patients alike.

Another “French” option is amineptine's cousin, tianeptine ( Stablon ). Tianeptine is a neuroprotective antidepressant that reverses the neuronal damage and lasting misery caused by uncontrolled stress. Chronic stress causes dysphoria by inducing corticotropin-releasing factor (CRF2) receptor stimulation of dynorphin release. The endogenous opioid peptide dynorphin activates the unpleasant kappa opioid receptors. Tianeptine acts both as a non-sedating anti-anxiety agent and a non-stimulating mood-brightener . Its use increases extracellular dopamine concentration in the nucleus accumbens and, at higher doses, in the frontal cortex. Uniquely in clinical medicine, tianeptine acts as a selective serotonin reuptake enhancer . Its puzzling efficacy as an antidepressant illustrates how little modern psychiatric medicine really understands about mind, mood and depression. Like other contemporary antidepressants , tianeptine's therapeutic action presumably depends on downstream adaptations both between and within neurons occurring over a period of several weeks. Chronic tianeptine use reverses stress-induced hippocampal dendritric atrophy and amgydaloid dendritic hypertrophy , which is just as nasty as it sounds. But the precise molecular mechanisms are obscure . Tianeptine/Stablon is not licensed in North America primarily because its patent has expired. REBOXETINE (EDRONAX); ADRAFINIL (OLMIFON); MODAFINIL (PROVIGIL)
Reboxetine (Edronax) is a relatively well-tolerated , relatively selective “noradrenergic” agent. Crudely, whereas serotonin plays a vital role in mood , noradrenaline is essential to maintaining drive, vigilance and the capacity for reward. There's a fair bit of evidence that chronically depressive people have dysfunctional and atypical noradrenergic systems – particularly their alpha2 - and beta -adrenoceptors. Reboxetine itself typically doesn't have the disruptive effects on cognitive function or psychomotor performance common to older clinical mood-brighteners – though alas antimuscarinic effects are still not completely absent. Multiple interactions between the different monoamine systems make it hard to target one neurotransmitter system without triggering a cascade of effects on the others. But NorAdrenaline Reuptake Inhibitors ( NARI s) – and dopaminergics like amineptine (Survector) – may be especially useful in drive-deficient “anergic” states where the capacity for sustained motivation is lacking; and for melancholic depressives with a poor ability to cope with stress . Reboxetine can be safely combined with an SSRI , though there is evidence that NARIs themselves indirectly enhance central serotonin function by a mechanism that doesn't depend on reuptake inhibition. More surprisingly perhaps, preliminary studies suggest reboxetine can actually reverse tranylcypromine-induced hypertensive crises. The “ cheese effect ” is triggered by ingesting tyramine-rich foods. Thus NARIs plus MAOIs may prove a potent form of combination-therapy if first options fail. EMSAM , the transdermal selegiline patch, is probably the safest choice of MAOI.

Depressive hypersomniacs who fare poorly on SSRIs , or can't get hold of amineptine or EC-licensed reboxetine, might consider trying a so-called eugeroic (“good arousal”) agent instead. Alpha1 -adrenergic agonists like adrafinil (Olmifon) and modafinil (Provigil, Alertec) are centrally-acting psychostimulants that can brighten mood and sharpen mental focus. They stimulate the noradrenergic post-synaptic receptors, increase glutamatergic transmission, and activate the wakefulness-promoting orexinergic neurons, thereby boosting alertness, memory, mood, motivation and energy. At sensible dosages, they are remarkably free of side-effects. Modafinil was licensed by the FDA as Provigil for the treatment of narcolepsy in Dec 1998; and in September 2003, an advisory panel to the FDA endorsed its use for treating shift work sleep disorder and sleep apnea . However, the significance of these prescribing indications is rapidly being eroded. Modafinil and adrafinil are now mainly used off-label as so-called lifestyle drugs.

Of course, many millions of insomniacs suffer from the opposite problem. They simply want regular sleep . Supracor's new sleep-aid eszopiclone (Lunesta) can be taken on a nightly basis indefinitely. It will be the first sleeping pill not to carry an FDA warning against long-term use. MIRTAZAPINE (REMERON); NEFAZODONE (SERZONE); VENLAFAXINE (EFFEXOR) & DESVENLAFAXINE (PRISTIQ); DULOXETINE (CYMBALTA); ROLIPRAM; AGOMELATINE (VALDOXAN)
NARIs are normally activating. Anxious and depressive insomniacs, on the other hand, may benefit more from “ dual-action ” mirtazapine; or from newly-licensed duloxetine.

Mirtazapine (Remeron) is a structural analogue of the off-patent mianserin (Bolvidon). It is a comparatively new drug – a so-called NaSSA . By blocking the inhibitory presynaptic alpha2 adrenergic autoreceptors and stimulating only the 5-HT1A receptors, mirtazapine enhances noradrenaline and serotonin release while also blocking two specific ( 5-HT2 and 5-HT3 ) serotonin receptors implicated in dark moods and anxiety. By contrast, stimulation of the 5-HT2A receptors accounts for the initial anxiety, insomnia and sexual dysfunction sometimes reported with the SSRIs; stimulation of the 5-HT3 receptors causes nausea. Unfortunately, mirtazapine is a potent blocker of the histamine H1 receptors too. So it tends to have a somewhat sedative effect. This profile may be good for agitated depressives and insomniacs . Again, it is scarcely a recipe for life-affirmation.

Nefazodone (Serzone) is another “dual action”, mainly serotonergic agent. It inhibits the reuptake of serotonin while displaying post-synaptic 5-HT2A -receptor antagonism. This may be useful for anxious depressives; but again, it may cause feelings of weakness, drowsiness and lack of energy. Nefazodone is less likely to cause priapism than its older cousin trazodone (Desyrel). It is less likely to cause sexual dysfunction than the SSRIs. But nefazodone can also be toxic to the liver , albeit rarely. It may soon be withdrawn altogether by its manufacturer Bristol-Myers Squibb under threat of litigation.

Venlafaxine (Effexor) is a phenethylamine . Thus it's a benign if distant chemical cousin of MDMA . Its manufacturers launched it as “Prozac with a punch”. In February 2008, the FDA licensed its extended-release active metabolite desvenlafaxine as the antidepressant Pristiq after Weyth's venlafaxine patent expired. Venlafaxine inhibits the neuronal reuptake of serotonin, noradrenaline and dopamine in descending order of potency. If dopaminergically augmented, it offers another opening for creative psychopharmacology . Such augmentation-therapy remains ( almost ) clinically unexplored. Taken on its own at low dosage, venlafaxine acts primarily as a serotonin re-uptake inhibitor. At the high-level dosages most suitable for melancholic and hypersomnic temperaments, its noradrenergic (and weakly dopaminergic) action becomes more pronounced. Venlafaxine lacks anticholinergic activity; but some users are troubled by its antihistamine side-effects. Like the SSRIs , it is sometimes useful for a broad spectrum of disorders beyond clinical depression.

It is possible that duloxetine (Cymbalta, Xeristar, Yentreve), licensed by the FDA in autumn 2004, and milnacipran (Ixel, Dalcipran, Toledomin), available in Europe, may be more effective than venlafaxine (Effexor) for a segment of the population that can benefit from dual serotonin-noradrenaline reuptake inhibition. Pain-ridden depressives in particular may respond well to this class of drug. Many depressed people suffer from poorly-defined aches and pains, persistent fatigue, and shoulder-, neck- and back-pain. Duloxetine relieves both the somatic and emotional symptoms of depression. Unlike venlafaxine, duloxetine exerts its more balanced serotonin and noradrenaline reuptake inhibition throughout the dosage range. Duloxetine also weakly inhibits the reuptake of dopamine, and shows minimal affinity for the histamine and cholinergic muscarinic receptors. Its side-effect profile appears to be relatively benign . Yet an authentic wonderdrug for mental health remains elusive. Early expectations that duloxetine would show superior efficacy in melancholic depressives have not yet been convincingly borne out in controlled clinical trials. Ill-served by mainstream medicine, victims of melancholic and retarded depression may actually do better on dual noradrenaline- dopamine reuptake inhibitors such as delicensed nomifensine (Merital) and/or mu opioid agonists/kappa opioid antagonists such as buprenorphine (Temgesic, Buprenex, Subutex). Duloxetine itself will probably prove a blockbuster product. It will most likely be marketed for everything from stress urinary incontinence, social phobia and generalised anxiety disorder, diabetic peripheral neuropathic pain and possibly irritable bowel syndrome. But alas it takes time to separate genuine therapeutic advance from drug company hype, typically not until the patents expire.

Phosphodiesterase-inhibitors, both selective (eg the PDE type 4 inhibitor rolipram ) and unselective, are another under-used option. The next few decades will take us much closer to the downstream intra-cellular action. For it is here that our minds will ultimately be healed, genetically or otherwise.

Agomelatine (Valdoxan) is a novel antidepressant and anti-anxiety agent developed by Servier and licensed in the European Union in February 2009. A synthetic analogue of the natural hormone melatonin , agomelatine is a potent melatonin receptor agonist and a serotonin 5-HT2C receptor antagonist. Blockade of the neural 5-HT2C receptors enhances frontocortical adrenergic and dopaminergic transmission, potentially improving cognitive performance. In “animal models”, agomelatine also reduces the adverse effects of stress on memory. By acting as a melatonin receptor agonist, agomelatine improves sleep quality. When taken once daily before bedtime, agomelatine doesn't cause daytime drowsiness and sedation like the old tricyclics; nor does its use kill libido like the SSRIs. Agomelatine is typically well tolerated and remarkably free from adverse side-effects at therapeutic dosages. Drug giant Novartis acquired the US rights to agomelatine from Servier in 2006. In July 2009, Novartis announced it was delaying submission for US regulatory approval another three years while it conducted additional Phase III trials. American consumers must now order agomelatine from Europe.

HYPERICUM
Hypericum is important for a different reason altogether. Many constitutionally unhappy people refuse to have anything to do with orthodox Western medicine. They won't take “unnatural” pharmaceutical products at all. In consequence, they spend much of their lives trapped in a squalid psychochemical ghetto of low spirits. The only sort of remedy that they'll conceivably contemplate taking must carry a “ natural ” label and soothingly “ herbal ” description.

Unfortunately, most folk remedies are only marginally effective. Our drug-metabolising enzymes are the product of an evolutionary arms race to counteract plant toxins. For plants tend to manufacture psychotropics because they poison or debilitate creatures tempted to eat them – not to heal our psychic woes. The Wisdom Of Nature is a quaint piece of make-believe. Perversely, several of the natural remedies that sometimes actually work – notably Cannabis sativa , Erythroxylon coca and Papaver somniferum – are now illegal to consume. Other “natural” interventions such as bright light therapy combined with good sleep discipline may be of limited use. But two options worth exploring are SAMe and St John's wort .

Hypericum , the active ingredient in St John's wort, appears to be an effective mood-brightener and anxiolytic – by today's standards at least. Its side-effect profile and efficacy in mild-to-moderate depression compares favourably with its synthetic counterparts. Hypericum's blend of serotonin-reuptake inhibiting and (mild) MAO-inhibiting properties ( not a combination otherwise to be explored with potent synthetics: the risk of the potentially fatal serotonin syndrome is too great) contributes to – without wholly explaining – its generally benign effects. Once again, much more research is needed, preferably not bankrolled by the makers of lucrative competing products. Thus a German trial published in the British Medical Journal in February 2005 reported that a proprietary standardised extract of hypericum/St John's wort was more effective and a better tolerated treatment of moderate to severe depression than the SSRI paroxetine (Paxil). This runs counter to the negative findings of the 2001 US trial sponsored by the makers of the SSRI sertraline (Zoloft) – which concluded that for moderate to severe depression, St John's wort was no better than a placebo. Faith in the integrity of biological psychiatry would be greater if the single strongest predictive factor in the outcome of any published clinical trial wasn't the identity of the funding body. A Cochrane Review published in October 2008 found that hypericum extracts used to treat major depression had similar efficacy to standard antidepressants but fewer side-effects.

INOSITOL
One further remedy, albeit at “unnatural” doses, is worth noting. Inositol levels tend to be low in depressives and high in euphoric people. Taking myo-inositol as a food supplement in doses of 12g and more per day represents perhaps the first successful use of the precursor strategy for a second messenger rather than a neurotransmitter in the search for long-term mood-brightening agents. Inositol and its derivatives serve as messenger molecules within the nervous system. The molecule itself is a naturally occurring isomer of glucose. It is a key intermediate of the phosphatidyl-inositol cycle. This is a second-messenger system used by several noradrenergic, serotonergic and cholinergic receptors. Adult westerners typically consume about one gram of inositol per day in their food. The richest dietary sources are fruits, nuts, beans and grains. The mood-darkening (“stabilising”) effect of lithium in manically euphoric people may be explicable in terms of its inositol-depleting effect. Potentially, if taken in high doses, inositol seems to be a good way of lightening the spirits and diminishing anxiety in “euthymic” and depressed people alike. Dosages of even 50g and more reportedly produce no toxic side-effects. This regimen shouldn't be attempted unsupervised by people with a history of bipolar disorder . As usual, much more research is in order. One “problem” is that naturally-occurring compounds – such as inositol and SAMe – can't be patented. So the scope for high profit-margins is diminished. Progress is unlikely to be brisk.

THE MAO INHIBITORS

A further option involves using both some of the oldest and the newest drugs on the block, the monoamine oxidase inhibitors ( MAOIs ). The older irreversible MAOIs certainly shouldn't be combined with SSRIs . It is inadvisable to combine them with stimulants or many other drugs. Yet both old and new, the MAOIs do have some very interesting properties. MAOIs may be particularly useful for rejection-sensitive, so-called atypical depressives who have “reversed vegetative symptoms” ie overeating and oversleeping.

Monoamine oxidase has two main forms, type A and type B . They are coded by separate genes. MAO may be inhibited with agents that act reversibly or irreversibly; and selectively or unselectively; these categories are not absolute. For instance, the beta-carboline alkaloids found in the world's most popular drink, coffee , are competitive and reversible inhibitors of both MAO type A and type B. MAO type-A preferentially deaminates serotonin and noradrenaline, and also non-selectively dopamine; type B primarily metabolises dopamine , phenylethylamine (the “ chocolate amphetamine “) and various trace amines .The mood-elevating properties of the MAOIs were discovered quite by chance in a US veterans' hospital early in the 1950s. Many patients given the anti-tuberculotic drug iproniazid were not merely cured of their tuberculosis. They became exceptionally happy as well. The animated enthusiasm for life of a previously crotchety bunch of old soldiers disconcerted their doctors. For it transpired that their new-found euphoria wasn't just an understandable reaction to being cured of physical disease. MAOIs typically have mood-brightening properties as well. At the time, there was no accepted and clinically effective treatment for depression. Fortunately, via the usual circuitous routes, the appropriate lessons were eventually drawn. Many millions of people were successfully treated with MAOIs in consequence.

Sadly, the role of MAO in deaminating tyramine (from the Greek word tyros , meaning cheese) wasn't at first understood. Certain MAOI-treated patients suffered hypertensive crises after eating varying amounts of tyramine-rich aged cheese; and several died. It is now recognised that the use of any MAOI which is both irreversible and unselective must be accompanied by dietary restrictions. But the adverse publicity of the initial inexplicable fatalities, combined with the introduction of a succession of dirty but sometimes tolerably effective tricyclic compounds, sent the use and reputation of MAOIs into a precipitous decline from which they still haven't fully recovered. The older non-selective and (more-or-less) irreversible inhibitors tranylcypromine (Parnate), phenelzine (Nardil) and isocarboxazid (Marplan) are nonetheless valuable antidepressants. Outside America, the the selective and reversible MAOI moclobemide . is used too. Of greater interest still are central-nervous-system-selective compounds, notably the neuroprotective antidepressant and anti-Alzheimer's drug TV3326 ( ladostigil ). MAOIs that lack the peripheral effects of currently explored drugs herald an exciting new window of therapeutic opportunity.

SELEGILINE ( l-deprenyl , ELDEPRYL, EMSAM)
A recent New York study showed that smokers had on average 40% less of the enzyme, monoamine oxidase type-B, in their brains than non-smokers. Levels returned to normal on their giving up smoking. Not merely is the extra dopamine in the synapses rewarding. The level of MAO-b inhibition smokers enjoy apparently contributes to their reduced incidence of Parkinson's and Alzheimer's disease. Unfortunately they are liable to die horribly and prematurely of other diseases first.

One option which the dopamine-craving nicotine addict might wish to explore is switching to the (relatively) selective MAO-b inhibitor selegiline, better known as l-deprenyl. Normally the brain's irreplaceable complement of 30-40 thousand odd dopaminergic cells tends to die off at around 13% per decade in adult life. Their death diminishes the quality and intensity of experience. It also saps what in more ontologically innocent times might have been called one's life-force. Eighty percent loss of dopamine neurons results in Parkinson's disease, often prefigured by depression. In future, the mood-enhancing transplantation of customized stem cells may restore a youthful zest for life in dopamine-depleted oldsters: such stem cell-derived monoaminergic grafts are currently on offer only to depressed rodents. Deprenyl has an anti-oxidant , immune-system -boosting and dopamine-cell-sparing effect. Its use boosts levels of tyrosine hydroxylase , growth hormone , superoxide dismutase and the production of key interleukins . Deprenyl offers protection against DNA damage and oxidative stress by hydroxyl and peroxyl radical trapping; and against excitotoxic damage from glutamate .

Whatever the full explanation, deprenyl-driven MAOI-users, unlike cigarette smokers, are likely to be around to enjoy its distinctive benefits for a long time to come, possibly longer than their drug-naïve contemporaries. For in low doses, deprenyl enhances life-expectancy, of rats at least, by 20% and more. It enhances drive, libido and motivation; sharpens cognitive performance both subjectively and on a range of objective tests; serves as a useful adjunct in the palliative treatment of Alzheimer's and Parkinson's disease; and makes you feel good too. It is used successfully to treat canine cognitive dysfunction syndrome (CDS) in dogs . At dosages of around 10 mg or below daily, deprenyl retains its selectivity for the type-B MAO iso-enzyme. At MAO-B-selective dosages, deprenyl doesn't provoke the “cheese-effect”; tyramine is also broken down by MAO type-A. Deprenyl isn't addictive, which probably reflects its different delivery-mechanism and delayed reward compared to inhaled tobacco smoke. In November 2004, Yale University researchers launched a study of deprenyl for smokers who want to quit tobacco. Whether the Government would welcome the billions of pounds of lost revenue and a swollen population of energetic non-taxpayers that a switch in people's MAOI habits might entail is unclear.

L-deprenyl/selegiline can now be delivered via a transdermal patch . In December 2004 , pharmaceutical firms Bristol-Myers Squibb and Somerset Pharmaceuticals announced they had entered into an agreement to distribute and commercialize EMSAM , the first transdermal treatment for major depression . After various delays, in February 2006 the FDA granted EMSAM a product license for the treatment of major depressive disorder in adults. EMSAM's pharmacokinetic and pharmacodynamic properties promote the inhibition of MAO-A and MAO-B in the CNS while avoiding significant inhibition of intestinal and liver MAO-A enzyme. Three different strengths of EMSAM patch are currently marketed: 20mg/20cm ² , 30mg/30cm ² , and 40mg/40cm ² , delivering daily doses averaging 6mg, 9mg and 12mg respectively. Use of the lowest dosage EMSAM 6 mg/24 hour patch calls for no dietary modification. At this dosage, MAO-A in the digestive tract is preserved at levels adequate to break down tyramine, while MAO in the brain is inhibited at levels adequate to induce an antidepressant effect. A restricted “ MAOI diet ” is prudently advised for the higher dosage EMSAM 9 mg/24 hr patch and the 12 mg/24 hr patch to avoid any risk of hypertensive crisis. But it's worth noting that (as of January 2011) no hypertensive crises following dietary indiscretions have been reported even in users of the high strength patches. RASAGILINE (AZILECT)
Unlike deprenyl, the novel irreversible selective MAO-B-inhibitor rasagiline (Azilect) is not metabolized to methamphetamine or amphetamine. These trace amines are unlikely to contribute to deprenyl's neuroprotective action. Rasagiline gained an EC product license as Azilect in mid-2005 for the symptomatic treatment of Parkinson's disease . Azilect finally gained a US product license in May 2006. In August 2008, Teva announced promising results from a late-stage Phase III 18-month rasagiline trial. Parkinsonians who took a 1mg Azilect pill once a day from the start of the trial showed “ significant improvement ” over patients who started taking Azilect nine months later.

MOCLOBEMIDE (MANERIX, AURORIX)
Humans now have the capacity to choose their own individual level of activity or inhibition of the two primary monoamine oxidases . This does not quite enable the fine-tuning of personality variables with the functional equivalent of a graphic equaliser. It still represents a promising start. In MAO-inhibition, as in life, more is not always better. Excessive dosages of l-deprenyl, for instance, may actually shorten , not increase, life expectancy – at least in Parkinsonians if it's combined with l-dopa . And levels of above 80% inhibition of MAO-A may lead to a sharp and possibly unwanted fall in dopamine synthesis. Repairing Nature's niggardliness will be a priority for the decades ahead.

Moclobemide (Manerix, Aurorix), the “gentle MAOI”, is both a selective and reversible inhibitor of MAO-A. It marks the first RIMA to win clinical acceptance. Moclobemide lacks anti-cholinergic side-effects. It promotes the healthy growth of new neurons in the hippocampus. No dietary restrictions are needed. It is valuable as more than a mood-enhancer and resilience-booster. For moclobemide is often useful in overcoming social phobia , panic disorder , obsessive-compulsive symptoms, irritability and aggression owing to the way it enhances serotonin function. (The casual use of gobbledygook such as “enhanced x function” will rightly alert the reader that many complications are being skirted or omitted. Those hungry for the greater technical detail of a non-popular account can rest assured the literature will leave them feeling abundantly well-nourished).

TRANYLCYPROMINE (PARNATE)
Gentleness doesn't suit everyone. Moclobemide isn't much good at lifting deep melancholy . Tranylcypromine (Parnate), on the other hand, is one of the older and non-selective MAOIs – and is often none the worse for it. Structurally related to amphetamine, tranylcypromine is generally the most stimulating , dopaminergic and relatively fast-acting of the MAOIs. Some doctors are uncomfortable with its properties. This isn't just because of the dietary restrictions its use demands. In adequate doses, tranylcypromine tends to induce a mild euphoria even in “normal” subjects. Tranylcypromine use increases trace amines, modulates phospholipid metabolism and up-regulates GABA(B) receptors. In fact, its nicest effects, as for all of the compounds cited here, will vary in nature and extent from person to person. To some extent, optimal dosage and long-term drug-regimen of choice can be discovered only by (cautious) empirical self-investigation.

Tranylcypromine is of course vastly preferable to the amphetamines and cocaine . Yet frequently and perversely, the more hazardous the drug, then the easier it is to get hold of in our society. The carcinogenic cocktail that carries off more people than all other toxins combined can be purchased quite legally and effortlessly at any tobacconist or newsagent. Obtaining the less lethal – but scarcely socially desirable – street opioids and psychostimulants requires a little more exertion. Yet they can still be readily purchased in pubs and clubs in all the big towns and cities. Many of the more beneficent drugs discussed here, on the other hand, are unlicensed, “investigational”, or available on a prescription-only basis. They're not illegal to possess. But they are hard to obtain short of visiting countries where they're available over-the-counter or using online pharmacies of uncertain reputation.

If the central principle at stake here were the preservation of a drug-free society, then some sort of totalitarian (or, more euphemistically, paternalistic) argument could be cobbled together for violating personal freedom so oppressively. Yet that's rarely the issue. For in most cases, the issue effectively amounts, not to drugs or no drugs, but to allowing people the choice to opt for better ones. Perhaps 80% of the population in Western countries currently drink ethyl alcohol or smoke cigarettes . Often they do both. Whether viewed in terms of mortality, morbidity or overall quality of life, we'd be better off if we switched to enhancing receptor sub-type selective dopaminergic, opioidergic, serotonergic and cholinergic function by the relatively safe, if crude, agents touched on here; and perhaps to the more exciting products under development . As a basic minimum, people shouldn't be legally robbed of the right to do so.

This freedom of choice isn't conventional wisdom. It will be suggested that the level of medical expertise required to make informed choices exceeds that of the average layperson. A quasi-priestly medical caste wielding the power of the prescription-pad would doubtless wish to keep it that way. But the intrinsic difficulty and complexity of psychopharmacology or nutritional medicine , say, doesn't demand greater mental effort than, for instance, all those thousands of grimly unnatural hours spent by school students learning mathematics . Moreover it's far more interesting to study something palpably relevant to one's emotional well-being than something that demonstrably isn't. The notion of an education system geared to schooling people in, and for, happiness would nonetheless strike adherents of the reigning educational orthodoxy as abhorrent were it not so largely incomprehensible.

WORKING FOR A DRUG-FREE FUTURE

Suppose, for a moment, that the reproductive success of our DNA had been best served by coding for ecstatically happy vehicles rather than malaise-haunted emotional slum-dwellers. If this had been the case, then none of the pharmacological interventions discussed in The Good Drug Guide would be necessary. Life-long well-being would seem only “natural”. We would all enjoy gloriously fulfilled lives. Each day would be animated by gradients of bliss . Unpleasant states of mind would be viewed as a tragic aberration. Bad thoughts and bad feelings could be diagnosed as a freakish but clinically treatable type of psychopathology.

Of course, it didn't work out that way. Instead, the inclusive fitness of our genes has been served by the “natural” manufacture of some of the most vicious psychological adaptations imaginable. Sadness and anxiety are “normal”. Discontent is “adaptive”. Everyday emotional pain is part of “what makes us human “.

The rot goes deeper. Selfish DNA can count on innumerable dupes to act as its distal representatives even today as the biotech revolution unfolds. The need for “character-building” emotional pain gets justified with all manner of sophistries, both religious and profane. Suffering is good for you, one may be told. It's all part of life's rich tapestry.

Actually, suffering exists only because it was good for our genes . Conditionally-activated negative emotions were fitness-enhancing in the ancestral environment. In the current era, apologists for mental pain are serving as the innocent mouthpieces of the nasty bits of code which spawned them. If pressed, primordial DNA's unwitting spokesmen would presumably disavow any such connection. Yet if one were purposely building an intelligent robotic survival-machine, then endowing it with the illusion of free-will would prove a highly fitness-enhancing adaptation. It's a trick which our genes stumbled upon; and then blindly exploited.

Fortunately, over the next few centuries humanity will be able to outwit its ancient genetic masters . Our present status as throwaway genetic vehicles will finally be subverted . When gradients of heavenly well-being become the genetically predestined norm of mental health, then the very notion of tampering with our new-won “natural” condition and feeling “drugged” may come to seem immoral. It may also seem perverse. Why should anyone want to contaminate the divine ecstasy of their spirituo-biological soul-stuff with chemical pollutants? No thanks.

Today's twisted victims of the primordial genetic code, on the other hand, view the notion of sullying their natural state of being through psychoactive drugs with a much more deep-seated ambivalence . They adopt it as a near-universal practice. Given the inadequacy of the third-rate pharmacological stopgaps on offer, and the lack of any serious drug-education, it's scarcely surprising we're so poor at using them. Thus concerned parents are surely right to worry about the trashy street drugs taken by their kids. Early in the 21st Century, “Just Say No” is frequently still a good rule-of-thumb. Yet with the right new genes and designer-drugs , there's no reason why mature Post-Darwinian life shouldn't just get better and better .

David Pearce
(last updated January 2012)

Source: http://www.biopsychiatry.com/