Black tar<unk>  When taken orally,<unk>  undergoes extensive first-pass metabolism via deacetylation, making it a prodrug for the systemic delivery of morphine. When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing the blood–brain barrier because of the presence of the acetyl groups, which render it much more fat soluble than morphine itself. Once in the brain, it then is deacetylated variously into the inactive 3-monoacetylmorphine and the active 6-monoacetylmorphine (6-MAM), and then to morphine, which bind to μ-opioid receptors, resulting in the drug's euphoric, analgesic (pain relief), and anxiolytic (anti-anxiety) effects;<unk>  itself exhibits relatively low affinity for the μ receptor. Analgesia follows from the activation of the μ receptor G-protein coupled receptor, which indirectly hyperpolarizes the neuron, reducing the release of nociceptive neurotransmitters, and hence, causes analgesia and increased pain tolerance. Unlike hydromorphone and oxymorphone, however, administered intravenously,<unk>  creates a larger histamine release, similar to morphine, resulting in the feeling of a greater subjective "body high" to some, but also instances of pruritus (itching) when they first start using. Normally GABA, released from inhibitory neurones, inhibits the release of dopamine. Opiates, like<unk>  and morphine, decrease the inhibitory activity of such neurones. This causes increased release of dopamine in the brain which is the reason for euphoric and rewarding effects of<unk> . Both morphine and 6-MAM are μ-opioid agonists that bind to receptors present throughout the brain, spinal cord, and gut of all mammals. The μ-opioid receptor also binds endogenous opioid peptides such as β-endorphin, Leu-enkephalin, and Met-enkephalin. Repeated use of<unk>  results in a number of physiological changes, including an increase in the production of μ-opioid receptors (upregulation). These physiological alterations lead to tolerance and dependence, so that stopping<unk>  use results in uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid withdrawal syndrome. Depending on usage it has an onset 4–24 hours after the last dose of<unk> . Morphine also binds to δ- and κ-opioid receptors. There is also evidence that 6-MAM binds to a subtype of μ-opioid receptors that are also activated by the morphine metabolite morphine-6β-glucuronide but not morphine itself. The third subtype of third opioid type is the mu-3 receptor, which may be a commonality to other six-position monoesters of morphine. The contribution of these receptors to the overall pharmacology of<unk>  remains unknown. A subclass of morphine derivatives, namely the 3,6 esters of morphine, with similar effects and uses, includes the clinically used strong analgesics nicomorphine (Vilan), and dipropanoylmorphine; there is also the latter's dihydromorphine analogue, diacetyldihydromorphine (Paralaudin). Two other 3,6 diesters of morphine invented in 1874–75 along with diamorphine, dibenzoylmorphine and acetylpropionylmorphine, were made as substitutes after it was outlawed in 1925 and, therefore, sold as the first "designer drugs" until they were outlawed by the League of Nations in 1930.
Heroin
Cannabis
Cannabis 
Cocaine
Cocaine 
Nicotine
Phencyclidine
Opioid