In terms of the 'harm' argument, there are two types of harm (to a society of individuals), associated with the 'drug problem':
The first is the harm associated with taking drugs. (Which is in itself contestable, i.e. good times on drugs argument).
The second is the harm associated with prohibition.
In order to justify prohibition in terms of harm reduction, (i.e. if that were your only criteria on assessing the worthiness of prohibition) it would seem that the amount of harm associated with taking drugs would have to be decreased by prohibition, by more than the amount of 'new harm' that the policy of prohibition itself brings, otherwise the policy is irrational. It is also worth noting that any harms associated with drug taking that are caused by prohibition (i.e. financing drug dealers), can only be used as an argument against prohibition.
Now, this is a difficult question to assess, with a multiplicity of factors, but I would suggest that the harm minimization effects of prohibition are dwarfed by the harm brought about by prohibition. Those harms are well documented, e.g. the flourishing of violent drug gangs, the curtailment of civil liberty, the criminalization and incarceration of a large portion of society, the economic expense of maintaining the policy, etc.
Even if the harm question was open and undecidable, there would be no reason to enact prohibition by default, unless you assume the ridiculous proposition that all behavior should be prohibited, until a compelling argument why it shouldn't be is presented.
Prohibition is irrational, unless, the reasons given for it, are not the real reasons that it has been enacted, in which case it may be a rational expression of authoritarian tendencies, i.e. prohibition is a fraud committed by authoritarians on the general populace to further special interests.